Post Hoc Data Show Darolutamide Improves MFS and OS in nmCRPC, Regardless of Prior Radical Prostatectomy or Radiotherapy

Darolutamide (Nubeqa) improved metastasis-free survival (MFS) and overall survival (OS) outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC), regardless of whether patients received prior local therapy with radical prostatectomy or radiotherapy, according to findings from a post hoc meta analysis of the phase 3 ARAMIS trial (NCT02200614).¹

Findings published in Cancer Medicine demonstrated that median MFS exceeded 40 months across darolutamide-treated subgroups, other than those previously treated with radiotherapy, where the median MFS was not reached (NR). This contrasted with a median MFS ranging from 14.7 to 19.1 months among placebo-treated patient subgroups across the corresponding prior local therapy strata. Darolutamide reduced the risk of metastasis or death vs placebo in patients who received prior local therapy (HR, 0.36; 95% CI, 0.26-0.48) and in those who did not (HR, 0.46; 95% CI, 0.36-0.59), with no evidence of a treatment-by–prior local therapy interaction for MFS (interaction effect HR, 0.78; 95% CI, 0.52-1.18).

OS findings were also directionally favorable. Median OS was NR in all darolutamide subgroups and the overall darolutamide population. In the placebo arm, median OS was lower among patients without prior radical prostatectomy or radiotherapy (median, 48.6 months; 95% CI, 45.6-not estimable), while OS was NR in placebo-treated patients who had received prior radical prostatectomy or radiotherapy. OS outcomes trended in favor of darolutamide vs placebo in patients with prior local therapy (HR, 0.80; 95% CI, 0.50-1.30) and showed a more pronounced reduction in the risk of death among those without prior local therapy (HR, 0.67; 95% CI, 0.50-0.90), with no interaction signal for OS (interaction effect HR, 1.19; 95% CI, 0.69-2.08).

“The findings of this post hoc analysis are consistent with those from the overall population of the long-term ARAMIS trial. In this post hoc analysis, patients with nmCRPC benefited from darolutamide independent of prior local therapies to treat the primary tumor, with consistent effects on disease progression and survival as observed in the overall ARAMIS population,” lead study author Matthias Saar, MD, and colleagues wrote in a publication of the data. “Darolutamide also delayed time to deterioration in health-related quality of life [HRQOL], including urinary and bowel symptoms. The improved disease control compared with placebo and low incidence of adverse effects [AEs] support the benefits of darolutamide for patients with and without prior radical prostatectomy or radiotherapy.”

How was this post hoc analysis of ARAMIS analysis designed to compare outcomes based on prior local therapy?

This post hoc, exploratory analysis of the phase 3 ARAMIS trial examined whether the efficacy and safety of darolutamide differed in patients with nmCRPC according to receipt of prior local therapy to the primary tumor—radical prostatectomy or radiotherapy vs no prior local therapy. Outcomes were evaluated by treatment group and stratified by prior local therapy status, including MFS, OS, time to prostate-specific antigen (PSA) progression, PSA response defined as at least a 50% decline from baseline (PSA50), HRQOL, deterioration-free survival (DetFS), and safety.

MFS was defined as time from randomization to confirmed distant metastasis on conventional imaging or death from any cause, whichever occurred first. PSA progression was defined per Prostate Cancer Working Group 2 criteria as a 25% PSA increase and an absolute rise of at least 2 ng/mL above nadir, confirmed by a subsequent value obtained at least 3 weeks later.

Time-to-event end points (MFS, OS, time to PSA progression, and DetFS) were summarized using Kaplan–Meier methods with medians and 95% confidence intervals, and treatment comparisons were estimated using Cox proportional hazards models. For MFS, OS, and time to PSA progression, Cox models were adjusted for baseline imbalances between prior local therapy groups, including age, ECOG performance status, Gleason score, and time from diagnosis.

What were the baseline patient characteristics observed in this post hoc analysis of ARAMIS?

