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Evaluation of Clinically Relevant Drug–Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial

Evaluation of Clinically Relevant Drug–Drug Interactions and Population Pharmacokinetics of... Background Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metas- tasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug–drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential—other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected. Objective Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC. Patients and Methods Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted. Results Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one come- dication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of come- dications with DDI potential, no signic fi ant ee ff cts on darolutamide pharmacokinetics were identie fi d. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses. Conclusions These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614. Plain Language Summary Background Darolutamide is a medicine used to treat men with prostate cancer that has not spread to other parts of the body (nonmetastatic). Often, these patients are taking other medicines for common age-related illnesses. Taking more than one Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1152 3-019-00674 -0) contains supplementary material, which is available to authorized users. * Neal Shore NShore@gsuro.com Extended author information available on the last page of the article Vol.:(0123456789) 528 N. Shore et al. medicine at the same time increases the chances of what is known as drug–drug interactions. Drug–drug interactions can decrease how well the medicines work or may sometimes increase side effects. Study Aim To test for possible drug–drug interactions in men with prostate cancer who take darolutamide alongside other medicines. Study Participants Men with nonmetastatic prostate cancer who were being treated with a medicine that lowers testosterone, a chemical in the body that causes prostate cancer tumors to grow. Participants took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. What Did the Researchers Measure? The researchers documented the number of medicines taken by each participant and the number of other medical conditions that they had. Tests were done to find out whether other medicines affected the way that darolutamide works in the body and whether patients taking darolutamide alongside other medicines experienced more side effects. Results As would be expected, based on the typical age of patients with prostate cancer, more than 90% of participants in this study used medicines other than darolutamide to manage common age-related illnesses or medical conditions. Taking medicines alongside darolutamide did not impact how darolutamide worked in the body and did not increase the number of side effects experienced by patients. Darolutamide is known to interact with rosuvastatin, a cholesterol-lowering drug. However, in this study, there was no overall increase in side effects among darolutamide-treated patients who took this type of drug compared with in those who did not. Conclusion In this study of patients with nonmetastatic prostate cancer, limited drug–drug interactions were seen when taking darolutamide alongside other medicines given to these patients to manage age-related medical conditions. Key Points interactions (DDIs) is also a fundamental component in clinical decision making [7]. Polypharmacy for age-related comorbidities is com- The second-generation androgen receptor inhibitors enza- mon in patients with nonmetastatic castration-resistant lutamide and apalutamide have recently been approved for prostate cancer, and this increases the risk of drug–drug the treatment of nmCRPC after demonstrating significantly interactions (DDIs). prolonged metastasis-free survival in phase III clinical tri- als [8, 9]. However, this change in the treatment landscape Subanalyses of the phase III ARAMIS trial indicate that has also brought decision-making challenges. Apalutamide darolutamide has low risk of clinically relevant DDIs and enzalutamide are associated with higher incidences of with comedications commonly used in these patients. certain AEs (e.g., falls, fatigue, hypertension, rashes, and seizures) than are placebo. They also both have the poten- tial for DDIs when coadministered with medications that are substrates for several metabolizing enzymes and drug transporters [8–14]. For example, coadministration of either drug may reduce the exposure of medications that are sub- 1 Introduction strates for the cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, and CYP2C19 [15, 16], resulting in loss of activ- A prime goal of treatment for patients with nonmetastatic ity of common comedications such as anticoagulants, anti- castration-resistant prostate cancer (nmCRPC) is to delay hypertensives, opioid analgesics, and proton pump inhibitors progression to metastatic disease (mCRPC) since increased (PPIs). tumor burden is associated with worse prognosis [1], Darolutamide is a novel androgen receptor antagonist although the recent introduction of multiple life-extending with a unique molecular structure recently approved by the therapies for mCRPC (radium-223, abiraterone, enzaluta- US FDA for the treatment of nmCRPC [17, 18]. In the phase mide, sipuleucel-T, and taxanes) has extended post-progres- III ARAMIS trial (NCT02200614), darolutamide demon- sion survival [2]. Along with disease progression, adverse strated signic fi antly prolonged metastasis-free survival com - events (AEs) associated with anticancer therapies may have pared with placebo (40.4 vs. 18.4 months; hazard ratio for a detrimental impact on patients’ quality of life [3], particu- metastasis or death in the darolutamide group 0.41; 95% larly in patients with nmCRPC, given the mostly asymp- confidence interval [CI] 0.34–0.50; p < 0.001) in patients tomatic nature of their disease. As nmCRPC is generally with nmCRPC receiving androgen-deprivation therapy and diagnosed in older men who are often prescribed multiple delayed time to pain progression (40.3 vs. 25.4 months; haz- concomitant medications for comorbid conditions [4–6], the ard ratio 0.65; 95% CI 0.53–0.79) [19]. The DDI potential of risk of AEs or loss of efficacy resulting from drug–drug Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 529 darolutamide has been extensively investigated in preclinical 2.2 Treatment and clinical phase I studies with metabolizing enzymes and drug transporters. Darolutamide was sensitive to induction Men were randomized 2:1 to receive darolutamide 600 mg of CYP3A4, the main enzyme mediating its metabolism. twice daily (given as two 300 mg tablets) or placebo while Inhibition of CYP3A4, P-glycoprotein (P-gp) and breast continuing androgen-deprivation therapy. Patients continued cancer resistance protein (BCRP)—both transporters for study medications until protocol-defined progression, dis- which darolutamide is a substrate—by comedications was continuation due to AEs, or withdrawal of consent. not considered clinically relevant. No relevant inhibition of any CYP enzymes by darolutamide was observed in vitro, 2.3 Population Pharmacokinetic Model and in vivo studies found weak induction of CYP3A4 only, suggesting darolutamide may have no clinically relevant An exploratory population pharmacokinetic analysis was effect on comedications metabolized by CYP enzymes [20]. performed to evaluate the variability in the pharmacokinetics Therapeutic levels of darolutamide were found to have no of darolutamide, its two pharmacologically active diastere- effect on P-gp substrates [20], though exposure of rosuvasta- omers, (S,R)-darolutamide and (S,S)-darolutamide, and the tin, a substrate for BCRP, organic anion-transporting peptide active metabolite, keto-darolutamide, based on data gener- (OATP)1B1, and OATP1B3, was moderately increased by ated from the phase III ARAMIS study [19]. The population darolutamide coadministration [21]. This effect was mainly pharmacokinetic model was developed using data from a attributed to inhibition of BCRP; however, a contribution subset of patients with valid pharmacokinetic samples col- of OATP inhibition is considered likely. Overall, the results lected sparsely at several times during the 12-h application of these studies indicated that darolutamide has a favorable interval (detailed in the Electronic Supplementary Material DDI profile. [ESM]—Methods) and information on drug disposition To evaluate the impact of clinically relevant DDIs with pathways identified preclinically. The bioanalytical meth- darolutamide in the target patient population, we conducted ods used for pharmacokinetic sampling are summarized in prespecified and post hoc analyses in patients with nmCRPC the ESM—Methods. who participated in the phase III ARAMIS trial [19], includ- All predefined concomitant medications taken by at least ing assessments of comorbidities and comedication use, the one patient during study treatment were included as a covari- effects of concomitant medications on the pharmacokinetics ate in the population pharmacokinetic model (Table 1 in the of darolutamide, and the impact of coadministering daroluta- ESM). The impact of BCRP inhibitors, CYP3A4 inducers/ mide with concomitant medications on patient safety. Given inhibitors, P-gp inducers/inhibitors, PPIs, and/or uridine that statin use is very common in this population and darolu- 5′-diphospho-glucuronosyltransferase (UGT) inducers/ tamide has been observed to increase rosuvastatin exposure inhibitors on the pharmacokinetics of darolutamide was [21], we conducted a subanalysis of the impact of using con- investigated. Comedications with any relevant DDI poten- comitant statins with darolutamide on patient safety. tial, weak or strong, were included. 2.4 Safety Analyses 2 Patients and Methods At each study visit, data on treatment-emergent AEs 2.1 Trial Design (TEAEs), including type, severity, seriousness, and whether they were related to study treatment based on investigator The phase III ARAMIS trial (NCT02200614) protocol and assessment, were recorded. A subgroup analysis was also design have been described in detail elsewhere [19]. Briefly, performed to compare the incidence of TEAEs for patients this was a randomized, double-blind, placebo-controlled, receiving statins (3-hydroxy-3-methylglutaryl-coenzyme A phase III clinical trial conducted globally in 409 centers in reductase inhibitors) versus those not receiving statins. This 36 countries to evaluate the efficacy and safety of darolu- analysis included all TEAEs reported in concomitant statin tamide in patients with nmCRPC. The trial was approved users versus nonusers regardless of when the event occurred by local institutional review boards and was conducted in during the study, i.e., without consideration for when daro- compliance with the principles of the Declaration of Hel- lutamide and the statin were coadministered. A post hoc sinki and in accordance with the International Conference analysis evaluating TEAE incidence in patients using statins on Harmonisation guidelines for Good Clinical Practice. All known to be BCRP substrates versus nonusers of BCRP- patients provided written informed consent. substrate statins was also performed. 530 N. Shore et al. systemic antibiotics, and anti-inflammatory/antirheumatic 2.5 Statistical Analysis agents were used by at least 20% of patients. These come- dications span a range of agents that act as inducers, inhibi- Patient demographics, comorbidities, and concomitant medications were summarized descriptively for all rand- tors, or substrates of the enzymes predominantly involved in drug metabolism or key drug transporters (e.g., P-gp, BCRP, omized patients, i.e., the full analysis set. Comedications were categorized according to potential for relevant DDIs OATP1B1, OATP1B3) (Table 3). (CYP inducers/inhibitors/substrates, UGT substrates, and drug transporter substrates) based on in vitro and phase I 3.3 Population Pharmacokinetic Analysis clinical studies of darolutamide [21] and established DDI profiles for the currently available androgen-receptor inhibi- In total, 388 patients (40% of the total who received darolu- tors, enzalutamide and apalutamide [11–14]. tamide in the phase III trial) were included in the pharma- Pharmacokinetic model development was conducted via cokinetic subset. Demographics and baseline characteristics nonlinear mixed-effects modelling using NONMEM (ver - were generally similar to those of the overall darolutamide- sion 7.3, ICON Development Solutions plc, Manchester, treated population, although the pharmacokinetic subset UK) and R software [22]. Full details of the population contained higher proportions of Japanese patients and pharmacokinetic analysis are given in the ESM—Methods. patients with mild renal impairment (Table 1). Safety evaluations were conducted in all patients who Evaluation of the population pharmacokinetic analysis were randomized and received at least one dose of study showed that none of the comedications included as covari- medication. ates in the population pharmacokinetic base model met the criteria for a significant covariate effect. These comedica- tions included CYP3A4 inhibitors (21.6%), P-gp inhibitors 3 Results (20.1%), PPIs (15.2%), BCRP inhibitors (14.9%), UGT1A9 inhibitors (2.8%), and CYP3A4 inducers (0.5%); examples 3.1 Patients of drugs in these categories are given in Table 3. No patients received P-gp or UGT1A9 inducers. PPIs exerted no effect In total, 1509 men were randomized to darolutamide on darolutamide clearance. It