Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC).

Abstract

5514 Background: DARO is a structurally distinct androgen receptor inhibitor with a favorable safety profile, approved for treating men with nmCRPC after demonstrating significantly prolonged metastasis-free survival, compared with placebo (PBO), in the phase III ARAMIS trial: median 40.4 vs 18.4 months, respectively (HR 0.41; 95% CI 0.34–0.50; P<0.0001). We report final analyses of OS and prospectively collected, patient-relevant secondary endpoints, and updated safety results. Methods: 1509 patients (pts) with nmCRPC were randomized 2:1 to DARO 600 mg twice daily (n=955) or PBO (n=554) while continuing ADT. Secondary endpoints included OS, and times to pain progression, first cytotoxic chemotherapy, and first symptomatic skeletal event. The OS analysis was planned to occur after approximately 240 deaths. Secondary endpoints were evaluated in a hierarchical order. Results: Final analysis was conducted after 254 deaths were observed (15.5% of DARO and 19.1% of PBO patients). After unblinding at the primary analysis, 170 pts crossed over from PBO to DARO. DARO showed a statistically significant OS benefit corresponding to a 31% reduction in the risk of death compared with placebo. All other secondary endpoints were significantly prolonged by DARO (Table), regardless of the effect of crossover and subsequent therapies on survival benefit. Incidences of treatment-emergent adverse events (AEs) with ≥5% frequency were generally comparable between DARO and PBO, similar to the safety profile observed at the primary analysis. Incidences of AEs of interest (including falls, CNS effects, and hypertension) were not increased with DARO compared with PBO when adjusted for treatment exposure. AEs in the crossover group were consistent with those for the DARO treatment arm. Conclusions: DARO showed a statistically significant OS benefit for men with nmCRPC. In addition, DARO delayed onset of cancer-related symptoms and subsequent chemotherapy, compared with PBO. With extended follow-up, safety and tolerability were favorable and consistent with the primary ARAMIS analysis (Fizazi et al, N Engl J Med 2019;380:1235-46). Clinical trial information: NCT02200614 .[Table: see text]

Patient and caregiver benefit‐risk preferences for nonmetastatic castration‐resistant prostate cancer treatment

“…As SGARIs are emerging as new treatment options for nm-CRPC patients given their impact on improving MFS and OS, [11][12][13][14][15][16] this study provides new and timely insights on how patients and caregivers weigh the benefits and risks of these new treatments. While these new SGARIs are similar in efficacy, they have different safety profiles that may differentially impact patients' QoL.…”

“…Unlike first generation AR inhibitors, SGARIs demonstrated a significant clinical benefit through the prolongation of MFS and in particular OS in this patient population. [11][12][13][14][15][16] However, since this patient population is relatively asymptomatic, it is important to carefully balance risks and benefits when selecting SGARI treatments to optimize the quality of a nmCRPC patient's survival. Our results indicate that nmCRPC patients and caregivers preferred treatments with lower AE burden and were willing to forego substantial amounts of OS to reduce the risk and severity of AEs.…”

“…[11][12][13] More recently, data demonstrating improved overall survival (OS) with SGARIs therapy have emerged, where the newly-approved SGARIs were shown to be associated with a 25% to 31% reduction in the risk of death. [14][15][16] Compared to the first generation antiandrogens, SGARIs also have increased specificity, higher affinity to the androgen receptor, and are not associated with androgen withdrawal syndrome. 17 As such, SGARIs have the potential to become the new standard of care.…”

Bone health effects of androgen-deprivation therapy and androgen receptor inhibitors in patients with nonmetastatic castration-resistant prostate cancer

“…ADT in terms of statistically significant improvement in metastasis-free survival [15][16][17]. Updated data from the ARI trials also showed increase in overall survival compared with placebo (HR for apalutamide 0.78 [95% CI 0.64-0.96; P = 0.0161]) [27]; HR for darolutamide 0.69 [95% CI 0.53-0.88; P < 0.003] [28]; HR for enzalutamide 0.73 [95% CI 0.61-0.89; P = 0.001] [29].…”

Novel therapies are changing treatment paradigms in metastatic prostate cancer

“…In the phase-3 ARAMIS trial, 1509 patients with nmCRPC were randomized to ADT plus either darolutamide or placebo [ 31 ]. The final analysis showed a statistically significant OS benefit corresponding to a 31% reduction in the risk of death in the treatment cohort (HR 0.69, 95% CI 0.53–0.88, p = 0.003) [ 32 ]. Regarding the most common AEs of darolutamide (any grade), only fatigue (12.1% vs. 8.7%), back pain (8.8% vs. 9.0%), arthralgia (8.1% vs. 9.2%), and hypertension (6.6% vs. 5.2%) were different between the two groups.…”