Drug–Drug Interaction Potential of Darolutamide: In Vitro and Clinical Studies

Darolutamide is a novel androgen receptor (AR) antagonist recently approved for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) [1‐3]. In phase I and II clinical studies in metastatic castration-resistant prostate cancer (mCRPC), darolutamide demonstrated significant antitumor activity and a good safety profile [4, 5]. Significant improvement in metastasis-free survival was demonstrated for darolutamide compared with placebo, with a safety profile similar to that of androgen deprivation therapy alone in the phase III ARAMIS trial in patients with nmCRPC [6]. A phase III trial (ARASENS) in metastatic hormone-sensitive prostate cancer is ongoing (NCT02799602).

Darolutamide is structurally distinct from other AR inhibitors [7] and comprises two pharmacologically active diastereomers, (S,R)-darolutamide and (S,S)-darolutamide. The major metabolite, keto-darolutamide, exhibits similar pharmacologic activity in vitro [1, 7], but has a ~ 40-fold lower fraction unbound in human plasma compared with darolutamide [3], and it is therefore of lower relevance in terms of mediating efficacy and potential drug interactions. Nonclinical studies have demonstrated that darolutamide acts by potently blocking AR signaling and inhibiting testosterone-induced nuclear translocation of AR in prostate cancer cells, leading to impaired tumor growth and survival [7]. In contrast to AR inhibitors currently approved for the treatment of nmCRPC, darolutamide shows low penetration of the blood-brain barrier in rodents, which may explain the observed lower propensity for central nervous system (CNS) effects compared with the approved AR inhibitors, and does not increase serum testosterone levels [6‐9].

As patients with nmCRPC are typically older men with multiple comorbidities requiring concomitant medications [10], it is important to evaluate the drug–drug interaction (DDI) potential of novel anticancer therapies. This information is also requested by health authorities worldwide, including the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) [11‐13]. Hence, in vitro and phase I clinical evaluations have been conducted to elucidate whether darolutamide is a clinically significant substrate, inhibitor or inducer for relevant drug-metabolizing enzymes or transporters.

As a novel agent intended for use in men with prostate cancer, a population with high comedication use for comorbidities [10, 17], it is important to evaluate the risk of clinically relevant DDIs with darolutamide. In the phase III ARAMIS study in men with nmCRPC, > 98% of patients were receiving at least one concomitant medication, and multiple medication use was common [18], consistent with other reports [19].

In vitro testing indicated that oxidative metabolism of darolutamide is predominantly catalyzed by CYP3A4. Other metabolizing enzymes (e.g., UGT) are involved, but the level of contribution renders inhibitors or inducers of these enzymes unlikely to result in clinically relevant DDIs with darolutamide. Consistent with the observation that darolutamide is a CYP3A4 substrate, phase I clinical data showed that darolutamide exposure was increased 1.7-fold when co-administered with the strong CYP3A4 inhibitor itraconazole 200 mg/day. However, the increase in darolutamide AUC is low when compared with increases of ≥ 5-fold when a sensitive CYP3A4 substrate (e.g., midazolam, lovastatin) is co-administered with a strong CYP3A4 inhibitor [20‐22]. When administered at a low dose of 100 mg/day for 4 days, itraconazole was reported to increase lovastatin AUC 15-fold [20]. Hence, the degree of increased exposure for darolutamide suggests weak sensitivity to CYP3A4 inhibition. Consistent with this observation, data from a covariate analysis within a population pharmacokinetic model based on the phase III ARAMIS clinical trial indicated that co-administration of CYP3A4 inhibitors, which were taken on the same day as darolutamide blood sampling, had no significant impact on the pharmacokinetics of darolutamide [18].

Preclinical data indicated that darolutamide is likely to be a substrate for the efflux transporters P-gp and BCRP. Consequently, strong inhibitors of P-gp or BCRP may be expected to alter the pharmacokinetics of darolutamide. As itraconazole inhibits P-gp and BCRP as well as CYP3A4, the 1.7-fold increase in darolutamide exposure observed with co-administered itraconazole may also be attributed to the effects of P-gp and BCRP inhibition. However, given the observed saturation of P-gp-mediated darolutamide transport in a Caco-2 cell system at test concentrations (< 10 µM) far below clinically relevant intestinal concentrations with darolutamide 600 mg [270 µM (data on file)], it is considered unlikely that P-gp would limit darolutamide absorption or that P-gp inhibition contributed to the observed effect. Furthermore, in the covariate analysis conducted during development of the population pharmacokinetics model, neither P-gp nor BCRP inhibitors had a significant influence on the pharmacokinetics of darolutamide [18].

As a substrate for CYP3A4 darolutamide also has the potential to be affected by CYP3A4 inducers. This was demonstrated when co-administration of a strong CYP3A4 inducer, rifampicin, led to a 72% reduction in darolutamide exposure in healthy volunteers. This level of AUC reduction suggests that darolutamide may be moderately sensitive to CYP3A4 induction. However, it is important to note that few drugs are strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin), and these agents are not often used in patients with prostate cancer [10, 17, 23], so co-administration with darolutamide could easily be avoided.