was not possible to specifi - (n = 955) or placebo (n = 554) in addition to androgen- cally assess an effect of CYP3A4 inducers as so few patients deprivation therapy. One patient randomized to the daro- received comedications that were CYP3A4 inducers, such lutamide arm did not receive study treatment and was as rifampicin or carbamazepine. These data suggest that, therefore excluded from the safety analyses [19]. Baseline although preclinical data indicate darolutamide exposure demographic and clinical characteristics were similar in the may be affected by drugs that are strong CYP3A4 and P-gp two treatment groups (Table 1). Median age was 74 years in inducers or inhibitors [23], there was no significant associa- both groups, and median follow-up time was 17.9 months. tion between the use of concomitant medications and the Most patients had at least one comorbid condition (98.4% pharmacokinetic variability of darolutamide in this study. in both treatment arms); the most common comorbidities were hypertension, obesity, anomalies of lipid metabolism, 3.4 Impact on Adverse Event Incidence of Drugs and diabetes (Table 2). Coadministered with Darolutamide, Including Breast Cancer Resistance Protein Substrates 3.2 Concomitant Medication Use We also assessed whether the DDIs that have been identified The overwhelming majority of men in the trial were receiv- ing at least one concomitant medication, and rates of come- as clinically relevant for darolutamide (notably, sensitivity to strong CYP3A4 inducers and inhibition of BCRP by darolu- dication use were balanced across the two treatment arms: 98.7% with darolutamide and 98.0% with placebo (Table 3). tamide [23]) had a possible impact on the safety of patients in the ARAMIS trial population. As already noted, the com- The most common concomitant medications for comorbid conditions in darolutamide- versus placebo-treated patients mon concomitant medications received by patients in ARA- MIS were similar between study arms (Table 3). We have were antihypertensives, including drugs affecting the renin–angiotensin system (54.7 vs. 49.8%), β-blockers (29.6 previously reported that the incidence of the most common AEs was similar in patients treated with darolutamide and vs. 27.6%), and calcium channel blockers (22.7% in both arms), as well as analgesics (53.8 vs. 50.4%), whereas more those who received placebo, and permanent discontinuations of the study drug due to AEs occurred in similar proportions than one-third of patients received antithrombotics (42.8 vs. 39.7%) or lipid-modifying agents (34.5 vs. 39.4%). Other of patients in each treatment arm [19]. cardiovascular agents, diuretics, urological agents, PPIs, Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 531 Table 1 Demographics and baseline characteristics of patients with nonmetastatic castration-resistant prostate cancer in the phase III study Characteristics Darolutamide Placebo (N = 554) PK subset (n = 388) Overall (N = 955) Age (years) 75 (48–95) 74 (48–95) 74 (50–92) Age group (years)  < 65 41 (10.6) 113 (11.8) 84 (15.2)  65–74 140 (36.1) 373 (39.1) 216 (39.0)  ≥ 75 207 (53.4) 469 (49.1) 254 (45.8) Race  Caucasian 292 (75.3) 760 (79.6) 434 (78.3)  Asian 76 (19.6) 122 (12.8) 71 (12.8)  Black 12 (3.1) 28 (2.9) 24 (4.3)  Missing/other 8 (2.1) 45 (4.7) 25 (4.5) Region  Asia-Pacific NA 119 (12.5) 67 (12.1)  Japan 58 (14.9) 62 (6.5) 33 (6.0)  North America NA 108 (11.3) 76 (13.7)  Rest of World NA 728 (76.2) 411 (74.2)  Not Japan 330 (85.1) 893 (93.5) 521 (94.0) Renal impairment  None 122 (31.4) 412 (43.1) 230 (41.5)  Mild 209 (53.9) 423 (44.3) 248 (44.8)  Moderate 56 (14.4) 119 (12.5) 76 (13.7)  Severe 1 (0.3) 1 (0.1) 0 Hepatic impairment  None 356 (91.8) 864 (90.5) 509 (91.9)  Mild 32 (8.2) 89 (9.3) 43 (7.8)  Moderate 0 2 (0.2) 1 (0.2)  Missing 0 0 1 (0.2) Data presented here are from the 17 January 2019 datacut. Data are presented as median (range) or n (%) unless otherwise indicated AST aspartate aminotransferase, eGFR estimated glomerular filtration rate, NA not available, PK pharmacokinetic, ULN upper limit of normal Full analysis set population (all randomized patients) None = eGFR ≥ 90 mL/min, mild = 60 to < 90 mL/min, moderate = 30 to < 60 mL/min, and severe = 15 to < 30 mL/min [28] None = total bilirubin and AST ≤ ULN, mild = total bilirubin > ULN to 1.5 × ULN or total bilirubin ≤ ULN and AST > ULN, and moder- ate = total bilirubin > 1.5 to 3 × ULN with any AST Concomitant use of statins was similar in the daroluta- population; Table 2 in the ESM), predefined AEs known mide and placebo arms (32.1 vs. 36.5%; Table 4). In both to be associated with statins occurred more frequently treatment arms, the incidence of TEAEs was comparable with darolutamide than placebo (8.6 vs. 3.5%; Table 5). between patients receiving concomitant statins and those This difference was due to greater incidences of abnor - not receiving statins (88.2 vs. 80.9% for darolutamide and malities in laboratory parameters. A similar difference was 82.2 vs. 73.9% for placebo; Table 4). With respect to the observed in the overall study population, indicating that type of AEs reported (based on system organ class and the difference occurred independently of statin exposure preferred term), no differences among statin users in either and excluding any relevant impact of darolutamide in sta- treatment arm was observed. No meaningful differences in tin users. The abnormalities in laboratory parameters were alanine aminotransferase (ALT) values occurred between notably increased aspartate aminotransferase levels (1.4% concomitant statin users and nonusers: in both treatment with darolutamide vs. 0.2% with placebo, respectively) arms, mean ALT values were slightly higher among sta- and increased blood bilirubin levels (1.3% with daroluta- tin users than nonusers at baseline and throughout the mide vs. 0% with placebo). treatment period. In a subset of patients using statins that are BCRP substrates (approximately 30% of the overall 532 N. Shore et al. contrast, enzalutamide is a strong CYP3A4 inducer and a Table 2 Proportion of patients with ongoing comorbid conditions by preferred MedDRA term (> 5% of total population; full analysis set) moderate CYP2C9 and CYP2C19 inducer, and apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak Comorbidity (preferred term) Patients with comorbidity, n (%) inducer of CYP2C9, UGT, P-gp, BCRP, and OATP1B1 [11, Darolu- Placebo (N = 554) 14]. Additional monitoring may be required as both drugs tamide may lead to suboptimal bioavailability of comedications (N = 955) with potential loss of efficacy. Hypertension 617 (64.6) 357 (64.4) The present analyses of the phase III ARAMIS trial Obesity 568 (59.5) 333 (60.1) demonstrated that almost all patients with nmCRPC receiv- Hypercholesterolemia 125 (13.1) 70 (12.6) ing androgen-deprivation therapy with androgen receptor Osteoarthritis 122 (12.8) 65 (11.7) inhibitor therapy have comorbid conditions that require the Benign prostatic hyperplasia 103 (10.8) 63 (11.4) use of concomitant medications. Individual patient data in Diabetes mellitus 101 (10.6) 68 (12.3) ARAMIS indicated that many patients were receiving mul- Atrioventricular block first degree 86 (9.0) 49 (8.8) tiple comedications, as others have also reported [10]. As Dyslipidemia 85 (8.9) 51 (9.2) expected in this population (median age 74 years), the most Type 2 diabetes mellitus 75 (7.9) 53 (9.6) common comorbidities included hypertension and other car- Hyperlipidemia 74 (7.7) 47 (8.5) diovascular disorders, obesity, hyperlipidemia, osteoarthri- Coronary artery disease 72 (7.5) 39 (7.0) tis, and diabetes. Consistent with the comorbidities reported, Arthralgia 71 (7.4) 27 (4.9) the most frequently prescribed comedications were antihy- Constipation 70 (7.3) 26 (4.7) pertensives and agents for other cardiovascular disorders, Myocardial ischemia 70 (7.3) 33 (6.0) along with a need for analgesia, treatments for urological Atrial fibrillation 69 (7.2) 43 (7.8) and acid-related gastrointestinal disorders, antidepressants, Bundle branch block, left 64 (6.7) 28 (5.1) anxiolytics, and dementia treatments. Our population phar- Renal cyst 64 (6.7) 37 (6.7) macokinetic analysis demonstrated that these frequently Back pain 62 (6.5) 38 (6.9) used concomitant drugs had no significant effect on the Nocturia 60 (6.3) 29 (5.2) pharmacokinetics of darolutamide. Comedications that are Insomnia 59 (6.2) 36 (6.5) potent CYP3A4 inducers were rarely used by the overall Hot flush 51 (5.3) 35 (6.3) ARAMIS population, so the risk of DDIs may also be low Gastroesophageal reflux disease 50 (5.2) 38 (6.9) in clinical practice. Erectile dysfunction 49 (5.1) 36 (6.5) Only the interaction between darolutamide and the com- bined BCRP and OATP substrate rosuvastatin has been Data presented here are from the 17 January 2019 datacut deemed clinically relevant [23], though our safety subgroup MedDRA Medical Dictionary for Regulatory Activities analysis in statin users and nonusers could not clearly attrib- ute any imbalance between the treatment arms to the effect of darolutamide on statins. However, the small sample size 4 Discussion may preclude observation of rare AEs such as myopathy or rhabdomyolysis, although these are well-characterized and The potential for DDIs is an important consideration when can readily be monitored. Overall, the incidence of AEs did selecting an androgen receptor-targeting therapy for patients not appear to be increased significantly by DDIs, as similar with nmCRPC. Loss of efficacy with treatments for patients’ AE rates are reported with darolutamide and placebo despite comorbidities or sustaining an increased risk of AEs are the equally high use of concomitant medications in both potential outcomes of DDIs [10, 24]. Extensive investigation treatment arms in the ARAMIS study [19]. This observa- in preclinical/phase I studies indicated that darolutamide has tion includes AEs previously reported more frequently with a favorable DDI profile. Overall, few DDIs were identified enzalutamide and apalutamide versus placebo in phase III at clinically relevant levels: darolutamide was sensitive to trials (PROSPER and SPARTAN, respectively) such as falls, CYP3A4 induction, but no clinically relevant effects on hypertension, and central nervous system (CNS)-related AEs darolutamide were expected from drugs that act as inhibi- [8, 9]. tors of CYP enzymes and drug transporters. The risk of AEs resulting from DDIs is an important con- Most importantly, darolutamide had few effects on other sideration for physicians. Enzalutamide and apalutamide drugs used to treat comorbid conditions; increased expo- have been identified as substrates, inducers, and/or inhibi- sure of rosuvastatin was the only interaction of note [23]. tors of metabolizing enzymes and inhibitors or inducers of This interaction was mainly attributed to BCRP inhibition, drug transporters [15, 16, 25, 26]. Given that the majority although darolutamide-mediated inhibition of OATP trans- of drugs are metabolized by at least one CYP enzyme [4], porters may have contributed to the observed effect. By Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 533 Table 3 Concomitant medication use (> 10% of total patient population; full analysis set) Comedications (by indication and ATC subclass) Patients using comedication, Examples of drug classes/individual agents with DDI poten- n (%) tial relevant to androgen receptor inhibitors [4, 29, 30] Daroluta- Pla- mide + ADT cebo + ADT (N = 955) (N = 554) Any comedication 943 (98.7) 543 (98.0) Cardiovascular disease  Agents acting on the renin–angiotensin system 522 (54.7) 276 (49.8) ACE inhibitors: atenolol (OATP1B1 substrate) ARBs: losartan (CYP3A4/CYP2C9 substrate), telmisartan (OATP1B1 substrate)  Antithrombotics 409 (42.8) 220 (39.7) Antiplatelet agents: clopidogrel (strong CYP2C8 inhibitor), ticagrelor (CYP3A4 substrate) Anticoagulants: rivaroxaban (CYP3A4 substrate), dabigatran etexilate (P-gp substrate)  Lipid-modifying agents 329 (34.5) 218 (39.4) Statins: atorvastatin (CYP3A4/OATP1B1/BCRP substrate), pravastatin (OATP1B1 substrate), rosuvastatin (BCRP/ OATP1B1 substrate) Gemfibrozil (strong CYP2C8 inhibitor)  β-blocking agents 283 (29.6) 153 (27.6) Propranolol (CYP2C19 substrate)  Calcium channel blockers 217 (22.7) 126 (22.7) Amlodipine (CYP3A4 substrate), verapamil (moderate CYP3A4 inhibitor, P-gp inhibitor)  Cardiac therapies (e.g., glycosides, anti- 212 (22.2) 115 (20.8) Glycosides: digoxin (P-gp substrate) arrhythmics, anti-anginals) Anti-arrhythmics: amiodarone (CYP3A4 substrate, CYP2C8/ CYP3A4 inhibitor); dronedarone, propafenone (CYP3A4 substrates) Anti-anginals: ranolazine (CYP3A4/P-gp substrate, weak CYP3A4/P-gp inhibitor) Spirolactones: eplerenone (CYP3A4 substrate)  Diuretics 217 (22.7) 102 (18.4) Furosemide (BCRP/OATP1B1 substrate)  Vasoprotectives 183 (19.2) 113 (20.4) – Pain and inflammation  Analgesics 514 (53.8) 279 (50.4) Opioids: fentanyl, oxycodone (CYP3A4/P-gp substrates)  Anti-inflammatories/DMARDs 249 (26.1) 124 (22.4) Sulfasalazine (BCRP substrate) Methotrexate (BCRP, OATP1B1, OAT1 and OAT3 substrate) NSAIDs: celecoxib (CYP2C9 substrate), diclofenac (CYP2C9/CYP3A4 substrate)  Corticosteroids (systemic) 122 (12.8) 81 (14.6) Dexamethasone (CYP3A4/P-gp inducer) Urological disorders  Urologicals 299 (31.3) 176 (31.8) ED agents: sildenafil, vardenafil (CYP3A4 substrates) BPH treatments: dutasteride, tamsulosin (CYP3A4 sub- strates); silodosin (CYP3A4/P-gp substrate) OAB treatments: darifenacin, oxybutynin (CYP3A4 sub- strates) GI and metabolic disorders  Acid-related disorders 281 (29.4) 170 (30.7) PPIs: lansoprazole (CYP2C19 substrate), omeprazole (CYP2C19 substrate), rabeprazole (CYP2C19 substrate)  Antidiabetics 176 (18.4) 119 (21.5) Glitazones: pioglitazone (CYP2C9/CYP3A4 substrate) Meglitinides: repaglinide (OATP1B1/CY2C8 substrate) Sulfonylureas: glimepiride (CYP2C9 substrate)  Antidiarrheals 145 (15.2) 95 (17.1) Loperamide: CYP3A4/P-gp substrate  Constipation medications 156 (16.3) 70 (12.6) – Infection  Antibiotics (systemic) 257 (26.9) 138 (24.9) Macrolides: clarithromycin (strong CYP3A4 inhibitor), eryth- romycin (moderate CYP3A4 inhibitor) 534 N. Shore et al. Table 3 (continued) Comedications (by indication and ATC subclass) Patients using comedication, Examples of drug classes/individual agents with DDI poten- n (%) tial relevant to androgen receptor inhibitors [4, 29, 30] Daroluta- Pla- mide + ADT cebo + ADT (N = 955) (N = 554) Nervous system disorders  Psycholeptics 188 (19.7) 109 (19.7) Antipsychotics: haloperidol, quetiapine, aripiprazole (CYP3A4 substrates) Anxiolytics: buspirone (CYP3A4 substrate) Carbamazepine (strong CYP3A4 inducer) Benzodiazepines: alprazolam, midazolam (CYP3A4 sub- strates); diazepam (CYP2C19 substrate)  Psychoanaleptics 108 (11.3) 52 (9.4) Bupropion (CYP2B6 substrate) SARIs: trazodone (CYP3A4 substrate) SSRIs: citalopram, escitalopram (CYP3A4 substrates) Dementia treatments: donepezil, galantamine (CYP3A4 substrates) Data presented here are from the 17 January 2019 datacut Includes medications ongoing at baseline or that were initiated after the study drug or after the end of the study drug but excludes any agents used locally/topically due to the lack of DDI risk (e.g., ophthalmologicals, nonsystemic respiratory products). As multiple ATC codes per drug are possible, some drugs may be counted in more than one category for the same patient ACE angiotensin-converting enzyme, ADT androgen-deprivation therapy, ARB angiotensin II receptor blocker, ATC Anatomical Therapeutic Chemical, BCRP breast cancer resistance protein, BPH benign prostatic hyperplasia, CYP cytochrome P450 enzyme, DDI drug–drug interaction, DMARD disease-modifying antirheumatic drug, ED erectile dysfunction, GI gastrointestinal, NSAID nonsteroidal anti-inflammatory drug, OAB overactive bladder, OAT organic anion transporter, OATP organic anion-transporting peptide, P-gp P-glycoprotein, PPI proton pump inhibitor, SARI serotonin antagonist and reuptake inhibitor, SSRI selective serotonin reuptake inhibitor Includes all uses of systemic corticosteroids Includes intestinal anti-inflammatory/anti-infective agents One or more agent in the drug class enzalutamide and apalutamide have the potential for DDIs or antidepressants [27]. Hence, the safety of prescribing with a range of medications that are commonly used by androgen receptor inhibitors in the setting of polypharmacy patients with prostate cancer, e.g., gastrointestinal, cardio- warrants consideration by the treating physician. vascular, and analgesic agents (Table 6) [10, 15, 16, 24–26]. Limitations of our study include the small sample size Consequently, the FDA labels for enzalutamide and apaluta- of the safety subanalyses and the population pharmacoki- mide suggest avoiding the use of susceptible comedications netic analysis and that the population pharmacokinetic and warn of the potential loss of efficacy of these comedi- analysis did not investigate the effect of darolutamide on cations, respectively [11, 14]. In a retrospective review of the pharmacokinetics of comedications. Strong CYP3A4 pharmacy records for patients with mCRPC, enzalutamide and P-gp inducers were identified as having a relevant effect was associated with a high prevalence of potential DDIs with on darolutamide, but such comedications were rarely used CNS drugs (e.g., opioid analgesics), which could increase in ARAMIS. For example, the strong CYP3A4-inducing the risk of cognitive adverse effects, falls, and fractures [10]. anti-epileptic drugs, carbamazepine, phenytoin, and pheno- In addition, enzalutamide reduces plasma concentrations of barbital, were used by few patients. However, as patients PPIs, which increases the risk of bleeding events in patients with severe infections (which may be treated with systemic receiving PPIs in combination with aspirin or nonsteroi- antibiotics such as rifampicin) and other serious comorbidi- dal anti-inflammatory drug prophylaxis. Overall, 85% of ties (e.g., recent stroke or myocardial infarction, active viral patients with mCRPC who received enzalutamide were at hepatitis, or human immunodeficiency virus) were excluded, risk for DDIs that would require treatment modification of the ARAMIS population did not fully represent the real- at least one comedication [10]. In a post hoc analysis of the world population likely to receive darolutamide treatment. phase III SPARTAN trial, the risk of falls was increased in Multiple interactions between drugs were possible since patients receiving apalutamide and concomitant α-blockers many patients received several comedications, but it was not possible to assess the impact of these on patient safety Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 535 Table 4 Overview of treatment-emergent adverse events by concomitant statin use (safety population) Patients Darolutamide (N = 954) Placebo (N = 554) Concomitant statin use Concomitant statin use Yes (n = 306) No (n = 648) Yes (n = 202) No (n = 352) Any TEAE 270 (88.2) 524 (80.9) 166 (82.2) 260 (73.9)  Grade 1 73 (23.9) 146 (22.5) 51 (25.2) 83 (23.6)  Grade 2 95 (31.0) 207 (31.9) 69 (34.2) 97 (27.6)  Grade 3 76 (24.8) 139 (21.5) 36 (17.8) 63 (17.9)  Grade 4 10 (3.3) 11 (1.7) 5 (2.5) 4 (1.1) SAE 97 (31.7) 140 (21.6) 42 (20.8) 69 (19.6) Death 16 (5.2) 21 (3.2) 5 (2.5) 13 (3.7) TEAE leading to dose modification 51 (16.7) 84 (13.0) 20 (9.9) 32 (9.1) TEAE leading to discontinuation of study drug 28 (9.2) 57 (8.8) 16 (7.9) 32 (9.1) Any drug-related TEAE 81 (26.5) 177 (27.3) 43 (21.3) 67 (19.0)  Grade 1 42 (13.7) 90 (13.9) 31 (15.3) 37 (10.5)  Grade 2 30 (9.8) 68 (10.5) 7 (3.5) 19 (5.4)  Grade 3 8 (2.6) 16 (2.5) 4 (2.0) 10 (2.8)  Grade 4 1 (0.3) 2 (0.3) 0 0 Drug-related SAE 3 (1.0) 7 (1.1) 3 (1.5) 3 (0.9) Drug-related death 0 1 (0.2) 1 (0.5) 1 (0.3) Drug-related TEAE leading to dose modification 15 (4.9) 34 (5.2) 5 (2.5) 9 (2.6) Drug-related TEAE leading to discontinuation of study drug 3 (1.0) 12 (1.9) 5 (2.5) 8 (2.3) This analysis used data from the 17 January 2019 datacut. Data are presented as n (%) TEAE treatment-emergent adverse event, SAE serious adverse event According to investigator’s assessment, with severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 [31] Table 5 Incidence of pre-defined treatment-emergent adverse events with concomitant use of statins that are breast cancer resistance protein sub- strates (safety population) TEAE (preferred term) Patients with TEAE Darolutamide (n = 280) Placebo (n = 171) Any TEAE 24 (8.6) 6 (3.5) Hepatobiliary disorders 3 (1.1) 0  Hyperbilirubinemia 3 (1.1) 0 Investigations 20 (7.1) 5 (2.9)  Blood creatinine increased 10 (3.6) 5 (2.9)  Aspartate aminotransferase increased 8 (2.9) 0  Blood bilirubin increased 5 (1.8) 0  Alanine aminotransferase increased 4 (1.4) 0  Blood lactate dehydrogenase increased 2 (0.7) 0  Blood alkaline phosphatase increased 1 (0.4) 0 Musculoskeletal and connective tissue disorders 1 (0.4) 1 (0.6)  Muscular weakness 1 (0.4) 1 (0.6) Renal and urinary disorders 1 (0.4) 0  Renal impairment 1 (0.4) 0 This analysis used data from the 19 November 2018 datacut. Data are presented as n (%) TEAE treatment-emergent adverse event 536 N. Shore et al. Table 6 Examples of potential drug–drug interactions between enzalutamide, apalutamide, or darolutamide and concomitant medications A. Effects of enzalutamide, apalutamide, or darolutamide on the exposure of CYP enzyme or transporter substrates Enzyme/transporter Apalutamide Enzalutamide Darolutamide Examples of drugs [4, 29, 30, 32, 33] [13, 14] [11, 12] [23] Effect on substrate exposure CYP3A4 Analgesics: fentanyl, oxycodone Anticoagulants: rivaroxaban Antihypertensives / CV agents: amlodipine, amiodarone, dronedarone, felodipine, nisoldipine, ranolazine Antiplatelet agents: ticagrelor CNS drugs: alprazolam, buspirone, donepezil, midazolam, quetiapine, triazolam Lipid-modifying agents: lovastatin, simvastatin Urological agents: avanafil, darifenacin, dutasteride, oxybutynin, solifenacin, tamsulosin, tolterodine, vardenafil CYP2C9 Anticoagulants: warfarin Antidiabetics: glimepiride Antihypertensives: losartan Anti-inflammatories: celecoxib Lipid-modifying agents: fluvastatin CYP2C19 Beta-blockers: propanolol CNS drugs: diazepam PPIs: lansoprazole, omeprazole, rabeprazole UGT Analgesics: buprenorphine Antiretrovirals: zidovudine CNS drugs: morphine Anti-epileptics: valproic acid P-gp Analgesics: fentanyl, oxycodone Anticoagulants: dabigatran etexilate CV agents: digoxin, ranolazine BCRP CV agents: furosemide Lipid-modifying agents: atorvastatin, rosuvastatin, fluvastatin DMARDs: sulfasalazine OATP1B1 Hypertension/CV agents: atenolol Lipid-modifying agents: atorvastatin, pitavastatin, rosuvastatin, pravastatin Antidiabetics: glyburide, nateglinide, repaglinide B. Effects of CYP enzyme or drug transporter inhibitors and inducers on the exposure of enzalutamide, apalutamide, or darolutamide Enzyme/transporter Apalutamide Enzalutamide Darolutamide Examples of drugs [4, 29, 30, 32, 33] [13, 14] [11, 12] [23] Effect on exposure of apalutamide, enzalutamide or darolutamide Inhibitors CYP3A4 Antibiotics: clarithromycin, erythromycin Antifungals: itraconazole, ketoconazole Antihypertensives: diltiazem, verapamil Antiretrovirals: indinavir, nelfinavir, ritonavir CYP2C8 Antibiotics (systemic): trimethoprim Antiplatelet agents: clopidogrel, gemfibrozil Inducers CYP3A4 Anti-epileptics: carbamazepine, phenobarbital Antibiotics (systemic): rifampicin P-gp Anti-epileptics: carbamazepine, phenobarbital Antibiotics (systemic): rifampicin Systemic corticosteroids: dexamethasone Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 537 Table 6 (continued) Blue symbols are supported by clinical data, orange symbols are supported by in vitro data only AR androgen receptor, BCRP breast cancer resistance protein, CNS central nervous system, CV cardiovascular, CYP cytochrome P450, DDI drug–drug interaction, DMARD disease-modifying antirheumatic drug, EMA European Medicines Agency, FDA Food and Drug Administration, mCRPC metastatic castration-resistant prostate cancer, OATP organic anion-transporting peptide, P-gp P-glycoprotein, PPI proton pump inhibi- tor, SPC summary of product characteristics, UGT ur idine 5′-diphospho-glucuronosyltransferase Indicates risk of increased exposure; strong effect, with avoidance or substitution of coadministered drug recommended Indicates risk of decreased exposure and loss of efficacy; strong effect, with avoidance or substitution of coadministered drug recommended ↑ Indicates risk of increased exposure; weak effect, with caution and/or dose adjustment based on efficacy/tolerability recommended ↓ Indicates risk of decreased exposure; weak effect, with caution and/or dose adjustment based on efficacy/tolerability recommended ‘–’ Indicates data indicate no clinically significant effect Based on the EMA SPC for XTANDI (UGT substrates are not mentioned in the US PI) [11, 12] Avoid concomitant use with drugs that are BCRP substrates where possible; if used together, monitor patients more frequently for adverse reac- tions and consider dose reduction of BCRP substrate drug [23] If combined P-gp and strong CYP3A4 inhibitors are used together, monitor patients more frequently for darolutamide adverse reactions [23] Note that the information for XTANDI differs between the US PI and the EMA SPC [11, 12] Avoid concomitant use of combined P-gp and strong or moderate CPY3A4 inducers [23] Author Contributions CZ, RF, HG, MK, BP, OP, GB, OP, and IK con- in our analyses. Our identification of potential DDIs is not tributed to the conception and design of the study; NS, CZ, RF, HG, exhaustive—DDIs may occur with drugs not investigated KG, MK, BP, OPr, GB, OP, TLT, IK, FV, MS, and KF contributed to in preclinical and phase I studies to date, and DDIs may be the acquisition of data; NS, RF, HG, BP, GB, OP, TLT, IK, FV, MS, specific to individual drugs within a drug class. The safety and KF contributed to the analysis and interpretation of the data; NS and KF drafted the manuscript; BP and JM carried out the statistical profile of darolutamide will continue to be monitored in analysis; all authors provided critical revision of the manuscript for post-marketing studies. important intellectual content. Data Sharing Availability of the data underlying this publication will 5 Conclusions be determined according to Bayer’s commitment to the EFPIA/PhRMA “Principles for responsible clinical trial data sharing.” This pertains to scope, timepoint, and process of data access. As such, Bayer commits These analyses of ARAMIS data suggest a limited poten- to sharing upon request from qualified scientific and medical research- tial for clinically relevant DDIs between darolutamide and ers patient-level clinical trial data, study-level clinical trial data, and comedications frequently used to treat age-related comorbid- protocols from clinical trials in patients for medicines and indications approved in the United States (US) and European Union (EU) as nec- ities in patients with nmCRPC (Table 6). Interactions noted essary for conducting legitimate research. This applies to data on new with the combined BCRP and OATP substrate rosuvastatin medicines and indications that have been approved by the EU and US did not seem to translate into increased AEs in the ARAMIS regulatory agencies on or