Clinical Pharmacokinetics and Pharmacodynamics of the Next Generation Androgen Receptor Inhibitor—Darolutamide

Prostate cancer is the second most common cancer in men worldwide and the fifth leading cause of cancer-related deaths. Although the mortality rate of prostate cancer is declining, its incidence continues to increase in most countries [1]. After the initial hormone-sensitive stage of prostate cancer, most patients develop castration-resistant prostate cancer (CRPC), which refers to tumors that are progressing despite castrate testosterone levels (< 50 ng/dL) [2]. Without evidence of distant metastases on conventional imaging modalities, the disease is referred to as non-metastatic CRPC (nmCRPC) and with distant metastases, it is referred to as metastatic CRPC (mCRPC) [3, 4]. The main goal of initiation of treatment in the nmCRPC setting is to delay time to onset of metastatic disease, which is associated with cancer-related symptoms, quality of life deterioration, and poor prognosis [4, 5].

In the last two decades, treatment options for CRPC have to a great extent improved from solely docetaxel chemotherapy to a wide range of anticancer drugs including multiple next-generation androgen receptor signaling inhibitors (ARSIs; abiraterone acetate, apalutamide, enzalutamide, and darolutamide) [6]. Apalutamide, enzalutamide, and darolutamide all act by competitively inhibiting the binding of androgens to the androgen receptor (AR), preventing AR nuclear translocation, and inhibiting AR mediated transcription of tumor genes, thereby inhibiting tumor growth [7‐13]. Abiraterone acetate acts through a different mechanism of action. Abiraterone is a selective inhibitor of the cytochrome p450 (CYP) 17 enzyme (CYP17), which is a crucial enzyme in androgen biosynthesis. Inhibition of this enzyme leads to undetectable androgen levels in serum and tumor tissue [14, 15].

In phase III clinical trials, apalutamide, enzalutamide, and darolutamide all demonstrated significantly longer median metastasis-free survival (mMFS) compared with placebo in patients with nmCRPC [5, 16, 17]. In addition, enzalutamide and abiraterone acetate prolonged median progression-free survival (PFS) and median overall survival (mOS) in patients with mCRPC [18‐21]. Furthermore, recent phase III clinical trials have demonstrated the efficacy of apalutamide or enzalutamide in combination with ADT for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and the efficacy of darolutamide or abiraterone in combination with androgen deprivation therapy (ADT) and docetaxel [22‐25].

Despite the effectiveness of the addition of ARSIs to ADT in different stages of prostate cancer, agents of this therapeutic group also have drawbacks. Both apalutamide and enzalutamide have a high potential for drug–drug interactions (DDI) as they induce the activity of several metabolic enzymes [12, 13, 26]. Enzalutamide is metabolized by CYP2C8 (majorly) and CYP3A (minorly), it is a strong inducer of CYP3A4, a moderate inducer of CYP2C9, CYP2C19, and CYP2D6, and has a yet to be determined effect on several transporters. Apalutamide is metabolized by CYP2C8 and CYP3A, is a strong inducer of CYP3A4 and CYP2C19, a potential inducer of uridine diphosphate glucuronosyltransferase (UGT), and a weak inducer of CYP2C9, breast cancer resistant protein (BCRP), P-glycoprotein (P-gp), and organic anion transporting polypeptides (OATP) 1B1 [12, 13, 26]. In addition, the use of apalutamide and enzalutamide is associated with a higher incidence of typical central nervous system (CNS) adverse effects (AEs), such as fatigue (30% and 34%, respectively), falls (16% and 4%, respectively), and seizures (0.2% and 0.8%, respectively) [12, 13, 16, 17]. These specific AEs are probably caused by their ability to penetrate the blood–brain barrier [12, 13]. Furthermore, apalutamide is associated with a significant risk of skin rash (24%) and hypertension (25%), and enzalutamide is associated with a higher incidence of hypertension (6%) [12, 13].