Of the 1509 patients with nmCRPC randomized in ARAMIS, 954 received darolutamide and 554 received placebo. Among patients treated with darolutamide, 239 had received prior radical prostatectomy, 177 had received prior radiotherapy, and 538 had received neither radical prostatectomy nor radiotherapy; in the placebo arm, 134 and 89 patients had received prior radical prostatectomy and radiotherapy, respectively, and 331 received neither modality. Baseline demographics and clinical characteristics were generally similar across prior local therapy subgroups and the overall darolutamide-treated population.

Median age ranged from 72 to 76 years across subgroups, including 72.0 years (range, 52-90) among darolutamide-treated patients with prior radical prostatectomy or radiotherapy and 76.0 years (range, 48-95) among those without prior radical prostatectomy or radiotherapy; corresponding values in the placebo arm were 71.0 years (range, 50-92) and 76.0 years (range, 52-91), respectively. Median baseline PSA levels were 7.2 ng/mL (range, 1.7-164.4) in darolutamide-treated patients with prior radical prostatectomy or radiotherapy vs 10.4 ng/mL (range, 0.3-858.3) in those without prior local therapy, with similar patterns observed in the placebo arm (8.5 ng/mL [range, 2.0-885.2] vs 10.3 ng/mL [range, 1.5-310.2], respectively). Median PSA doubling time was 4.1 months (range, 0.7-10.4) among darolutamide-treated patients with prior radical prostatectomy or radiotherapy vs 4.7 months (range, 1.0-11.0) among those without prior local therapy.

Patients treated with darolutamide who had not received radical prostatectomy or radiotherapy also had a shorter median time from initial diagnosis to study treatment (74.5 months; range, 2.6-242.1) compared with those who had received radical prostatectomy or radiotherapy (107.6 months; range, 14.2-337.5). ECOG performance status was 0 in 73.6% and 1 in 26.4% of darolutamide-treated patients, respectively, with prior radical prostatectomy or radiotherapy, whereas a higher proportion of those without prior radical prostatectomy or radiotherapy had an ECOG performance status of 1 (36.2%).

Did prior radical prostatectomy or radiotherapy influence PSA50 response or DetFS with darolutamide?

PSA50 response rates with darolutamide were consistent irrespective of prior local therapy status, ranging from 83.8% to 85.8% across subgroups and aligning with the overall darolutamide population (84.6%). In the placebo arm, PSA50 response rates were substantially lower but similarly uniform across prior local therapy subgroups (30.3%-33.6%), consistent with the overall placebo group (33.0%).

HRQOL analyses also favored darolutamide. The agent improved DetFS for EORTC QLQ-PR25 urinary symptoms by 40% regardless of prior local therapy; however, median urinary symptom DetFS was shorter among patients who had received radical prostatectomy or radiotherapy vs those who had not, suggesting a negative impact of prior local therapy on urinary symptoms. Darolutamide additionally improved DetFS for EORTC QLQ-PR25 bowel symptoms and FACT-P physical and functional well-being, with a greater magnitude of benefit in patients with prior local therapy compared with those without (38%-41% vs 20%-26%). Across treatment arms, HRQOL deterioration contributed to more than 55% of total DetFS events in the darolutamide group and 40% to 50% in the placebo group, whereas earlier metastases accounted for 25% to 30% of DetFS effects with darolutamide and 40% to 50% with placebo.

References

1. Saar M, Fizazi K, Shore ND, et al. Effects of prior local therapy by radical prostatectomy or radiotherapy on the efficacy and quality of life of patients treated with darolutamide in ARAMIS. Cancer Med. 2025;15(1). doi:10.1002/cam4.71343 ‌
2. Efficacy and safety study of darolutamide (ODM-201) in men with high-risk non-metastatic castration-resistant prostate cancer (ARAMIS). ClinicalTrials.gov. Updated June 8, 2025. Accessed January 5, 2025. https://clinicaltrials.gov/study/NCT02200614