The impact of darolutamide on the pharmacokinetics of other drugs has been investigated extensively. In vitro findings suggested that darolutamide may inhibit CYP2C9, CYP2C19 and CYP2D6 activity, with no or minimal inhibitory effects on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2E1 and CYP3A4. The lowest in vitro IC₅₀ values were observed for the inhibition of CYP2C9, suggesting that this is the most sensitive CYP enzyme. However, a mechanistic modeling assessment of DDI risk that considers the clinically observed absorption rate of darolutamide indicated that darolutamide is not an inhibitor of CYP2C9 in vivo and is therefore unlikely to inhibit other CYP enzymes [13]. Similarly, in vitro data suggested that darolutamide may induce CYP3A4 metabolism, but clinical data revealed darolutamide to have only a weak inducing effect on clearance of the sensitive CYP3A4 substrate, midazolam, leading to a 29% decrease in exposure [24]. This is not considered clinically relevant in line with label information for other sensitive CYP3A4 substrates such as tacrolimus, for which frequent monitoring and dose adjustment are only recommended with co-administration of strong, but not moderate or weak, CYP3A4 inducers [25].

Preclinical evaluation has shown that darolutamide may have the potential to inhibit some drug transporters: intestinal efflux transporters (P-gp, BCRP), hepatic uptake transporters (OATP1B1, OATP1B3) and the active renal elimination transporter OAT3. However, in a phase I clinical study, darolutamide demonstrated no clinically relevant interaction with the P-gp transporter substrate. In another clinical study, co-administration of darolutamide demonstrated a substantial effect on the pharmacokinetics of rosuvastatin, a substrate for BCRP, OATP1B1, OATP1B3 and OAT3 [22], increasing exposure approximately fivefold. Nevertheless, times to reach peak plasma concentration and elimination rate were not affected, indicating that total plasma clearance was unchanged. Given a fraction absorbed (f_a) of rosuvastatin of 0.5 [26], BCRP inhibition was expected to only lead to a maximum exposure increase of twofold [20]. However, it was noted that rosuvastatin exposure is reduced upon administration with food [16], likely because of a reduction in f_a. The observed exposure value of rosuvastatin in the current study is only 34% of the reported AUC_(0–24) value of 19.2 h µg/l following a single dose of 5 mg rosuvastatin to healthy subjects in the fasted condition [27]. This opens up the possibility of a larger dynamic range for exposure increase as a result of BCRP inhibition. In addition, the darolutamide-mediated inhibition of hepatic BCRP, OATP1B1 and OATP1B3 may have contributed to the observed effect. It is, however, difficult to attribute the exact contributions of these transporters and interactions to the overall effect. Taking the unchanged elimination rate of rosuvastatin into account, the exposure increase observed during concomitant darolutamide administration seems to be mainly due to absorption changes of rosuvastatin or the effect of darolutamide on BCRP inhibition. Renal clearance of rosuvastatin remained unchanged after dosing with darolutamide, indicating no clinically relevant effect of darolutamide on OAT3, consistent with in vitro results. Based on current knowledge, the observed effect likely constitutes a worst case scenario for co-administered drugs that are sensitive BCRP and OATP substrates.

In the phase I clinical studies in healthy subjects, darolutamide was safe and well tolerated when administered alone or in combination with single oral doses of dabigatran etexilate, midazolam or rosuvastatin or with multiple doses of itraconazole or rifampicin. There were no clinically relevant changes in the safety profiles of darolutamide or the comedications when administered concomitantly.

Taken together, these in vitro and clinical studies demonstrate that darolutamide has a low potential for DDIs, except for BCRP and probably OATP substrates. Statins are often BCRP and OATP substrates and were used by approximately 30% of patients with nmCRPC in the phase III ARAMIS study. In these patients, there were no significant differences in AEs between groups in patients receiving darolutamide or placebo in addition to usual care despite equally high use of concomitant medications in each group [18]. In a safety subgroup analysis in statin users and non-users, no imbalance between the darolutamide and placebo arms was observed that might be attributed to DDIs between darolutamide and statins [28]. While darolutamide has shown low DDI potential, AR inhibitors approved for the treatment of nmCRPC, enzalutamide and apalutamide have demonstrated the potential for DDIs with a range of medications that may require therapy modification, including anticoagulants and opioid analgesics (Table S6) [10, 29‐31]. These AR inhibitors have demonstrated DDI potential with metabolizing enzymes as well as efflux and hepatic uptake drug transporters [32‐34].

In vitro studies indicated that darolutamide has low or no inhibitory effects on metabolizing enzymes but the potential for a range of other DDIs. However, in confirmatory phase I clinical trials investigating the DDI potential of darolutamide, only weak effects were observed for co-administration of darolutamide with CYP3A4 and P-gp substrates. Inhibition of BCRP and hepatic uptake transporters was reported in the phase I study of darolutamide co-administered with rosuvastatin, but no clinically relevant impact on the AE profile was observed in the pivotal phase III ARAMIS study.

In conclusion, darolutamide is a substrate for a variety of absorption and/or elimination pathways (CYP3A4, several UGTs, P-gp and BCRP) and, at therapeutic concentrations, has few inhibitory or inducing interactions with other compounds, with increased exposure of BCRP and probably OATP substrates being the main interaction of note [3]. Therefore, darolutamide is unique among AR-targeted therapies in having demonstrated a low potential for clinically relevant DDIs. Minimizing DDIs is expected to reduce complications arising from polypharmacy when treating nmCRPC.