Abiraterone acetate has less DDI potential and a very distinct side-effect profile. The use of abiraterone acetate is mostly associated with typical AEs due to mineralocorticoid excess such as hypertension (22%), hyperkalemia (18%), and fluid retention (23%) [15]. These AEs are caused by decreased glucocorticoid production, and an upregulation of steroids upstream of CYP17 inhibition; therefore, abiraterone acetate treatment should always be combined with prednisolone according to the label [27, 28]. In addition, cardiac disorders such as tachycardia, atrial fibrillation, or cardiac failure have been reported in 13% of patients treated with abiraterone acetate [15].

Darolutamide (Nubeqa^®) is structurally different from other ARSI. It is a mixture of two pharmacologically active diastereomers: (S,R)-darolutamide and (S,S)-darolutamide. The major metabolite of darolutamide, keto-darolutamide, exhibits similar in vitro activity [10]. Compared with apalutamide and enzalutamide, darolutamide has been associated with a lower incidence of CNS AEs such as fatigue (16%) and falls (4%) [5, 9, 10]. Importantly, no seizure potential was observed in either preclinical or clinical studies. Nevertheless, cardiac disorders such as cardiac arrhythmias (7%), coronary artery disease (3%), and heart failures (2%) were observed more frequently with darolutamide (12%) compared with placebo (7%) [5, 9, 10]. In contrast to other ARSIs, darolutamide is not associated with a higher incidence of hypertension compared with placebo (7% and 6%, respectively) [10].

ARSIs are registered for different stages of prostate cancer. Darolutamide and apalutamide are now registered for nmCRPC and mHSPC, enzalutamide for nmCRPC, mCRPC, and mHSPC, while abiraterone acetate is registered for mCRPC and mHSPC [8, 28‐30]. Nevertheless, ARSIs show comparable efficacy data for the treatment of different stages of prostate cancer. For this reason, other drug characteristics, such as safety profile and PK properties, should be considered when selecting the most appropriate drug for a patient. The main objective of this review is to provide an overview of the PK and pharmacodynamic (PD) properties of darolutamide. In addition, we would like to present the results of studies on potential DDIs, the involvement of drug transporters, the effects of patient characteristics on pharmacokinetics, and data on the exposure–response relationship.

Studies published before November 22, 2022, were retrieved from PubMed, EMBASE and Cochrane Library databases. The following search terms were used: 'Darolutamide' OR 'ODM201' OR 'Keto-darolutamide' OR 'Nubeqa' in combination with 'Absorption' OR 'Distribution' OR 'Blood-brain barrier' OR 'Metabolism' OR 'Biotransformation' OR 'Cytochrome p450 enzyme' OR 'CYP' OR 'Excretion' OR 'Bioavailability' OR 'Availability' OR 'Pharmacokinetics' OR 'Drug-drug interaction' OR 'Transporter' OR 'Exposure response relationship'. In addition, citation snowballing was performed to find additional eligible studies.

Our search revealed 230 publications, of which 46 were duplicates. The abstracts and full texts of each publication were screened and assessed for inclusion by one reviewer. Findings of the search were summarized and discussed with two independent reviewers. Studies were excluded for several reasons: 55 articles did not contain PK data, 56 articles were reviews without original data, 9 articles were not in English, 13 did not describe PK data in humans, 24 articles were expert opinions, commentary, or patient perspectives, and 16 articles did not contain data about darolutamide. Finally, 11 original English articles regarding the pharmacokinetics of darolutamide in humans were included in this review (Fig. 1). In addition, the most recent registration and prescribing information from the European Medicines Agency (EMA) and the United States Food and Drug Administration (US FDA) were included.

Several clinical trials have investigated the influence of different doses of darolutamide on the occurrence of AEs and/or response to treatment [7, 34, 40, 41]. In a phase I study, patients with progressive mCRPC received 200–1800 mg of darolutamide per day [34]. Darolutamide was well tolerated by patients regardless of the daily dose. In addition, no dose-limiting toxicities were observed. The maximum tolerated dose was not reached; however, doses > 1800 mg were not tested because saturation of absorption was observed at doses > 1400 mg. Patients with a history of seizures were also allowed to participate in the study [34]. No dose-dependent increase in the frequency or severity of AEs was observed in any of the clinical trials [7, 34]. Prior systemic treatment also had no effect on the occurrence of AEs [34]. Moreover, no new safety concerns were identified in follow-up studies over time [40, 41]. Although darolutamide is registered for nmCRPC, phase I and II studies only included patients with mCRPC. Nevertheless, no unsuspected AEs were reported in the ARAMIS phase III study with nmCRPC patients [5]. Overall, the clinical trials suggest that darolutamide is well tolerated by patients, with no dose-limiting toxicities or dose-dependent increase in the frequency or severity of AEs observed at clinically relevant doses.