after 1 January 2014. Interested researchers trial to date. Determining the risk–benefit balance of andro- can use http://www.clini calst udyda tareq uest.com to request access to anonymized patient-level data and supporting documents from clini- gen receptor-targeted therapies for patients with nmCRPC cal studies to conduct further research that can help advance medi- who receive multiple comedications is important for optimal cal science or improve patient care. Information on the Bayer criteria management. The findings presented here provide additional for listing studies and other relevant information is provided in the information for clinical decision making. Study sponsors section of the portal. Data access will be granted to anonymized patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is Acknowledgements The authors thank the patients, their families, and not involved in the decisions made by the independent review panel. all investigators involved in this study. The authors wish to acknowl- Bayer will take all necessary measures to ensure that patient privacy edge the contribution of Christian Kappeler and Marie-Aude Le Berre is safeguarded. for statistical analysis performed from the ARAMIS study. Medical writing support, including assisting authors with the development of the outline and initial draft and incorporation of comments was Compliance with Ethical Standards provided by Tamsin Williamson, and editorial support, including for- matting, proofreading, and submission was provided by Annabel Ola Funding This work was supported by Bayer HealthCare and Orion and Beth King all of Scion Medica, London, supported by Bayer AG Pharma. according to Good Publication Practice guidelines (http://annal s.org/ aim/article/24248 69/good-publi catio n-pr actice-commu nicat ing-com pa ny-spons ored-medic al-resea rch-gpp3). The study sponsors Bayer AG Conflict of interest Dr. Shore reports personal fees from Ferring, Bay- and Orion Pharma were involved in the study design, collection, anal- er, Amgen, Janssen, Dendreon, Tolmar, Astellas, Pfizer, AstraZeneca, ysis and interpretation of data. However, ultimate responsibility for Genentech/Roche, Myovant Sciences, Merck, AstraZeneca, Bristol opinions, conclusions, and data interpretation lies with the authors. Meyers Squibb, and Nymox outside the submitted work. Drs. Zurth, 538 N. Shore et al. Fricke, Gieschen, Graudenz, Ploeger, Prien, Borghesi, Petrenciuc, prostate cancer. N Engl J Med. 2018;378(26):2465–74. https://doi. and Kuss report employment by and stock ownership in Bayer. Dr. org/10.1056/NEJMo a1800 536. Koskinen reports employment by and stock ownership in Orion. Dr. 9. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff Moss reports personal fees from Akari, AstraZeneca, Bayer, Carrick JN, et al. Apalutamide treatment and metastasis-free survival in Therapeutics, Debiopharm, Orphazym, Proveca, Richmond Pharma- prostate cancer. N Engl J Med. 2018;378(15):1408–18. https :// cology, and the University of Leicester outside the submitted work. doi.org/10.1056/NEJMo a1715 546. Dr. Tammela reports personal fees from Janssen, and grants and per- 10. Benoist GE, van Oort IM, Smeenk S, Javad A, Somford DM, sonal fees from Bayer, Lidds AB, and Astellas, outside the submitted Burger DM, et  al. Drug-drug interaction potential in men work. Dr. Verholen reports employment by Bayer. Dr. Smith reports treated with enzalutamide: mind the gap. Br J Clin Pharmacol. personal fees from Amgen, Astellas, Bayer, Clovis, Gilead, Janssen, 2018;84(1):122–9. https ://doi.org/10.1111/bcp.13425 . Lilly, Novartis, and Pfizer, outside the submitted work. Dr. Fizazi re- 11. Astellas Pharma US Inc. Xtandi (enzalutamide) US prescribing ports personal fees from Amgen, Astellas, AstraZeneca, Bayer, Clovis, information. 2018. https ://www .acces sdat a .fda.gov/dr ugs atfda Curevac, ESSA, Janssen, Orion Pharma, Roche/Genentech, and Sanofi _docs/label /2018/20341 5s014 lbl.pdf. Accessed 11 June 2019. outside the submitted work. 12. European Medicines Agency. Summary of product characteristics: XTANDI. 2019. https: //www.ema.europa .eu/en/docume nts/produ Informed consent Informed consent was obtained from all individual ct-informatio n/xt andi-epar -product-inf ormatio n_en.pdf . Accessed participants in the study. 11 June 2019. 13. European Medicines Agency. Summary of product characteristics: ERLEADA. 2019. h t t p s : / / w w w . e m a . e u r o p a . e u / e n / d o c u m e n t s / Open Access This article is distributed under the terms of the Crea- produ ct-infor matio n/erlea da-epar-produ ct-infor matio n_en.pdf. tive Commons Attribution-NonCommercial 4.0 International License Accessed 11 June 2019. (http://creat iveco mmons .org/licen ses/by-nc/4.0/), which permits any 14. Janssen Ortho LLC. Erleada (apalutamide) US prescribing infor- noncommercial use, distribution, and reproduction in any medium, mation. 2018. https ://www.acces sdata .fda.gov/drugs atfda _docs/ provided you give appropriate credit to the original author(s) and the label /2018/21095 1s000 lbl.pdf. Accessed 22 July 2019. source, provide a link to the Creative Commons license, and indicate 15. European Medicines Agency. Xtandi CHMP assessment report. if changes were made. 2013. http://www.ema.europa.eu/docs/en_GB/docum ent_libr ar y/ EPAR_-_Public_asses sment _r eport/human /00263 9/W C50014499 8.pdf. Accessed 1 Oct 2018. 16. European Medicines Agency. Erleada CHMP assessment report. References 2018. https://www .ema.europa.eu/en/docum ents/asses sment -r epor t/erlea da-epar-publi c-asses sment -repor t_en.pdf. Accessed 1 Oct 1. National Cancer Institute. Surveillance, epidemiology, and end results program. Cancer stat facts: prostate cancer. 2019. https :// 17. Fizazi K, Smith MR, Tombal B. Clinical development of daro- seer.cancer .gov/statfacts/html/pr ost.html . Accessed 16 May 2019. lutamide: a novel androgen receptor antagonist for the treatment 2. Francini E, Gray KP, Shaw GK, Evan CP, Hamid AA, Perry of prostate cancer. Clin Genitourin Cancer. 2018;16(5):332–40. CE, et al. Impact of new systemic therapies on overall survival https ://doi.org/10.1016/j.clgc.2018.07.017. of patients with metastatic castration-resistant prostate can- 18. US Food and Drug Administration. FDA approves darolutamide cer in a hospital-based registry. Prostate Cancer Prostatic Dis. for non-metastatic castration-resistant prostate cancer. 2019. https 2019;22(3):420–7. https://doi.or g/10.1038/s41391-018-0121-2 . ://www.fda.gov/drugs/ resour ces-inform ation- approv ed-drugs/ fda- 3. Basch E, Autio K, Ryan CJ, Mulders P, Shore N, Kheoh T, et al. appro ves-darol utami de-non-metas tatic -castr ation -resis tant-prost Abiraterone acetate plus prednisone versus prednisone alone in ate-cance r. Accessed 31 July 2019. chemotherapy-naive men with metastatic castration-resistant 19. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, prostate cancer: patient-reported outcome results of a randomised et al. Darolutamide in nonmetastatic, castration-resistant pros- phase 3 trial. Lancet Oncol. 2013;14(12):1193–9. https ://doi. tate cancer. N Engl J Med. 2019;380(13):1235–46. https ://doi. org/10.1016/S1470 -2045(13)70424 -8. org/10.1056/NEJMo a1815 671. 4. Del Re M, Fogli S, Derosa L, Massari F, De Souza P, Crucitta S, 20. Zurth C, Graudenz K, Denner K, Vairlein M, Korjamo T, Fricke et al. The role of drug-drug interactions in prostate cancer treat- R, et al. Drug-drug interaction of darolutamide with cytochrome ment: focus on abiraterone acetate/prednisone and enzalutamide. P450 and P-glycoprotein substrates: results from clinical and Cancer Treat Rev. 2017;55:71–82. https ://doi.or g/10.1016/j. in vitro studies. San Francisco: ASCO Genitourinary Cancers ctrv.2017.03.001. Symposium; 2019. 5. Stepney R, Lichtman SM, Danesi R. Drug-drug interactions in 21. Zurth C, Koskinen M, Fricke R, Prien O, Korjamo T, Graudenz older patients with cancer: a report from the 15th Conference of K, et al. Drug–drug interaction potential of darolutamide: in vitro the International Society of Geriatric Oncology, Prague, Czech and clinical studies. Eur J Drug Metab Pharmacokinet. 2019. https Republic, November 2015. Ecancermedicalscience. 2016;10:611. ://doi.org/10.1007/s1331 8-019-00577 -5. https ://doi.org/10.3332/ecanc er.2016.611. 22. R (Version 3.1.1) Development Core Team. R: a language and 6. Bohnert T, Patel A, Templeton I, Chen Y, Lu C, Lai G, et al. Eval- environment for statistical computing. Vienna: R Foundation for uation of a new molecular entity as a victim of metabolic drug- Statistical Computing; 2008. drug interactions-an industry perspective. Drug Metab Dispos. 23. Bayer HealthCare Pharmaceuticals Inc. Nubeqa (darolutamide) 2016;44(8):1399–423. https ://doi.org/10.1124/dmd.115.06909 6. US prescribing information. 2019. h t t p s : / / w w w. a c c e s s d a t a 7. Guthrie B, Makubate B, Hernandez-Santiago V, Dreischulte T. .fda.gov/drugs atfda _docs/label /2019/21209 9Orig 1s000 lbl.pdf. The rising tide of polypharmacy and drug-drug interactions: popu- Accessed 31 July 2019. lation database analysis 1995-2010. BMC Med. 2015;13:74. https 24. Benoist GE, van Oort IM, Burger DM, Koch BCP, Mehra N, van ://doi.org/10.1186/s1291 6-015-0322-7. Erp NP. The combination of enzalutamide and opioids: a painful 8. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, pitfall? Eur Urol. 2019;75(2):351–2. https ://doi.org/10.1016/j. et al. Enzalutamide in men with nonmetastatic, castration-resistant eurur o.2018.09.011. Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 539 25. US Center for Drug Evaluation and Research. NDA/BLA clinical 29. Hansten PD, Horn JR. Top 100 drug interactions 2018. A guide pharmacology and biopharmaceutics review NDA 203415 Xtandi to patient management. 19th ed. LLP: H&H Publications; 2018. (enzalutamide). 2012. https://www .accessdat a.fda.go v/drugsatfda 30. US Food and Drug Administration. Drug development and drug _docs/nda/2012/203415Or ig1s000 ClinP har mR.pdf . Accessed 26 interactions: table of substrates, inhibitors and inducers. 2017. Sept 2018.https:/ /www.fda.gov/drugs/d rug-interac tions -labelin g/drug-devel 26. US Center for Drug Evaluation and Research. NDA/BLA multi- o p me n t - an d - d r ug - i n te r a c t io n s - t a b l e - s u bs t r a t e s - i nh i b i t o r s - a n d- disciplinary review and evaluation NDA 210951 Erleada (apalu-induc ers. Accessed 15 Aug 2019. tamide). 2018. https://www .accessdat a.fda.go v/drugsatfda _docs/ 31. National Cancer Institute. Common Terminology Criteria for nda/2018/21095 1Orig 1s000 Multi disci pline R.pdf. Accessed 26 Adverse Events, version 4.03. Bethesda, MD: Cancer Therapy Sept 2018. Evaluation Program. 2010. https ://ctep.cance r .gov/pr o t o colde 27. Pollock Y, Smith M, Saad F, Chowdhury S, Oudard S, Hadaschik velop ment/elect r onic _appli catio ns/ctc.htm. Accessed 16 Sept B, et al. Predictors of falls and fractures in patients (pts) with 2019. nonmetastatic castration-resistant prostate cancer (nmCRPC) 32. De Gregori S, De Gregori M, Ranzani GN, Allegri M, Minella C, treated with apalutamide (APA) plus ongoing androgen depriva- Regazzi M. Morphine metabolism, transport and brain disposi- tion therapy (ADT). J Clin Oncol. 2019;37(15_suppl):5025. https tion. Metab Brain Dis. 2012;27(1):1–5. https ://doi.org/10.1007/ ://doi.org/10.1200/jco.2019.37.15_suppl .5025.s1101 1-011-9274-6. 28. Kidney Disease: Improving Global Outcomes (KDIGO) CKD 33. Ge S, Tu Y, Hu M. Challenges and opportunities with predicting Work Group. KDIGO 2012 clinical practice guideline for the in vivo phase II metabolism via glucuronidation from in vitro data. evaluation and management of chronic kidney disease. Kidney Curr Pharmacol Rep. 2016;2(6):326–38. https://doi.or g/10.1007/ Int. 2012;3:1–150.s4049 5-016-0076-8. Affiliations 1 2 2 2 2 3 Neal Shore  · Christian Zurth  · Robert Fricke  · Hille Gieschen  · Kristina Graudenz  · Mikko Koskinen  · 2 4 2 2 2 5 2 Bart Ploeger  · Jonathan Moss  · Olaf Prien  · Gustavo Borghesi  · Oana Petrenciuc  · Teuvo L. Tammela  · Iris Kuss  · 2 6 7 Frank Verholen  · Matthew R. Smith  · Karim Fizazi 1 5 Carolina Urologic Research Center, 823 82nd Parkway, Suite Tampere University Hospital and Tampere University, B, Myrtle Beach, SC 29572, USA Tampere, Finland 2 6 Bayer AG, Berlin, Germany Massachusetts General Hospital Cancer Center, Boston, USA 3 7 Orion Corporation Orion Pharma, Espoo, Finland Institut Gustave Roussy, Université Paris-Sud, Villejuif, France BAST Inc. Ltd., Loughborough, UK http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Targeted Oncology Springer Journals

Evaluation of Clinically Relevant Drug–Drug Interactions and Population Pharmacokinetics of Darolutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer: Results of Pre-Specified and Post Hoc Analyses of the Phase III ARAMIS Trial

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Springer Journals
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Copyright © 2019 by The Author(s)
Subject
Medicine & Public Health; Oncology; Biomedicine, general
ISSN
1776-2596
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1776-260X
DOI
10.1007/s11523-019-00674-0
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Abstract

