Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial

Abstract

Purpose: For patients with metastatic hormone-sensitive prostate cancer (mHSPC), delaying progression to castration-resistant disease is important not only for overall survival (OS) but also for patients' quality of life. Darolutamide plus androgen-deprivation therapy (ADT) with docetaxel improved OS versus ADT and docetaxel in patients with mHSPC. The ARANOTE trial evaluated darolutamide and ADT without chemotherapy in patients with mHSPC.

Methods: In this global phase III trial, patients were randomly assigned 2:1 to receive darolutamide 600 mg twice daily or placebo, with concomitant ADT. The primary end point was radiological progression-free survival (rPFS).

Results: From March 2021 to August 2022, 669 patients were randomly assigned (darolutamide n = 446; placebo n = 223). At the primary cutoff date (June 7, 2024), darolutamide plus ADT significantly improved rPFS, reducing the risk of radiological progression or death by 46% versus placebo plus ADT (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.71]; P < .0001), with consistent benefits across subgroups, including high- and low-volume disease. OS results were suggestive of benefit with darolutamide versus placebo (HR, 0.81 [95% CI, 0.59 to 1.12]), and clinical benefits were seen across all other secondary end points, including delayed time to metastatic castration-resistant prostate cancer (HR, 0.40 [95% CI, 0.32 to 0.51]) and time to pain progression (HR, 0.72 [95% CI, 0.54 to 0.96]). Adverse events were similar in the two groups. Notably, the incidence of fatigue was lower in patients receiving darolutamide (5.6%) versus those receiving placebo (8.1%), and fewer patients receiving darolutamide (6.1%) versus placebo (9.0%) discontinued treatment because of adverse events.

Conclusion: These results confirm the efficacy and tolerability of darolutamide plus ADT in patients with mHSPC, demonstrating clinically and statistically significant improvement in rPFS and a favorable safety profile consistent with prior phase III darolutamide trials.

Trial registration: ClinicalTrials.gov NCT04736199.

FIG 1.

CONSORT flow diagram. ^aOther includes required study drug interruption longer than allowed per protocol, additional primary malignancy, noncompliance with study drug, loss to follow-up, and unspecified other reason. ^bTwo patients who were randomly assigned to the placebo group but received darolutamide are analyzed in the darolutamide group for the safety analysis set. ADT, androgen deprivation therapy.

FIG 2.

rPFS (full analysis set). (A) Kaplan-Meier estimates and (B) subgroup analyses. The HR and 95% CI were calculated using the Cox regression model stratified by the presence of visceral metastases and prior therapy. Subgroup analyses of rPFS provide HRs and 95% CIs obtained from univariate analysis using an unstratified Cox regression model. ADT, androgen-deprivation therapy; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; NR, not reached; PSA, prostate-specific antigen; RoW, rest of the world; rPFS, radiological progression-free survival.

FIG 3.

Additional secondary time-to-event end points (full analysis set). (A) Time to metastatic castration-resistant prostate cancer and (B) time to PSA progression. Hazard ratios and 95% CIs were calculated using the Cox regression model stratified by the presence of visceral metastases and prior therapy. ADT, androgen-deprivation therapy; NR, not reached; PSA, prostate-specific antigen.

FIG A1.

OS (full analysis set). (A) Kaplan–Meier estimates and (B) subgroup analyses. The HR and 95% CI were calculated using the Cox regression model stratified by the presence of visceral metastases and prior therapy. Subgroup analyses of OS provide HRs and 95% CIs obtained from univariate analysis using an unstratified Cox regression model. ADT, androgen-deprivation therapy; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; NR, not reached; OS, overall survival; PSA prostate-specific antigen; RoW, rest of the world.