In a phase II study investigating PSA response in mCRPC patients treated with 200 mg, 400 mg, and 1400 mg daily, anticancer activity was observed across all tested doses [34]. Nevertheless, patients who were both chemotherapy- and CYP17 inhibitor-naïve showed the best PSA response compared with patients previously treated with chemotherapy or CYP17 inhibitors. Although based only on a small number of patients, a PSA decline of at least 50% was observed in 85.7% of chemotherapy- and CYP17 inhibitor-naïve patients, in 36.4% of patients previously treated with chemotherapy, and in 6.7% of patients previously treated with CYP17 inhibitors, while being treated with 1400 mg of darolutamide daily [34]. In addition, a dose-dependent response was observed in chemotherapy- and CYP17 inhibitor-naïve patients. A PSA decline of at least 50% was observed in 85.7% of chemotherapy- and CYP17 inhibitor-naïve patients treated with 1400 mg, in 69.2% treated with 400 mg, and in 50.0% treated with 200 mg daily [34]. Similar results were observed in mCRPC patients in another study in which 83.3% of chemotherapy-naïve patients treated with 1200 mg daily experienced a PSA decline of at least 50% [35]. Darolutamide was later registered at a dose of 1200 mg daily (600 mg twice daily [BID]). A trend towards better PSA response on higher doses was also observed in a follow-up study in which chemotherapy- and CYP17 inhibitor-naïve patients responded better to 1000–1800 mg than to 200–600 mg of darolutamide daily [40]. In terms of radiological response, no clear difference was observed in mCRPC patients between the studied dose levels. Nevertheless, the highest activity was again observed in chemotherapy- and CYP17 inhibitor-naïve patients [34]. Darolutamide treatment also had a positive effect on the number of circulating tumor cells, with no clear difference in response between doses [10, 34].

In contrast, no data on dose–response relationship are available for nmCRPC patients because these patients were not included in the phase I and phase II studies and different dose levels were not tested in the phase III studies. Nevertheless, a post-hoc exploratory exposure–response analysis of the ARAMIS phase III study, where nmCRPC patients received 600 mg of darolutamide BID, indicated a flat relationship between darolutamide exposure and metastasis-free survival (MFS) [10]. This suggests that darolutamide 1200 mg daily, administered as 600 mg BID, provides maximal PSA response and MFS [10]. To conclude, darolutamide showed a dose-dependent PSA response in mCRPC patients who were both chemotherapy- and CYP17 inhibitor-naïve, with the best response observed in patients treated with 1000 mg daily or more. With regard to nmCRPC patients, no dose–response data are available; however, it is suggested that there is no exposure–response relationship in this early state of PC at the registered dose. This is in line with the observation that CRPC gets increasingly less sensitive in more advanced stages of disease as has been shown for other ARSIs [42].