Background Darolutamide, an androgen receptor antagonist with a distinct molecular structure, significantly prolonged metas- tasis-free survival versus placebo in the phase III ARAMIS study in men with nonmetastatic castration-resistant prostate cancer (nmCRPC). In this population, polypharmacy for age-related comorbidities is common and may increase drug–drug interaction (DDI) risks. Preclinical/phase I study data suggest darolutamide has a low DDI potential—other than breast cancer resistance protein/organic anion transporter protein substrates (e.g., statins), no clinically relevant effect on comedications is expected. Objective Our objective was to evaluate the effect of commonly administered drugs on the pharmacokinetics of darolutamide and the effect of comedications potentially affected by darolutamide on safety in patients with nmCRPC. Patients and Methods Comorbidities and comedication use in the 1509 ARAMIS participants treated with darolutamide 600 mg twice daily or placebo were assessed. A population pharmacokinetic analysis evaluated whether comedications affected the pharmacokinetics of darolutamide in a subset of 388 patients. A subgroup analysis of adverse events (AEs) in statin users versus nonusers was conducted. Results Most participants (median age 74 years) had at least one comorbidity (98.4% in both arms) and used at least one come- dication (98.7% with darolutamide vs. 98.0% with placebo); these were similar across study arms. Despite frequent use of come- dications with DDI potential, no signic fi ant ee ff cts on darolutamide pharmacokinetics were identie fi d. Comedications included lipid-modifying agents (34.5%), β-blockers (29.7%), antithrombotics (42.8%), and systemic antibiotics (26.9%). AE incidence was similar across study arms in statin users and nonusers. Study limitations include the small sample size for sub-analyses. Conclusions These analyses suggest the pharmacokinetic profile of darolutamide is not affected by a number of commonly administered drugs in patients with nmCRPC. Although pharmacokinetic data have indicated that darolutamide has the potential to interact with rosuvastatin, used to assess DDI in these studies, this finding did not seem to translate into increased AEs due to statin use in the ARAMIS trial. Clinicaltrials.gov identifier: NCT02200614. Plain Language Summary Background Darolutamide is a medicine used to treat men with prostate cancer that has not spread to other parts of the body (nonmetastatic). Often, these patients are taking other medicines for common age-related illnesses. Taking more than one Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1152 3-019-00674 -0) contains supplementary material, which is available to authorized users. * Neal Shore NShore@gsuro.com Extended author information available on the last page of the article Vol.:(0123456789) 528 N. Shore et al. medicine at the same time increases the chances of what is known as drug–drug interactions. Drug–drug interactions can decrease how well the medicines work or may sometimes increase side effects. Study Aim To test for possible drug–drug interactions in men with prostate cancer who take darolutamide alongside other medicines. Study Participants Men with nonmetastatic prostate cancer who were being treated with a medicine that lowers testosterone, a chemical in the body that causes prostate cancer tumors to grow. Participants took two darolutamide 300 mg tablets, or an inactive placebo, twice a day. What Did the Researchers Measure? The researchers documented the number of medicines taken by each participant and the number of other medical conditions that they had. Tests were done to find out whether other medicines affected the way that darolutamide works in the body and whether patients taking darolutamide alongside other medicines experienced more side effects. Results As would be expected, based on the typical age of patients with prostate cancer, more than 90% of participants in this study used medicines other than darolutamide to manage common age-related illnesses or medical conditions. Taking medicines alongside darolutamide did not impact how darolutamide worked in the body and did not increase the number of side effects experienced by patients. Darolutamide is known to interact with rosuvastatin, a cholesterol-lowering drug. However, in this study, there was no overall increase in side effects among darolutamide-treated patients who took this type of drug compared with in those who did not. Conclusion In this study of patients with nonmetastatic prostate cancer, limited drug–drug interactions were seen when taking darolutamide alongside other medicines given to these patients to manage age-related medical conditions. Key Points interactions (DDIs) is also a fundamental component in clinical decision making [7]. Polypharmacy for age-related comorbidities is com- The second-generation androgen receptor inhibitors enza- mon in patients with nonmetastatic castration-resistant lutamide and apalutamide have recently been approved for prostate cancer, and this increases the risk of drug–drug the treatment of nmCRPC after demonstrating significantly interactions (DDIs). prolonged metastasis-free survival in phase III clinical tri- als [8, 9]. However, this change in the treatment landscape Subanalyses of the phase III ARAMIS trial indicate that has also brought decision-making challenges. Apalutamide darolutamide has low risk of clinically relevant DDIs and enzalutamide are associated with higher incidences of with comedications commonly used in these patients. certain AEs (e.g., falls, fatigue, hypertension, rashes, and seizures) than are placebo. They also both have the poten- tial for DDIs when coadministered with medications that are substrates for several metabolizing enzymes and drug transporters [8–14]. For example, coadministration of either drug may reduce the exposure of medications that are sub- 1 Introduction strates for the cytochrome P450 (CYP) enzymes CYP3A4, CYP2C9, and CYP2C19 [15, 16], resulting in loss of activ- A prime goal of treatment for patients with nonmetastatic ity of common comedications such as anticoagulants, anti- castration-resistant prostate cancer (nmCRPC) is to delay hypertensives, opioid analgesics, and proton pump inhibitors progression to metastatic disease (mCRPC) since increased (PPIs). tumor burden is associated with worse prognosis [1], Darolutamide is a novel androgen receptor antagonist although the recent introduction of multiple life-extending with a unique molecular structure recently approved by the therapies for mCRPC (radium-223, abiraterone, enzaluta- US FDA for the treatment of nmCRPC [17, 18]. In the phase mide, sipuleucel-T, and taxanes) has extended post-progres- III ARAMIS trial (NCT02200614), darolutamide demon- sion survival [2]. Along with disease progression, adverse strated signic fi antly prolonged metastasis-free survival com - events (AEs) associated with anticancer therapies may have pared with placebo (40.4 vs. 18.4 months; hazard ratio for a detrimental impact on patients’ quality of life [3], particu- metastasis or death in the darolutamide group 0.41; 95% larly in patients with nmCRPC, given the mostly asymp- confidence interval [CI] 0.34–0.50; p < 0.001) in patients tomatic nature of their disease. As nmCRPC is generally with nmCRPC receiving androgen-deprivation therapy and diagnosed in older men who are often prescribed multiple delayed time to pain progression (40.3 vs. 25.4 months; haz- concomitant medications for comorbid conditions [4–6], the ard ratio 0.65; 95% CI 0.53–0.79) [19]. The DDI potential of risk of AEs or loss of efficacy resulting from drug–drug Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 529 darolutamide has been extensively investigated in preclinical 2.2 Treatment and clinical phase I studies with metabolizing enzymes and drug transporters. Darolutamide was sensitive to induction Men were randomized 2:1 to receive darolutamide 600 mg of CYP3A4, the main enzyme mediating its metabolism. twice daily (given as two 300 mg tablets) or placebo while Inhibition of CYP3A4, P-glycoprotein (P-gp) and breast continuing androgen-deprivation therapy. Patients continued cancer resistance protein (BCRP)—both transporters for study medications until protocol-defined progression, dis- which darolutamide is a substrate—by comedications was continuation due to AEs, or withdrawal of consent. not considered clinically relevant. No relevant inhibition of any CYP enzymes by darolutamide was observed in vitro, 2.3 Population Pharmacokinetic Model and in vivo studies found weak induction of CYP3A4 only, suggesting darolutamide may have no clinically relevant An exploratory population pharmacokinetic analysis was effect on comedications metabolized by CYP enzymes [20]. performed to evaluate the variability in the pharmacokinetics Therapeutic levels of darolutamide were found to have no of darolutamide, its two pharmacologically active diastere- effect on P-gp substrates [20], though exposure of rosuvasta- omers, (S,R)-darolutamide and (S,S)-darolutamide, and the tin, a substrate for BCRP, organic anion-transporting peptide active metabolite, keto-darolutamide, based on data gener- (OATP)1B1, and OATP1B3, was moderately increased by ated from the phase III ARAMIS study [19]. The population darolutamide coadministration [21]. This effect was mainly pharmacokinetic model was developed using data from a attributed to inhibition of BCRP; however, a contribution subset of patients with valid pharmacokinetic samples col- of OATP inhibition is considered likely. Overall, the results lected sparsely at several times during the 12-h application of these studies indicated that darolutamide has a favorable interval (detailed in the Electronic Supplementary Material DDI profile. [ESM]—Methods) and information on drug disposition To evaluate the impact of clinically relevant DDIs with pathways identified preclinically. The bioanalytical meth- darolutamide in the target patient population, we conducted ods used for pharmacokinetic sampling are summarized in prespecified and post hoc analyses in patients with nmCRPC the ESM—Methods. who participated in the phase III ARAMIS trial [19], includ- All predefined concomitant medications taken by at least ing assessments of comorbidities and comedication use, the one patient during study treatment were included as a covari- effects of concomitant medications on the pharmacokinetics ate in the population pharmacokinetic model (Table 1 in the of darolutamide, and the impact of coadministering daroluta- ESM). The impact of BCRP inhibitors, CYP3A4 inducers/ mide with concomitant medications on patient safety. Given inhibitors, P-gp inducers/inhibitors, PPIs, and/or uridine that statin use is very common in this population and darolu- 5′-diphospho-glucuronosyltransferase (UGT) inducers/ tamide has been observed to increase rosuvastatin exposure inhibitors on the pharmacokinetics of darolutamide was [21], we conducted a subanalysis of the impact of using con- investigated. Comedications with any relevant DDI poten- comitant statins with darolutamide on patient safety. tial, weak or strong, were included. 2.4 Safety Analyses 2 Patients and Methods At each study visit, data on treatment-emergent AEs 2.1 Trial Design (TEAEs), including type, severity, seriousness, and whether they were related to study treatment based on investigator The phase III ARAMIS trial (NCT02200614) protocol and assessment, were recorded. A subgroup analysis was also design have been described in detail elsewhere [19]. Briefly, performed to compare the incidence of TEAEs for patients this was a randomized, double-blind, placebo-controlled, receiving statins (3-hydroxy-3-methylglutaryl-coenzyme A phase III clinical trial conducted globally in 409 centers in reductase inhibitors) versus those not receiving statins. This 36 countries to evaluate the efficacy and safety of darolu- analysis included all TEAEs reported in concomitant statin tamide in patients with nmCRPC. The trial was approved users versus nonusers regardless of when the event occurred by local institutional review boards and was conducted in during the study, i.e., without consideration for when daro- compliance with the principles of the Declaration of Hel- lutamide and the statin were coadministered. A post hoc sinki and in accordance with the International Conference analysis evaluating TEAE incidence in patients using statins on Harmonisation guidelines for Good Clinical Practice. All known to be BCRP substrates versus nonusers of BCRP- patients provided written informed consent. substrate statins was also performed. 