Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor (ARi) that demonstrated strong efficacy and a consistently favorable safety and tolerability profile in the phase 3 ARAMIS and ARASENS studies in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and patients with metastatic hormone-sensitive prostate cancer (mHSPC) [1, 2]. Darolutamide in combination with androgen-deprivation therapy (ADT) or ADT and docetaxel, respectively, reduced the risk of death by more than 30% compared with placebo [1, 2]. In ARAMIS, most treatment-emergent adverse events (TEAEs) commonly associated with ARi therapy showed ≤2% difference between darolutamide and placebo, and discontinuation rates due to TEAEs were low and similar to placebo (8.9% vs 8.7%) [1]. The overall incidence of TEAEs was also similar between darolutamide and placebo in ARASENS, with the highest incidences of TEAEs occurring during the overlapping docetaxel treatment period [2].

Among patients with metastatic castration-resistant prostate cancer (mCRPC), darolutamide was well tolerated for up to 25 months in the previously reported ARADES, ARAFOR, and Japanese phase 1/2 studies [3,4,5]. ARADES was a phase 1 dose-escalation/phase 2 randomized dose-expansion study (NCT01317641/NCT01429064) of 136 patients in whom darolutamide was administered twice daily (BID) at doses of 200, 300, or 700 mg [3]. The ARAFOR study (NCT01784757) was a food-effect study that enrolled 30 patients who received darolutamide 600 mg BID [4]. A Japanese phase 1 study (NCT02363855) included nine patients who received darolutamide 300 mg or 600 mg BID [5]. Minimal safety data are available from extended treatment with darolutamide in this population. Thus, we performed a pooled analysis of individual patient data including mCRPC patients who were treated with darolutamide for >2 years. Patients were assessed every 3 months to evaluate the safety and tolerability of long-term darolutamide.

A total of 13 patients received darolutamide for >2 years, with seven patients receiving 2 to 4 years of treatment and six patients receiving more than 4 years of treatment. The median (range) age of patients was 68 (55–81) years, 12 patients were White, and one patient was Asian. Patients were treated in France (n = 4), the United Kingdom (n = 3), Latvia (n = 3), Finland (n = 2), and Japan (n = 1). Most patients had normal renal and hepatic function (77%), Eastern Cooperative Oncology Group performance status of 0 (92%), and Gleason score of seven or higher (69%). The median (range) time from initial diagnosis until first darolutamide dose was 32.4 (9.7–191.0) months, and median (range) baseline prostate-specific antigen level before initiating darolutamide was 18.1 (4.6–53.6) μg/L. All patients received endocrine therapy before darolutamide treatment (bicalutamide, 77%; triptorelin acetate, 46%; goserelin/goserelin acetate, 31%; leuprorelin acetate, 23%; cyproterone acetate, 23%; degarelix/degarelix acetate, 15%; abiraterone, 8%). No patient received prior chemotherapy. The median (range) treatment duration of darolutamide was 38.1 (24.2–90.0) months for all 13 patients receiving >2 years of treatment and 62.6 (48.6–90.0) months for those receiving >4 years of treatment. One patient completed ARAFOR and entered the darolutamide rollover study (NCT04464226).

TEAEs were reported by all 13 patients, with worst grade 1 or 2 events in seven patients and worst grade 3 events in six patients; no grade 4 or 5 events were reported (Table 1). No grade 3 events occurred in more than one patient and none were considered related to darolutamide. Grade 3 TEAEs included rectal adenocarcinoma and presyncope in a patient treated for >2 and ≤4 years and one event each of nausea, hepatic cirrhosis, pyelonephritis, accident, femoral neck fracture, spinal compression fracture, paraneoplastic syndrome, hematuria, lung disorder, and pulmonary embolism in five patients treated for >4 years. Serious TEAEs were reported in six patients and none were considered related to darolutamide. One patient treated for >2 years developed a new locally advanced rectal adenocarcinoma that was not considered related to darolutamide but led to treatment discontinuation. Five patients reported TEAEs considered related to darolutamide (tinnitus, abdominal distention, diarrhea, dyspepsia, fatigue, gynecomastia, and solar dermatitis) and all were grade 1 in severity. No treatment-related TEAEs led to discontinuation of darolutamide. The most common TEAEs were diarrhea, abdominal pain, and nausea (Table 1). During long-term darolutamide therapy, few patients experienced TEAEs commonly associated with ARi therapy (fatigue, n = 3; falls, including accidents, n = 3; bone fractures, n = 2; hypertension, n = 2; rash, n = 1).

Table 1 Treatment-emergent adverse events during long-term darolutamide treatment.
Full size table

The favorable safety and tolerability profile of long-term darolutamide treatment in patients with mCRPC are consistent with that previously reported from the early phase studies and in patients with nmCRPC and mHSPC [1,2,3,4,5]. In addition, extended treatment with darolutamide in the open-label phase of the ARAMIS trial (median treatment duration 25.8 months) showed minimal increase in the incidences of TEAEs from the darolutamide double-blind period (18.5 months) that disappeared when adjusted for longer exposure, and no new safety signals were observed [6, 7]. The randomized, crossover, phase 2 ODENZA trial compared darolutamide and enzalutamide in 200 patients with mCRPC for treatment preference and cognitive outcomes [8]. Darolutamide was preferred by 48.5% of patients versus 40.0% for enzalutamide (P = 0.92). A clinically meaningful benefit in episodic memory and less fatigue was observed in patients receiving darolutamide compared with those receiving enzalutamide. Matching-adjusted indirect comparisons and meta-analyses have shown a lower risk of adverse events and similar efficacy with darolutamide versus apalutamide and enzalutamide [9, 10].

In conclusion, long-term treatment with darolutamide in this small group of patients with mCRPC was well tolerated. These findings provide valuable information for patients and clinicians in selecting treatment for prostate cancer.