In vitro studies suggest that darolutamide is a substrate for CYP3A4 enzyme and P-gp and BCRP efflux transporters at clinically relevant intestinal concentrations (Table 2) [36]. Their involvement in the disposition of darolutamide has been demonstrated in clinical DDI studies with itraconazole and rifampicin [39]. Darolutamide exposure (AUC_{72 h}) and C_max increased 1.7- and 1.4-fold, respectively, when co-administered with itraconazole, a strong CYP3A4, P-gp, and BCRP inhibitor [39]. It is stated that no clinically relevant DDI is expected when darolutamide is combined with selective CYP3A4, P-gp, or BCRP inhibitors; however, concomitant use of strong CYP3A4 and P-gp inhibitors could increase darolutamide exposure and increase the risk for AEs [9, 10]. Because most CYP3A inhibitors also affect P-gp transport, it is unlikely that known CYP3A inhibitors do not affect darolutamide exposure [43]. Therefore, it is recommended that patients treated with strong CYP3A inhibitors be monitored more closely for the development of AEs and the dose adjusted if necessary. In another DDI study, darolutamide was co-administered with a strong CYP3A4 and P-gp inducer, rifampicin. Rifampicin use resulted in a 72% decrease in darolutamide exposure (AUC_{72 h}) and a 52% decrease in C_max, indicating that darolutamide is moderately sensitive to CYP3A4 induction [39]. Based on these data, concomitant use of moderate and strong CYP3A4 inducers and P-gp inducers is not recommended by the EMA unless there is no therapeutic alternative and should be avoided according to the FDA [9, 10]. Fortunately, only a few drugs are strong CYP3A4 inducers, and they are rarely used in patients with PC [39]. In addition, a post-hoc analysis of the ARAMIS phase III study showed that commonly used concomitant drugs did not significantly affect darolutamide exposure [44]. Nevertheless, study populations generally do not represent the real-world population, in which patients are often treated with more drugs due to comorbidities, making this post-hoc analysis of little value in daily clinical practice [44].

Darolutamide is also a substrate for UGT1A9, 1A1, and 1A3 according to in vitro studies [10]. No clinical DDI studies with UGT isoform-selective inhibitors were requested since UGT enzymes are responsible for < 25% of darolutamide elimination and therefore no clinically relevant effect of perpetrators of these enzymes is expected [10]. In a population PK analysis, the hypothesis of little effect was supported by showing only a 1.2-fold increase in darolutamide exposure (AUC_{72 h}) when used concomitantly with UGT1A9 inhibitors [10]. For this reason, it is suggested that darolutamide may be used together with UGT1A9 inhibitors [10].

In vitro, darolutamide, its diastereomers, and keto-darolutamide had little inhibitory or no effect on the activity of CYP enzymes [39]. It was shown that they all exhibited a concentration-dependent induction of CYP3A4 enzymatic activity. An increase in CYP3A4 enzymatic activity of up to 5.3- and 5.4-fold was observed for darolutamide and its diastereomers, and keto-darolutamide, respectively [39]. However, this pronounced in vitro effect was not confirmed in a clinical DDI study with the sensitive CYP3A4 substrate midazolam, where only a 29% decrease in midazolam exposure and a 32% decrease in C_max of midazolam was shown in combination with darolutamide (Table 3) [39]. This decrease is not considered clinically relevant and suggests that darolutamide has only weak inducing potential [39]. It is therefore concluded that darolutamide may be used concomitantly with CYP substrates [10].

Darolutamide demonstrated in vitro inhibitory potential for BCRP, OAT3, Multidrug And Toxic Compound Extrusion (MATE) 2K, P-gp, OATP1B1, MATE1, and OATP1B3 transporters in descending order of relevance. Keto-darolutamide showed similar inhibitory effects with the exception of OAT3-mediated uptake [9, 39]. Nevertheless, no P-gp inhibitory potential of darolutamide was observed in a clinical DDI study with the P-gp substrate dabigatran, suggesting that darolutamide may be co-administered with P-gp substrates [39]. Another clinical DDI study investigated the influence of darolutamide on the exposure of rosuvastatin—a BRCP, OAT1B1, OATP1B3, and OAT3 substrate. It showed a 5.2-fold increase in AUC₂₄ and a 4.9-fold increase in C_max of rosuvastatin, indicating that concomitant use of darolutamide and rosuvastatin should be avoided [39]. Interestingly, the clearance of rosuvastatin remained the same, suggesting that the increase in rosuvastatin exposure was mainly driven by altered absorption and therefore the effect is mainly attributed to inhibition of BCRP transporters [9, 39]. The inhibitory effect of darolutamide on OATP may also contribute as it often results in decreased hepatic uptake. The registration label recommends that the concomitant use of darolutamide with BCRP substrates should be avoided whenever possible. If used together, patients should be monitored more frequently, and dose reduction of the BCRP substrate drug needs to be considered [9, 10]. In addition, both the EMA and FDA also advise frequent monitoring of patients taking concomitant drugs that are OATP1B1 or 1B3 substrates, as their exposure may increase, however, it is not yet clear whether this is true [9, 10]. A post-hoc subgroup analysis of the ARAMIS phase III trial showed that patients treated concomitantly with statins did not experience more AEs compared with patients treated with darolutamide alone [38]. As the sample size of the post-hoc analysis was small, this might have prevented the observation of rare AEs caused by concomitant use of statins and darolutamide, such as myopathies and rhabdomyolysis [44].