530 N. Shore et al. systemic antibiotics, and anti-inflammatory/antirheumatic 2.5 Statistical Analysis agents were used by at least 20% of patients. These come- dications span a range of agents that act as inducers, inhibi- Patient demographics, comorbidities, and concomitant medications were summarized descriptively for all rand- tors, or substrates of the enzymes predominantly involved in drug metabolism or key drug transporters (e.g., P-gp, BCRP, omized patients, i.e., the full analysis set. Comedications were categorized according to potential for relevant DDIs OATP1B1, OATP1B3) (Table 3). (CYP inducers/inhibitors/substrates, UGT substrates, and drug transporter substrates) based on in vitro and phase I 3.3 Population Pharmacokinetic Analysis clinical studies of darolutamide [21] and established DDI profiles for the currently available androgen-receptor inhibi- In total, 388 patients (40% of the total who received darolu- tors, enzalutamide and apalutamide [11–14]. tamide in the phase III trial) were included in the pharma- Pharmacokinetic model development was conducted via cokinetic subset. Demographics and baseline characteristics nonlinear mixed-effects modelling using NONMEM (ver - were generally similar to those of the overall darolutamide- sion 7.3, ICON Development Solutions plc, Manchester, treated population, although the pharmacokinetic subset UK) and R software [22]. Full details of the population contained higher proportions of Japanese patients and pharmacokinetic analysis are given in the ESM—Methods. patients with mild renal impairment (Table 1). Safety evaluations were conducted in all patients who Evaluation of the population pharmacokinetic analysis were randomized and received at least one dose of study showed that none of the comedications included as covari- medication. ates in the population pharmacokinetic base model met the criteria for a significant covariate effect. These comedica- tions included CYP3A4 inhibitors (21.6%), P-gp inhibitors 3 Results (20.1%), PPIs (15.2%), BCRP inhibitors (14.9%), UGT1A9 inhibitors (2.8%), and CYP3A4 inducers (0.5%); examples 3.1 Patients of drugs in these categories are given in Table 3. No patients received P-gp or UGT1A9 inducers. PPIs exerted no effect In total, 1509 men were randomized to darolutamide on darolutamide clearance. It was not possible to specifi - (n = 955) or placebo (n = 554) in addition to androgen- cally assess an effect of CYP3A4 inducers as so few patients deprivation therapy. One patient randomized to the daro- received comedications that were CYP3A4 inducers, such lutamide arm did not receive study treatment and was as rifampicin or carbamazepine. These data suggest that, therefore excluded from the safety analyses [19]. Baseline although preclinical data indicate darolutamide exposure demographic and clinical characteristics were similar in the may be affected by drugs that are strong CYP3A4 and P-gp two treatment groups (Table 1). Median age was 74 years in inducers or inhibitors [23], there was no significant associa- both groups, and median follow-up time was 17.9 months. tion between the use of concomitant medications and the Most patients had at least one comorbid condition (98.4% pharmacokinetic variability of darolutamide in this study. in both treatment arms); the most common comorbidities were hypertension, obesity, anomalies of lipid metabolism, 3.4 Impact on Adverse Event Incidence of Drugs and diabetes (Table 2). Coadministered with Darolutamide, Including Breast Cancer Resistance Protein Substrates 3.2 Concomitant Medication Use We also assessed whether the DDIs that have been identified The overwhelming majority of men in the trial were receiv- ing at least one concomitant medication, and rates of come- as clinically relevant for darolutamide (notably, sensitivity to strong CYP3A4 inducers and inhibition of BCRP by darolu- dication use were balanced across the two treatment arms: 98.7% with darolutamide and 98.0% with placebo (Table 3). tamide [23]) had a possible impact on the safety of patients in the ARAMIS trial population. As already noted, the com- The most common concomitant medications for comorbid conditions in darolutamide- versus placebo-treated patients mon concomitant medications received by patients in ARA- MIS were similar between study arms (Table 3). We have were antihypertensives, including drugs affecting the renin–angiotensin system (54.7 vs. 49.8%), β-blockers (29.6 previously reported that the incidence of the most common AEs was similar in patients treated with darolutamide and vs. 27.6%), and calcium channel blockers (22.7% in both arms), as well as analgesics (53.8 vs. 50.4%), whereas more those who received placebo, and permanent discontinuations of the study drug due to AEs occurred in similar proportions than one-third of patients received antithrombotics (42.8 vs. 39.7%) or lipid-modifying agents (34.5 vs. 39.4%). Other of patients in each treatment arm [19]. cardiovascular agents, diuretics, urological agents, PPIs, Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 531 Table 1 Demographics and baseline characteristics of patients with nonmetastatic castration-resistant prostate cancer in the phase III study Characteristics Darolutamide Placebo (N = 554) PK subset (n = 388) Overall (N = 955) Age (years) 75 (48–95) 74 (48–95) 74 (50–92) Age group (years)  < 65 41 (10.6) 113 (11.8) 84 (15.2)  65–74 140 (36.1) 373 (39.1) 216 (39.0)  ≥ 75 207 (53.4) 469 (49.1) 254 (45.8) Race  Caucasian 292 (75.3) 760 (79.6) 434 (78.3)  Asian 76 (19.6) 122 (12.8) 71 (12.8)  Black 12 (3.1) 28 (2.9) 24 (4.3)  Missing/other 8 (2.1) 45 (4.7) 25 (4.5) Region  Asia-Pacific NA 119 (12.5) 67 (12.1)  Japan 58 (14.9) 62 (6.5) 33 (6.0)  North America NA 108 (11.3) 76 (13.7)  Rest of World NA 728 (76.2) 411 (74.2)  Not Japan 330 (85.1) 893 (93.5) 521 (94.0) Renal impairment  None 122 (31.4) 412 (43.1) 230 (41.5)  Mild 209 (53.9) 423 (44.3) 248 (44.8)  Moderate 56 (14.4) 119 (12.5) 76 (13.7)  Severe 1 (0.3) 1 (0.1) 0 Hepatic impairment  None 356 (91.8) 864 (90.5) 509 (91.9)  Mild 32 (8.2) 89 (9.3) 43 (7.8)  Moderate 0 2 (0.2) 1 (0.2)  Missing 0 0 1 (0.2) Data presented here are from the 17 January 2019 datacut. Data are presented as median (range) or n (%) unless otherwise indicated AST aspartate aminotransferase, eGFR estimated glomerular filtration rate, NA not available, PK pharmacokinetic, ULN upper limit of normal Full analysis set population (all randomized patients) None = eGFR ≥ 90 mL/min, mild = 60 to < 90 mL/min, moderate = 30 to < 60 mL/min, and severe = 15 to < 30 mL/min [28] None = total bilirubin and AST ≤ ULN, mild = total bilirubin > ULN to 1.5 × ULN or total bilirubin ≤ ULN and AST > ULN, and moder- ate = total bilirubin > 1.5 to 3 × ULN with any AST Concomitant use of statins was similar in the daroluta- population; Table 2 in the ESM), predefined AEs known mide and placebo arms (32.1 vs. 36.5%; Table 4). In both to be associated with statins occurred more frequently treatment arms, the incidence of TEAEs was comparable with darolutamide than placebo (8.6 vs. 3.5%; Table 5). between patients receiving concomitant statins and those This difference was due to greater incidences of abnor - not receiving statins (88.2 vs. 80.9% for darolutamide and malities in laboratory parameters. A similar difference was 82.2 vs. 73.9% for placebo; Table 4). With respect to the observed in the overall study population, indicating that type of AEs reported (based on system organ class and the difference occurred independently of statin exposure preferred term), no differences among statin users in either and excluding any relevant impact of darolutamide in sta- treatment arm was observed. No meaningful differences in tin users. The abnormalities in laboratory parameters were alanine aminotransferase (ALT) values occurred between notably increased aspartate aminotransferase levels (1.4% concomitant statin users and nonusers: in both treatment with darolutamide vs. 0.2% with placebo, respectively) arms, mean ALT values were slightly higher among sta- and increased blood bilirubin levels (1.3% with daroluta- tin users than nonusers at baseline and throughout the mide vs. 0% with placebo). treatment period. In a subset of patients using statins that are BCRP substrates (approximately 30% of the overall 532 N. Shore et al. contrast, enzalutamide is a strong CYP3A4 inducer and a Table 2 Proportion of patients with ongoing comorbid conditions by preferred MedDRA term (> 5% of total population; full analysis set) moderate CYP2C9 and CYP2C19 inducer, and apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak Comorbidity (preferred term) Patients with comorbidity, n (%) inducer of CYP2C9, UGT, P-gp, BCRP, and OATP1B1 [11, Darolu- Placebo (N = 554) 14]. Additional monitoring may be required as both drugs tamide may lead to suboptimal bioavailability of comedications (N = 955) with potential loss of efficacy. Hypertension 617 (64.6) 357 (64.4) The present analyses of the phase III ARAMIS trial Obesity 568 (59.5) 333 (60.1) demonstrated that almost all patients with nmCRPC receiv- Hypercholesterolemia 125 (13.1) 70 (12.6) ing androgen-deprivation therapy with androgen receptor Osteoarthritis 122 (12.8) 65 (11.7) inhibitor therapy have comorbid conditions that require the Benign prostatic hyperplasia 103 (10.8) 63 (11.4) use of concomitant medications. Individual patient data in Diabetes mellitus 101 (10.6) 68 (12.3) ARAMIS indicated that many patients were receiving mul- Atrioventricular block first degree 86 (9.0) 49 (8.8) tiple comedications, as others have also reported [10]. As Dyslipidemia 85 (8.9) 51 (9.2) expected in this population (median age 74 years), the most Type 2 diabetes mellitus 75 (7.9) 53 (9.6) common comorbidities included hypertension and other car- Hyperlipidemia 74 (7.7) 47 (8.5) diovascular disorders, obesity, hyperlipidemia, osteoarthri- Coronary artery disease 72 (7.5) 39 (7.0) tis, and diabetes. Consistent with the comorbidities reported, Arthralgia 71 (7.4) 27 (4.9) the most frequently prescribed comedications were antihy- Constipation 70 (7.3) 26 (4.7) pertensives and agents for other cardiovascular disorders, Myocardial ischemia 70 (7.3) 33 (6.0) along with a need for analgesia, treatments for urological Atrial fibrillation 69 (7.2) 43 (7.8) and acid-related gastrointestinal disorders, antidepressants, Bundle branch block, left 64 (6.7) 28 (5.1) anxiolytics, and dementia treatments. Our population phar- Renal cyst 64 (6.7) 37 (6.7) macokinetic analysis demonstrated that these frequently Back pain 62 (6.5) 38 (6.9) used concomitant drugs had no significant effect on the Nocturia 60 (6.3) 29 (5.2) pharmacokinetics of darolutamide. Comedications that are Insomnia 59 (6.2) 36 (6.5) potent CYP3A4 inducers were rarely used by the overall Hot flush 51 (5.3) 35 (6.3) ARAMIS population, so the risk of DDIs may also be low Gastroesophageal reflux disease 50 (5.2) 38 (6.9) in clinical practice. Erectile dysfunction 49 (5.1) 36 (6.5) Only the interaction between darolutamide and the com- bined BCRP and OATP substrate rosuvastatin has been Data presented here are from the 17 January 2019 datacut deemed clinically relevant [23], though our safety subgroup MedDRA Medical Dictionary for Regulatory Activities analysis in statin users and nonusers could not clearly attrib- ute any imbalance between the treatment arms to the effect of darolutamide on statins. However, the small sample size 4 Discussion may preclude observation of rare AEs such as myopathy or rhabdomyolysis, although these are well-characterized and The potential for DDIs is an important consideration when can readily be monitored. Overall, the incidence of AEs did selecting an androgen receptor-targeting therapy for patients not appear to be increased significantly by DDIs, as similar with nmCRPC. Loss of efficacy with treatments for patients’ AE rates are reported with darolutamide and placebo despite comorbidities or sustaining an increased risk of AEs are the equally high use of concomitant medications in both potential outcomes of DDIs [10, 24]. Extensive investigation treatment arms in the ARAMIS study [19]. This observa- in preclinical/phase I studies indicated that darolutamide has tion includes AEs previously reported more frequently with a favorable DDI profile. Overall, few DDIs were identified enzalutamide and apalutamide versus placebo in phase III at clinically relevant levels: darolutamide was sensitive to trials (PROSPER and SPARTAN, respectively) such as falls, CYP3A4 induction, but no clinically relevant effects on hypertension, and central nervous system (CNS)-related AEs darolutamide were expected from drugs that act as inhibi- [8, 9]. tors of CYP enzymes and drug transporters. The risk of AEs resulting from DDIs is an important con- Most importantly, darolutamide had few effects on other sideration for physicians. Enzalutamide and apalutamide drugs used to treat comorbid conditions; increased expo- have been identified as substrates, inducers, and/or inhibi- sure of rosuvastatin was the only interaction of note [23]. tors of metabolizing enzymes and inhibitors or inducers of This interaction was mainly attributed to BCRP inhibition, drug transporters [15, 16, 25, 26]. Given that the majority although darolutamide-mediated inhibition of OATP trans- of drugs are metabolized by at least one CYP enzyme [4], porters may have contributed to the observed effect. By Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 533 Table 3 Concomitant medication use (> 10% of total patient population; full analysis set) Comedications (by indication and ATC subclass) Patients using comedication, Examples of drug classes/individual agents with DDI poten- n (%) tial relevant to androgen receptor inhibitors [4, 29, 30] Daroluta- Pla- mide + ADT cebo + ADT (N = 955) (N = 554) Any comedication 943 (98.7) 543 (98.0) Cardiovascular disease  Agents acting on the renin–angiotensin system 522 (54.7) 276 (49.8) ACE inhibitors: atenolol (OATP1B1 substrate) ARBs: losartan (CYP3A4/CYP2C9 substrate), telmisartan (OATP1B1 substrate)  Antithrombotics 409 (42.8) 220 (39.7) Antiplatelet agents: clopidogrel (strong CYP2C8 inhibitor), ticagrelor (CYP3A4 substrate) Anticoagulants: rivaroxaban (CYP3A4 substrate), dabigatran etexilate (P-gp substrate)  Lipid-modifying agents 329 (34.5) 218 (39.4) Statins: atorvastatin (CYP3A4/OATP1B1/BCRP substrate), pravastatin (OATP1B1 substrate), rosuvastatin (BCRP/ OATP1B1 substrate) Gemfibrozil (strong CYP2C8 inhibitor)  β-blocking agents 283 (29.6) 153 (27.6) Propranolol (CYP2C19 substrate)  Calcium channel blockers 217 (22.7) 126 (22.7) Amlodipine (CYP3A4 substrate), verapamil (moderate CYP3A4 inhibitor, P-gp inhibitor)  Cardiac therapies (e.g., glycosides, anti- 212 (22.2) 115 (20.8) Glycosides: digoxin (P-gp substrate) arrhythmics, anti-anginals) Anti-arrhythmics: amiodarone (CYP3A4 substrate, CYP2C8/ CYP3A4 inhibitor); dronedarone, propafenone (CYP3A4 substrates) Anti-anginals: ranolazine (CYP3A4/P-gp substrate, weak CYP3A4/P-gp inhibitor) Spirolactones: eplerenone (CYP3A4 substrate)  Diuretics 217 (22.7) 102 (18.4) Furosemide (BCRP/OATP1B1 substrate)  Vasoprotectives 183 (19.2) 113 (20.4) – Pain and inflammation  Analgesics 514 (53.8) 279 (50.4) Opioids: fentanyl, oxycodone (CYP3A4/P-gp substrates)  Anti-inflammatories/DMARDs 249 (26.1) 124 (22.4) Sulfasalazine (BCRP substrate) Methotrexate (BCRP, OATP1B1, OAT1 and OAT3 substrate) NSAIDs: celecoxib (CYP2C9 substrate), diclofenac (CYP2C9/CYP3A4 substrate)  Corticosteroids (systemic) 122 (12.8) 81 (14.6) Dexamethasone (CYP3A4/P-gp inducer) Urological disorders  Urologicals 299 (31.3) 176 (31.8) ED agents: sildenafil, vardenafil (CYP3A4 substrates) BPH treatments: dutasteride, tamsulosin (CYP3A4 sub- strates); silodosin (CYP3A4/P-gp substrate) OAB treatments: darifenacin, oxybutynin (CYP3A4 sub- strates) GI and metabolic disorders  Acid-related disorders 281 (29.4) 170 (30.7) PPIs: lansoprazole (CYP2C19 substrate), omeprazole (CYP2C19 substrate), rabeprazole (CYP2C19 substrate)  Antidiabetics 176 (18.4) 119 (21.5) Glitazones: pioglitazone (CYP2C9/CYP3A4 substrate) Meglitinides: repaglinide (OATP1B1/CY2C8 substrate) Sulfonylureas: glimepiride (CYP2C9 substrate)  Antidiarrheals 145 (15.2) 95 (17.1) Loperamide: CYP3A4/P-gp substrate  Constipation medications 156 (16.3) 70 (12.6) – Infection  Antibiotics (systemic) 257 (26.9) 138 (24.9) Macrolides: clarithromycin (strong CYP3A4 inhibitor), eryth- romycin (moderate CYP3A4 inhibitor) 534 N. Shore et al. Table 3 (continued) Comedications (by indication and ATC subclass) Patients using comedication, Examples of drug classes/individual agents with DDI poten- n (%) tial relevant to androgen receptor inhibitors [4, 29, 30] Daroluta- Pla- mide + ADT cebo + ADT (N = 955) (N = 554) Nervous system disorders  Psycholeptics 188 (19.7) 109 (19.7) Antipsychotics: haloperidol, quetiapine, aripiprazole (CYP3A4 substrates) Anxiolytics: buspirone (CYP3A4 substrate) Carbamazepine (strong CYP3A4 inducer) Benzodiazepines: alprazolam, midazolam (CYP3A4 sub- strates); diazepam (CYP2C19 substrate)  Psychoanaleptics 108 (11.3) 52 (9.4) Bupropion (CYP2B6 substrate) SARIs: trazodone (CYP3A4 substrate) SSRIs: citalopram, escitalopram (CYP3A4 substrates) Dementia treatments: donepezil, galantamine (CYP3A4 substrates) Data presented here are from the 17 January 2019 datacut Includes medications ongoing at baseline or that were initiated after the study drug or after the end of the study drug but excludes any agents used locally/topically due to the lack of DDI risk (e.g., ophthalmologicals, nonsystemic respiratory products). As multiple ATC codes per drug are possible, some drugs may be counted in more than one category for the same patient ACE angiotensin-converting enzyme, ADT androgen-deprivation therapy, ARB angiotensin II receptor blocker, ATC Anatomical Therapeutic Chemical, BCRP breast cancer resistance protein, BPH benign prostatic hyperplasia, CYP cytochrome P450 enzyme, DDI drug–drug interaction, DMARD disease-modifying antirheumatic drug, ED erectile dysfunction, GI gastrointestinal, NSAID nonsteroidal anti-inflammatory drug, OAB overactive bladder, OAT organic anion transporter, OATP organic anion-transporting peptide, P-gp P-glycoprotein, PPI proton pump inhibitor, SARI serotonin antagonist and reuptake inhibitor, SSRI selective serotonin reuptake inhibitor Includes all uses of systemic corticosteroids Includes intestinal anti-inflammatory/anti-infective agents One or more agent in the drug class enzalutamide and apalutamide have the potential for DDIs or antidepressants [27]. Hence, the safety of prescribing with a range of medications that are commonly used by androgen receptor inhibitors in the setting of polypharmacy patients with prostate cancer, e.g., gastrointestinal, cardio- warrants consideration by the treating physician. vascular, and analgesic agents (Table 6) [10, 15, 16, 24–26]. Limitations of our study include the small sample size Consequently, the FDA labels for enzalutamide and apaluta- of the safety subanalyses and the population pharmacoki- mide suggest avoiding the use of susceptible comedications netic analysis and that the population pharmacokinetic and warn of the potential loss of efficacy of these comedi- analysis did not investigate the effect of darolutamide on cations, respectively [11, 14]. In a retrospective review of the pharmacokinetics of comedications. Strong CYP3A4 pharmacy records for patients with mCRPC, enzalutamide and P-gp inducers were identified as having a relevant effect was associated with a high prevalence of potential DDIs with on darolutamide, but such comedications were rarely used CNS drugs (e.g., opioid analgesics), which could increase in ARAMIS. For example, the strong CYP3A4-inducing the risk of cognitive adverse effects, falls, and fractures [10]. anti-epileptic drugs, carbamazepine, phenytoin, and pheno- In addition, enzalutamide reduces plasma concentrations of barbital, were used by few patients. However, as patients PPIs, which increases the risk of bleeding events in patients with severe infections (which may be treated with systemic receiving PPIs in combination with aspirin or nonsteroi- antibiotics such as rifampicin) and other serious comorbidi- dal anti-inflammatory drug prophylaxis. Overall, 85% of ties (e.g., recent stroke or myocardial infarction, active viral patients with mCRPC who received enzalutamide were at hepatitis, or human immunodeficiency virus) were excluded, risk for DDIs that would require treatment modification of the ARAMIS population did not fully represent the real- at least one comedication [10]. In a post hoc analysis of the world population likely to receive darolutamide treatment. phase III SPARTAN trial, the risk of falls was increased in Multiple interactions between drugs were possible since patients receiving apalutamide and concomitant α-blockers many patients received several comedications, but it was not possible to assess the impact of these on patient safety Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 535 Table 4 Overview of treatment-emergent adverse events by concomitant statin use (safety population) Patients Darolutamide (N = 954) Placebo (N = 554) Concomitant statin use Concomitant statin use Yes (n = 306) No (n = 648) Yes (n = 202) No (n = 352) Any TEAE 270 (88.2) 524 (80.9) 166 (82.2) 260 (73.9)  Grade 1 73 (23.9) 146 (22.5) 51 (25.2) 83 (23.6)  Grade 2 95 (31.0) 207 (31.9) 69 (34.2) 97 (27.6)  Grade 3 76 (24.8) 139 (21.5) 36 (17.8) 63 (17.9)  Grade 4 10 (3.3) 11 (1.7) 5 (2.5) 4 (1.1) SAE 97 (31.7) 140 (21.6) 42 (20.8) 69 (19.6) Death 16 (5.2) 21 (3.2) 5 (2.5) 13 (3.7) TEAE leading to dose modification 51 (16.7) 84 (13.0) 20 (9.9) 32 (9.1) TEAE leading to discontinuation of study drug 28 (9.2) 57 (8.8) 16 (7.9) 32 (9.1) Any drug-related TEAE 81 (26.5) 177 (27.3) 43 (21.3) 67 (19.0)  Grade 1 42 (13.7) 90 (13.9) 31 (15.3) 37 (10.5)  Grade 2 30 (9.8) 68 (10.5) 7 (3.5) 19 (5.4)  Grade 3 8 (2.6) 16 (2.5) 4 (2.0) 10 (2.8)  Grade 4 1 (0.3) 2 (0.3) 0 0 Drug-related SAE 3 (1.0) 7 (1.1) 3 (1.5) 3 (0.9) Drug-related death 0 1 (0.2) 1 (0.5) 1 (0.3) Drug-related TEAE leading to dose modification 15 (4.9) 34 (5.2) 5 (2.5) 9 (2.6) Drug-related TEAE leading to discontinuation of study drug 3 (1.0) 12 (1.9) 5 (2.5) 8 (2.3) This analysis used data from the 17 January 2019 datacut. Data are presented as n (%) TEAE treatment-emergent adverse event, SAE serious adverse event According to investigator’s assessment, with severity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 [31] Table 5 Incidence of pre-defined treatment-emergent adverse events with concomitant use of statins that are breast cancer resistance protein sub- strates (safety population) TEAE (preferred term) Patients with TEAE Darolutamide (n = 280) Placebo (n = 171) Any TEAE 24 (8.6) 6 (3.5) Hepatobiliary disorders 3 (1.1) 0  Hyperbilirubinemia 3 (1.1) 0 Investigations 20 (7.1) 5 (2.9)  Blood creatinine increased 10 (3.6) 5 (2.9)  Aspartate aminotransferase increased 8 (2.9) 0  Blood bilirubin increased 5 (1.8) 0  Alanine aminotransferase increased 4 (1.4) 0  Blood lactate dehydrogenase increased 2 (0.7) 0  Blood alkaline phosphatase increased 1 (0.4) 0 Musculoskeletal and connective tissue disorders 1 (0.4) 1 (0.6)  Muscular weakness 1 (0.4) 1 (0.6) Renal and urinary disorders 1 (0.4) 0  Renal impairment 1 (0.4) 0 This analysis used data from the 19 November 2018 datacut. Data are presented as n (%) TEAE treatment-emergent adverse event 536 N. Shore et al. Table 6 Examples of potential drug–drug interactions between enzalutamide, apalutamide, or darolutamide and concomitant medications A. Effects of enzalutamide, apalutamide, or darolutamide on the exposure of CYP enzyme or transporter substrates Enzyme/transporter Apalutamide Enzalutamide Darolutamide Examples of drugs [4, 29, 30, 32, 33] [13, 14] [11, 12] [23] Effect on substrate exposure CYP3A4 Analgesics: fentanyl, oxycodone Anticoagulants: rivaroxaban Antihypertensives / CV agents: amlodipine, amiodarone, dronedarone, felodipine, nisoldipine, ranolazine Antiplatelet agents: ticagrelor CNS drugs: alprazolam, buspirone, donepezil, midazolam, quetiapine, triazolam Lipid-modifying agents: lovastatin, simvastatin Urological agents: avanafil, darifenacin, dutasteride, oxybutynin, solifenacin, tamsulosin, tolterodine, vardenafil CYP2C9 Anticoagulants: warfarin Antidiabetics: glimepiride Antihypertensives: losartan Anti-inflammatories: celecoxib Lipid-modifying agents: fluvastatin CYP2C19 Beta-blockers: propanolol CNS drugs: diazepam PPIs: lansoprazole, omeprazole, rabeprazole UGT Analgesics: buprenorphine Antiretrovirals: zidovudine CNS drugs: morphine Anti-epileptics: valproic acid P-gp Analgesics: fentanyl, oxycodone Anticoagulants: dabigatran etexilate CV agents: digoxin, ranolazine BCRP CV agents: furosemide Lipid-modifying agents: atorvastatin, rosuvastatin, fluvastatin DMARDs: sulfasalazine OATP1B1 Hypertension/CV agents: atenolol Lipid-modifying agents: atorvastatin, pitavastatin, rosuvastatin, pravastatin Antidiabetics: glyburide, nateglinide, repaglinide B. Effects of CYP enzyme or drug transporter inhibitors and inducers on the exposure of enzalutamide, apalutamide, or darolutamide Enzyme/transporter Apalutamide Enzalutamide Darolutamide Examples of drugs [4, 29, 30, 32, 33] [13, 14] [11, 12] [23] Effect on exposure of apalutamide, enzalutamide or darolutamide Inhibitors CYP3A4 Antibiotics: clarithromycin, erythromycin Antifungals: itraconazole, ketoconazole Antihypertensives: diltiazem, verapamil Antiretrovirals: indinavir, nelfinavir, ritonavir CYP2C8 Antibiotics (systemic): trimethoprim Antiplatelet agents: clopidogrel, gemfibrozil Inducers CYP3A4 Anti-epileptics: carbamazepine, phenobarbital Antibiotics (systemic): rifampicin P-gp Anti-epileptics: carbamazepine, phenobarbital Antibiotics (systemic): rifampicin Systemic corticosteroids: dexamethasone Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 537 Table 6 (continued) Blue symbols are supported by clinical data, orange symbols are supported by in vitro data only AR androgen receptor, BCRP breast cancer resistance protein, CNS central nervous system, CV cardiovascular, CYP cytochrome P450, DDI drug–drug interaction, DMARD disease-modifying antirheumatic drug, EMA European Medicines Agency, FDA Food and Drug Administration, mCRPC metastatic castration-resistant prostate cancer, OATP organic anion-transporting peptide, P-gp P-glycoprotein, PPI proton pump inhibi- tor, SPC summary of product characteristics, UGT ur idine 5′-diphospho-glucuronosyltransferase Indicates risk of increased exposure; strong effect, with avoidance or substitution of coadministered drug recommended Indicates risk of decreased exposure and loss of efficacy; strong effect, with avoidance or substitution of coadministered drug recommended ↑ Indicates risk of increased exposure; weak effect, with caution and/or dose adjustment based on efficacy/tolerability recommended ↓ Indicates risk of decreased exposure; weak effect, with caution and/or dose adjustment based on efficacy/tolerability recommended ‘–’ Indicates data indicate no clinically significant effect Based on the EMA SPC for XTANDI (UGT substrates are not mentioned in the US PI) [11, 12] Avoid concomitant use with drugs that are BCRP substrates where possible; if used together, monitor patients more frequently for adverse reac- tions and consider dose reduction of BCRP substrate drug [23] If combined P-gp and strong CYP3A4 inhibitors are used together, monitor patients more frequently for darolutamide adverse reactions [23] Note that the information for XTANDI differs between the US PI and the EMA SPC [11, 12] Avoid concomitant use of combined P-gp and strong or moderate CPY3A4 inducers [23] Author Contributions CZ, RF, HG, MK, BP, OP, GB, OP, and IK con- in our analyses. Our identification of potential DDIs is not tributed to the conception and design of the study; NS, CZ, RF, HG, exhaustive—DDIs may occur with drugs not investigated KG, MK, BP, OPr, GB, OP, TLT, IK, FV, MS, and KF contributed to in preclinical and phase I studies to date, and DDIs may be the acquisition of data; NS, RF, HG, BP, GB, OP, TLT, IK, FV, MS, specific to individual drugs within a drug class. The safety and KF contributed to the analysis and interpretation of the data; NS and KF drafted the manuscript; BP and JM carried out the statistical profile of darolutamide will continue to be monitored in analysis; all authors provided critical revision of the manuscript for post-marketing studies. important intellectual content. Data Sharing Availability of the data underlying this publication will 5 Conclusions be determined according to Bayer’s commitment to the EFPIA/PhRMA “Principles for responsible clinical trial