Indirect Comparison of Darolutamide versus Apalutamide and Enzalutamide for Nonmetastatic Castration-Resistant Prostate Cancer

Abstract

Purpose: No published head-to-head randomized trials have compared the safety and efficacy of darolutamide vs apalutamide or enzalutamide in nonmetastatic castration-resistant prostate cancer. This study compares prespecified adverse events and metastasis-free survival associated with darolutamide vs apalutamide, and darolutamide vs enzalutamide, via matching-adjusted indirect comparisons. Materials and Methods: Individual patient data from the phase III ARAMIS trial (N PLACEBO [553; N DAROLUTAMIDE [943) were selected and reweighted to match the inclusion criteria and baseline characteristics published for the phase III SPARTAN (N PLACEBO [401; N APALUTAMIDE [806) and PROSPER (N PLACEBO [468; N ENZALUTAMIDE [933) trials. Only baseline factors consistentlyreported across trials were included as matching covariates. Both indirect comparisons matched on age, prostate specific antigen level and doubling time, Eastern Cooperative Oncology Group performance status, Gleason score, and bone-sparing agent use. Darolutamide vs apalutamide also matched on prior surgery and darolutamide vs enzalutamide also matched on region. Risk differences and odds ratios were calculated for adverse events and hazard ratios for metastasis-free survival. Results: No differences in metastasis-free survival hazard ratios were found after matching in either comparison. However, fall, fracture and rash rates were statistically significantly lower in favor of darolutamide vs apalutamide. Fall, dizziness, mental impairment, fatigue and severe fatigue rates were statistically significantly lower in favor of darolutamide vs enzalutamide.

Real-world burden of adverse events for apalutamide- or enzalutamide-treated non-metastatic castration-resistant prostate cancer patients in the United States

“…Within the confines of this type of analysis, falls, fractures and rash rates were statistically significantly lower in favor of darolutamide vs apalutamide. Fall, dizziness, mental impairment, fatigue and severe fatigue rates were statistically significantly lower in favor of darolutamide vs enzalutamide [ 14 ]. This study adds to the collective body of knowledge by examining the comparative safety of emerging nmCRPC therapies in a real-world setting.…”

“…Although all the second-generation ARIs target the androgen receptor signaling axis and demonstrate significant anti-PC activity, they can display somewhat different AE profiles. Enzalutamide and apalutamide cross the blood–brain barrier, whereas darolutamide has a lower propensity to do so [ 13 ], which may account for some of the differences in central nervous system (CNS)-related AEs (falls and resulting fractures, fatigue, mental impairment) reported to date with the different second-generation ARIs [ 14 ]. Avoiding or minimizing AEs becomes especially relevant in treatment selection for relatively asymptomatic disease states; therefore, it is important to understand the real-world consequences of treating nmCRPC patients with the newer ARIs.…”

An oral first‐in‐class small molecule RSK inhibitor suppresses AR variants and tumor growth in prostate cancer

“… 2 In addition to apalutamide and enzalutamide, another second‐generation antiandrogen darolutamide has been shown to improve metastasis‐free survival and overall survival in nonmetastatic castration‐resistant prostate cancer. 3 Notably, darolutamide was different in molecular structure from apalutamide and enzalutamide, leading to a different pharmaceutical outcome. 3 Although the treatment‐mediated manipulations on AR signaling initially show excellent anticancer effects, most tumors eventually recur and become fatal.…”

Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer: A Window of Opportunity

“…These results were consistent with the study results when risk differences were used. The MAICs carried out, such as that of Halabi et al, confirm these data, which points to their validity [37]. However, despite these studies, it is also noteworthy that the monitoring and toxicity records have been more exhaustive in SPARTAN than in PROSPER and ARAMIS (4 vs. 16 weeks), and both SPARTAN and PROSPER currently have a higher follow-up.…”