As for the inhibitory effect of darolutamide on the enzymatic activity of UGTs, (S,R)-darolutamide showed the strongest inhibitory effect on the activity of UGT1A9, followed by UGT1A1 [39]. (S,S)-darolutamide and keto-darolutamide exhibited only notable UGT1A1 inhibition [39].

As mentioned above, darolutamide has the potential to be used in combination therapy for the treatment of prostate cancer. For this reason, potential treatment combinations were also the subject of investigation in DDI studies. In a study investigating the impact of darolutamide on cabazitaxel (CYP3A4 substrate) exposure, no significant change in the AUC₂₄ of cabazitaxel was observed in mCRPC patients when co-administered with darolutamide [45]. Furthermore, cabazitaxel had no effect on darolutamide exposure [46]. Another DDI study evaluated the pharmacokinetics, safety, and tolerability of ipatasertib in combination with darolutamide in mCRPC patients [46]. Ipatasertib is an Akt inhibitor currently being developed for the treatment of mCRPC. It is a CYP3A4 substrate and a weak CYP3A4 inhibitor. When co-administered with darolutamide, a slight reduction in ipatasertib exposure (AUC₂₄) and C_max was observed (8% and 21%, respectively), which is not considered clinically relevant [46]. The exposure of darolutamide and keto-darolutamide in combination with ipatasertib was also not affected [46]. In the phase III ARASENS trial, darolutamide was used in combination with ADT and docetaxel (a CYP3A4, OATP1B1, and OATP1B3 substrate) to treat mHSPC [47]. Concomitant use resulted in a slight increase in docetaxel exposure (AUC_last) and C_max (6% and 15%, respectively), which is not considered clinically relevant [47]. In addition, darolutamide exposure (AUC_12,ss) was slightly (10%) lower than in the ARAMIS phase III trial, in which patients were not treated concomitantly with docetaxel [47]. Therefore, darolutamide can be safely combined with docetaxel [47].

In general, androgen deprivation therapy may prolong the QT interval. Therefore, the possible concomitant use of drugs known to prolong the QT interval or induce Torsade de Pointes (TdP) should be carefully evaluated [10]. However, with darolutamide, only a 5.9 ms (90% upper CI 12.7 ms) prolongation of the corrected QT interval was observed, resulting in a moderate risk classification of darolutamide for the development of TdP [48].