data sharing.” This pertains to scope, timepoint, and process of data access. As such, Bayer commits These analyses of ARAMIS data suggest a limited poten- to sharing upon request from qualified scientific and medical research- tial for clinically relevant DDIs between darolutamide and ers patient-level clinical trial data, study-level clinical trial data, and comedications frequently used to treat age-related comorbid- protocols from clinical trials in patients for medicines and indications approved in the United States (US) and European Union (EU) as nec- ities in patients with nmCRPC (Table 6). Interactions noted essary for conducting legitimate research. This applies to data on new with the combined BCRP and OATP substrate rosuvastatin medicines and indications that have been approved by the EU and US did not seem to translate into increased AEs in the ARAMIS regulatory agencies on or after 1 January 2014. Interested researchers trial to date. Determining the risk–benefit balance of andro- can use http://www.clini calst udyda tareq uest.com to request access to anonymized patient-level data and supporting documents from clini- gen receptor-targeted therapies for patients with nmCRPC cal studies to conduct further research that can help advance medi- who receive multiple comedications is important for optimal cal science or improve patient care. Information on the Bayer criteria management. The findings presented here provide additional for listing studies and other relevant information is provided in the information for clinical decision making. Study sponsors section of the portal. Data access will be granted to anonymized patient-level data, protocols, and clinical study reports after approval by an independent scientific review panel. Bayer is Acknowledgements The authors thank the patients, their families, and not involved in the decisions made by the independent review panel. all investigators involved in this study. The authors wish to acknowl- Bayer will take all necessary measures to ensure that patient privacy edge the contribution of Christian Kappeler and Marie-Aude Le Berre is safeguarded. for statistical analysis performed from the ARAMIS study. Medical writing support, including assisting authors with the development of the outline and initial draft and incorporation of comments was Compliance with Ethical Standards provided by Tamsin Williamson, and editorial support, including for- matting, proofreading, and submission was provided by Annabel Ola Funding This work was supported by Bayer HealthCare and Orion and Beth King all of Scion Medica, London, supported by Bayer AG Pharma. according to Good Publication Practice guidelines (http://annal s.org/ aim/article/24248 69/good-publi catio n-pr actice-commu nicat ing-com pa ny-spons ored-medic al-resea rch-gpp3). The study sponsors Bayer AG Conflict of interest Dr. Shore reports personal fees from Ferring, Bay- and Orion Pharma were involved in the study design, collection, anal- er, Amgen, Janssen, Dendreon, Tolmar, Astellas, Pfizer, AstraZeneca, ysis and interpretation of data. However, ultimate responsibility for Genentech/Roche, Myovant Sciences, Merck, AstraZeneca, Bristol opinions, conclusions, and data interpretation lies with the authors. Meyers Squibb, and Nymox outside the submitted work. Drs. Zurth, 538 N. Shore et al. Fricke, Gieschen, Graudenz, Ploeger, Prien, Borghesi, Petrenciuc, prostate cancer. N Engl J Med. 2018;378(26):2465–74. https://doi. and Kuss report employment by and stock ownership in Bayer. Dr. org/10.1056/NEJMo a1800 536. Koskinen reports employment by and stock ownership in Orion. Dr. 9. Smith MR, Saad F, Chowdhury S, Oudard S, Hadaschik BA, Graff Moss reports personal fees from Akari, AstraZeneca, Bayer, Carrick JN, et al. Apalutamide treatment and metastasis-free survival in Therapeutics, Debiopharm, Orphazym, Proveca, Richmond Pharma- prostate cancer. N Engl J Med. 2018;378(15):1408–18. https :// cology, and the University of Leicester outside the submitted work. doi.org/10.1056/NEJMo a1715 546. Dr. Tammela reports personal fees from Janssen, and grants and per- 10. Benoist GE, van Oort IM, Smeenk S, Javad A, Somford DM, sonal fees from Bayer, Lidds AB, and Astellas, outside the submitted Burger DM, et  al. Drug-drug interaction potential in men work. Dr. Verholen reports employment by Bayer. Dr. Smith reports treated with enzalutamide: mind the gap. Br J Clin Pharmacol. personal fees from Amgen, Astellas, Bayer, Clovis, Gilead, Janssen, 2018;84(1):122–9. https ://doi.org/10.1111/bcp.13425 . Lilly, Novartis, and Pfizer, outside the submitted work. Dr. Fizazi re- 11. Astellas Pharma US Inc. Xtandi (enzalutamide) US prescribing ports personal fees from Amgen, Astellas, AstraZeneca, Bayer, Clovis, information. 2018. https ://www .acces sdat a .fda.gov/dr ugs atfda Curevac, ESSA, Janssen, Orion Pharma, Roche/Genentech, and Sanofi _docs/label /2018/20341 5s014 lbl.pdf. Accessed 11 June 2019. outside the submitted work. 12. European Medicines Agency. Summary of product characteristics: XTANDI. 2019. https: //www.ema.europa .eu/en/docume nts/produ Informed consent Informed consent was obtained from all individual ct-informatio n/xt andi-epar -product-inf ormatio n_en.pdf . Accessed participants in the study. 11 June 2019. 13. European Medicines Agency. Summary of product characteristics: ERLEADA. 2019. h t t p s : / / w w w . e m a . e u r o p a . e u / e n / d o c u m e n t s / Open Access This article is distributed under the terms of the Crea- produ ct-infor matio n/erlea da-epar-produ ct-infor matio n_en.pdf. tive Commons Attribution-NonCommercial 4.0 International License Accessed 11 June 2019. (http://creat iveco mmons .org/licen ses/by-nc/4.0/), which permits any 14. Janssen Ortho LLC. Erleada (apalutamide) US prescribing infor- noncommercial use, distribution, and reproduction in any medium, mation. 2018. https ://www.acces sdata .fda.gov/drugs atfda _docs/ provided you give appropriate credit to the original author(s) and the label /2018/21095 1s000 lbl.pdf. Accessed 22 July 2019. source, provide a link to the Creative Commons license, and indicate 15. European Medicines Agency. Xtandi CHMP assessment report. if changes were made. 2013. http://www.ema.europa.eu/docs/en_GB/docum ent_libr ar y/ EPAR_-_Public_asses sment _r eport/human /00263 9/W C50014499 8.pdf. Accessed 1 Oct 2018. 16. European Medicines Agency. Erleada CHMP assessment report. References 2018. https://www .ema.europa.eu/en/docum ents/asses sment -r epor t/erlea da-epar-publi c-asses sment -repor t_en.pdf. Accessed 1 Oct 1. National Cancer Institute. Surveillance, epidemiology, and end results program. Cancer stat facts: prostate cancer. 2019. https :// 17. Fizazi K, Smith MR, Tombal B. Clinical development of daro- seer.cancer .gov/statfacts/html/pr ost.html . Accessed 16 May 2019. lutamide: a novel androgen receptor antagonist for the treatment 2. Francini E, Gray KP, Shaw GK, Evan CP, Hamid AA, Perry of prostate cancer. Clin Genitourin Cancer. 2018;16(5):332–40. CE, et al. Impact of new systemic therapies on overall survival https ://doi.org/10.1016/j.clgc.2018.07.017. of patients with metastatic castration-resistant prostate can- 18. US Food and Drug Administration. FDA approves darolutamide cer in a hospital-based registry. Prostate Cancer Prostatic Dis. for non-metastatic castration-resistant prostate cancer. 2019. https 2019;22(3):420–7. https://doi.or g/10.1038/s41391-018-0121-2 . ://www.fda.gov/drugs/ resour ces-inform ation- approv ed-drugs/ fda- 3. Basch E, Autio K, Ryan CJ, Mulders P, Shore N, Kheoh T, et al. appro ves-darol utami de-non-metas tatic -castr ation -resis tant-prost Abiraterone acetate plus prednisone versus prednisone alone in ate-cance r. Accessed 31 July 2019. chemotherapy-naive men with metastatic castration-resistant 19. Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, prostate cancer: patient-reported outcome results of a randomised et al. Darolutamide in nonmetastatic, castration-resistant pros- phase 3 trial. Lancet Oncol. 2013;14(12):1193–9. https ://doi. tate cancer. N Engl J Med. 2019;380(13):1235–46. https ://doi. org/10.1016/S1470 -2045(13)70424 -8. org/10.1056/NEJMo a1815 671. 4. Del Re M, Fogli S, Derosa L, Massari F, De Souza P, Crucitta S, 20. Zurth C, Graudenz K, Denner K, Vairlein M, Korjamo T, Fricke et al. The role of drug-drug interactions in prostate cancer treat- R, et al. Drug-drug interaction of darolutamide with cytochrome ment: focus on abiraterone acetate/prednisone and enzalutamide. P450 and P-glycoprotein substrates: results from clinical and Cancer Treat Rev. 2017;55:71–82. https ://doi.or g/10.1016/j. in vitro studies. San Francisco: ASCO Genitourinary Cancers ctrv.2017.03.001. Symposium; 2019. 5. Stepney R, Lichtman SM, Danesi R. Drug-drug interactions in 21. Zurth C, Koskinen M, Fricke R, Prien O, Korjamo T, Graudenz older patients with cancer: a report from the 15th Conference of K, et al. Drug–drug interaction potential of darolutamide: in vitro the International Society of Geriatric Oncology, Prague, Czech and clinical studies. Eur J Drug Metab Pharmacokinet. 2019. https Republic, November 2015. Ecancermedicalscience. 2016;10:611. ://doi.org/10.1007/s1331 8-019-00577 -5. https ://doi.org/10.3332/ecanc er.2016.611. 22. R (Version 3.1.1) Development Core Team. R: a language and 6. Bohnert T, Patel A, Templeton I, Chen Y, Lu C, Lai G, et al. Eval- environment for statistical computing. Vienna: R Foundation for uation of a new molecular entity as a victim of metabolic drug- Statistical Computing; 2008. drug interactions-an industry perspective. Drug Metab Dispos. 23. Bayer HealthCare Pharmaceuticals Inc. Nubeqa (darolutamide) 2016;44(8):1399–423. https ://doi.org/10.1124/dmd.115.06909 6. US prescribing information. 2019. h t t p s : / / w w w. a c c e s s d a t a 7. Guthrie B, Makubate B, Hernandez-Santiago V, Dreischulte T. .fda.gov/drugs atfda _docs/label /2019/21209 9Orig 1s000 lbl.pdf. The rising tide of polypharmacy and drug-drug interactions: popu- Accessed 31 July 2019. lation database analysis 1995-2010. BMC Med. 2015;13:74. https 24. Benoist GE, van Oort IM, Burger DM, Koch BCP, Mehra N, van ://doi.org/10.1186/s1291 6-015-0322-7. Erp NP. The combination of enzalutamide and opioids: a painful 8. Hussain M, Fizazi K, Saad F, Rathenborg P, Shore N, Ferreira U, pitfall? Eur Urol. 2019;75(2):351–2. https ://doi.org/10.1016/j. et al. Enzalutamide in men with nonmetastatic, castration-resistant eurur o.2018.09.011. Clinically Relevant Drug–Drug Interactions with Darolutamide in the Phase III ARAMIS Trial 539 25. US Center for Drug Evaluation and Research. NDA/BLA clinical 29. Hansten PD, Horn JR. Top 100 drug interactions 2018. A guide pharmacology and biopharmaceutics review NDA 203415 Xtandi to patient management. 19th ed. LLP: H&H Publications; 2018. (enzalutamide). 2012. https://www .accessdat a.fda.go v/drugsatfda 30. US Food and Drug Administration. Drug development and drug _docs/nda/2012/203415Or ig1s000 ClinP har mR.pdf . Accessed 26 interactions: table of substrates, inhibitors and inducers. 2017. Sept 2018.https:/ /www.fda.gov/drugs/d rug-interac tions -labelin g/drug-devel 26. US Center for Drug Evaluation and Research. NDA/BLA multi- o p me n t - an d - d r ug - i n te r a c t io n s - t a b l e - s u bs t r a t e s - i nh i b i t o r s - a n d- disciplinary review and evaluation NDA 210951 Erleada (apalu-induc ers. Accessed 15 Aug 2019. tamide). 2018. https://www .accessdat a.fda.go v/drugsatfda _docs/ 31. National Cancer Institute. Common Terminology Criteria for nda/2018/21095 1Orig 1s000 Multi disci pline R.pdf. Accessed 26 Adverse Events, version 4.03. Bethesda, MD: Cancer Therapy Sept 2018. Evaluation Program. 2010. https ://ctep.cance r .gov/pr o t o colde 27. Pollock Y, Smith M, Saad F, Chowdhury S, Oudard S, Hadaschik velop ment/elect r onic _appli catio ns/ctc.htm. Accessed 16 Sept B, et al. Predictors of falls and fractures in patients (pts) with 2019. nonmetastatic castration-resistant prostate cancer (nmCRPC) 32. De Gregori S, De Gregori M, Ranzani GN, Allegri M, Minella C, treated with apalutamide (APA) plus ongoing androgen depriva- Regazzi M. Morphine metabolism, transport and brain disposi- tion therapy (ADT). J Clin Oncol. 2019;37(15_suppl):5025. https tion. Metab Brain Dis. 2012;27(1):1–5. https ://doi.org/10.1007/ ://doi.org/10.1200/jco.2019.37.15_suppl .5025.s1101 1-011-9274-6. 28. Kidney Disease: Improving Global Outcomes (KDIGO) CKD 33. Ge S, Tu Y, Hu M. Challenges and opportunities with predicting Work Group. KDIGO 2012 clinical practice guideline for the in vivo phase II metabolism via glucuronidation from in vitro data. evaluation and management of chronic kidney disease. Kidney Curr Pharmacol Rep. 2016;2(6):326–38. https://doi.or g/10.1007/ Int. 2012;3:1–150.s4049 5-016-0076-8. Affiliations 1 2 2 2 2 3 Neal Shore  · Christian Zurth  · Robert Fricke  · Hille Gieschen  · Kristina Graudenz  · Mikko Koskinen  · 2 4 2 2 2 5 2 Bart Ploeger  · Jonathan Moss  · Olaf Prien  · Gustavo Borghesi  · Oana Petrenciuc  · Teuvo L. Tammela  · Iris Kuss  · 2 6 7 Frank Verholen  · Matthew R. Smith  · Karim Fizazi 1 5 Carolina Urologic Research Center, 823 82nd Parkway, Suite Tampere University Hospital and Tampere University, B, Myrtle Beach, SC 29572, USA Tampere, Finland 2 6 Bayer AG, Berlin, Germany Massachusetts General Hospital Cancer Center, Boston, USA 3 7 Orion Corporation Orion Pharma, Espoo, Finland Institut Gustave Roussy, Université Paris-Sud, Villejuif, France BAST Inc. Ltd., Loughborough, UK

Journal

Targeted Oncology – Springer Journals

Published: Sep 30, 2019

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