A population PK covariate analysis indicates that darolutamide exposure is not significantly affected by body weight or age [10]. Similar results were seen in PK covariate analyses of other ARSIs, with the exception of apalutamide, whose exposure may be affected by weight by up to 25% [12, 13, 15]. In addition, no significant differences were observed based on ethnicity for darolutamide or any other ARSI [10, 12, 13, 15, 26]. In a phase I study with Japanese mCRPC patients, darolutamide was well tolerated with no significant difference in safety and pharmacokinetics [7, 32]. Although a 1.4-fold increase in exposure (AUC_∞) was observed in Japanese patients in a population PK analysis, no dose adjustments were required [10]. In contrast, moderate hepatic impairment (Child–Pugh classification B) and severe renal impairment (estimated glomerular filtration rate [eGFR] = 15–29 mL/min/1.73 m²) significantly affect darolutamide exposure. In a phase I study, non-cancer patients with moderate hepatic impairment had 1.9- and 1.5-fold higher darolutamide exposure (AUC_{48 h}) and C_max, respectively, compared with healthy volunteers after a single dose of darolutamide 600 mg [31]. No data are available for severe hepatic impairment. In addition, a 2.5-fold increase in exposure (AUC_{48 h}), a 1.6-fold increase in C_max, and prolonged terminal half-life (t_½) were observed in patients with severe renal impairment [31]. In contrast, in a population PK analysis, 1.1-, 1.3-, and 1.5-fold higher exposure of darolutamide was observed in patients with mild, moderate, and severe renal impairment, respectively, compared with patients with normal renal function. The exposure (AUC_{48 h}) of keto-darolutamide was also increased in both severe renal (1.7-fold increase) and moderate hepatic (1.2-fold increase) impairment in a phase I study, but to a lesser extent [31]. No significant difference was observed in protein binding between healthy subjects and patients with impaired renal or hepatic function [31]. Overall, no significant increase in exposure is expected in patients with mild hepatic or mild and moderate renal impairment. Therefore, no dose adjustment is required in patients with mild hepatic impairment or a GFR ≥30 mL/min. In the case of moderate hepatic and severe renal impairment, both the EMA and FDA recommend a starting dose of 300 mg of darolutamide twice daily [9, 10]. The EMA also recommends 300 mg BID for patients with severe hepatic impairment, while the FDA makes no recommendation [9, 10]. The authors recommend dose reduction to 300 mg BID in the case of moderate or severe hepatic impairment, a GFR <30 mL/min, or hemodialysis. Apalutamide and enzalutamide do not require dose adjustment in case of mild or moderate renal impairment and may be used with caution in patients with severe renal impairment. In addition, no dose adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A or B). Despite the 2-fold prolongation of the elimination half-life of enzalutamide, enzalutamide can also be used in patients with severe hepatic impairment (Child-Pugh classification C), while the use of apalutamide is not recommended due to lack of data [12, 13, 29, 30]. In addition, abiraterone acetate also does not require dose adjustment in patients with renal impairment. In contrast, abiraterone acetate exposure in patients with moderate hepatic impairment (Child-Pugh classification B) increases 4-fold after a single dose of 1000 mg [15, 26]. For this reason, a starting dose of 250 mg is recommended for patients with moderate hepatic impairment, and abiraterone acetate should not be used in patients with severe hepatic impairment [15, 26, 28]. Overall, apalutamide and enzalutamide may be a better treatment option for patients with renal or hepatic impairment.

No data are available on the influence of albumin levels, cachexia, or ECOG performance status because patients with poor performance were excluded from the ARAMIS phase III trial [10]. It would be really helpful if phase III studies were more inclusive, as in clinical practice a wide variaty of patients with multiple comorbidities need to be treated and clinicians should be informed on the risk-benefit ratio for their patient population.

Darolutamide is a next-generation androgen receptor inhibitor that is currently approved for the treatment of nmCRPC and mHSPC, and may be approved for the treatment of other stages of PC in the near future. Although ARSIs have a similar mode of action, darolutamide cannot be used in all patients due to registration restrictions; however, for a subset of patients, this ARSI would be the preferred candidate based on patient characteristics and comorbidities. Darolutamide is a promising ARSI with some favorable PK properties. Due to its low brain penetration, it is not associated with seizures and potentially causes less CNS adverse effects. It has a low potential for DDI, especially compared with enzalutamide and apalutamide. It can be concomitantly administered with CYP and P-gp substrates. This makes it a more suitable drug for patients with comorbidities treated with many other drugs. Furthermore, its limited DDI potential allows for future combination therapy for the treatment of PC. On the other hand, potential concomitant use with BCRP substrates should be carefully evaluated, as darolutamide may significantly increase their exposure. In addition, darolutamide should be taken twice daily with food to increase bioavailability and reduce patient burden. This may potentially result in poorer adherence compared with other ARSIs administered once daily and/or independent of food intake.

The PK-PD relationship for the target population of darolutamide is unknown, as all phase I and phase II studies have only evaluated darolutamide in mCRPC patients, while it is currently registered for nmCRPC. More data on the PK-PD relationship in the target population may pave the way for dose optimization to improve the risk-benefit balance of patients treated with this drug.

Because ARSIs have similar efficacy in the treatment of CRPC and mHSPC, a better understanding of the patient-specific and PK/PD characteristics of these drugs may help to select the appropriate drug for the individual patient. This review provides an overview of the currently available data on the PK/PD properties of darolutamide, including its challenges.