Darolutamide/ADT Improves Outcomes in mHSPC Across Disease Volumes

The ARANOTE phase 3 trial showed darolutamide plus ADT improved outcomes in mHSPC regardless of disease volume.

Efficacy outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC) were improved following treatment with darolutamide (Nubeqa) in combination with androgen deprivation therapy (ADT) compared with placebo plus ADT irrespective of disease volume, according to findings from the phase 3 ARANOTE trial (NCT04736199).¹

Data from a subgroup analysis of ARANOTE presented during the 2025 Genitourinary Cancers Symposium demonstrated that patients with high-volume disease who received darolutamide (n = 315) achieved a median radiological progression-free survival (rPFS) of 30.2 months (95% CI, 28.8-not reached [NR]) compared with 19.2 months (95% CI, 16.1-26.0) among those who received placebo (n = 157; HR, 0.60; 95% CI, 0.44-0.80). Patients with low-volume disease achieved a median rPFS of NR (95% CI, NR-NR) in the investigational arm (n = 131) vs NR (95% CI, 25.0-NR) in the control arm (n = 66; HR, 0.30; 95% CI, 0.15-0.60).

“The phase 3 ARASENS study [NCT02799602] demonstrated a greater than 30% reduction in the risk of death with the combination of darolutamide plus ADT and docetaxel, which has become a standard of care for the treatment of patients with mHSPC,” Fred Saad, MD, FRCS, said during a presentation of the data. “In ARANOTE, darolutamide plus ADT significantly improved rPFS, reducing the risk of radiological progression or death by 46%. Volume of disease is a prognostic factor for patients with mHSPC and here we report a post-hoc analysis of ARANOTE to evaluate the efficacy and safety of darolutamide by disease volume.”

Saad is the director of prostate cancer research at the Montreal Cancer Institute, a uro-oncologist in the Urology Department, and a full professor in the Department of Surgery at the Centre Hospitalier de l'Université de Montréal in Canada.

In November 2024, the FDA accepted a supplemental new drug application (sNDA) seeking the approval of darolutamide plus ADT for the treatment of patients with mHSPC.² The sNDA was supported by previous data from ARANOTE. Findings from ARANOTE presented during the 2024 ESMO Congress showed that regardless of disease volume patients who received darolutamide plus ADT (n = 446) achieved a median rPFS of NR (95% CI, NR-NR) vs 25.0 months (95% CI, 19.0-NR) in the placebo arm (n = 223; HR, 0.54; 95% CI, 0.41-0.71; P < .0001).³

Diving Into the ARANOTE Trial and Baseline Characteristics

ARANOTE was a global, double-blind study that enrolled patients with mHSPC who had an ECOG performance status of 0 to 2. Patients were stratified based on the presence of visceral metastases (yes vs no) and receipt of prior local therapy (yes vs no). Eligible patients were randomly assigned 2:1 to receive darolutamide at a dose of 600 mg twice daily or placebo, both in combination with ADT.

The primary end point was rPFS by central blinded review. Secondary end points included overall survival (OS), time to initiation of subsequent anticancer therapy, time to metastatic castration-resistant prostate cancer (mCRPC), time to prostate-specific antigen (PSA) progression, rates of undetectable PSA (< 0.2 ng/mL), time to pain progression, and safety.

In the post-hoc analysis that Saad presented, patients were evaluated based on disease volume per CHAARTED criteria.¹ High-volume disease was defined as the presence of visceral metastases and/or at least 4 bone lesions with at least 1 lesion beyond the vertebral bodies and pelvis. Low-volume disease was defined as not meeting the high-volume criteria.

At baseline, the median age of the overall patient population was 70.0 years (range, 43-93). Most patients had a Gleason score of at least 8 at initial diagnosis (68.3%) and de novo metastasis at initial diagnosis (72.5%). The study also included patients with visceral metastases (12.0%), those who had received prior local therapy (17.9%), and those with an ECOG performance status of 0 (49.8%). The median serum PSA level at baseline was 21.3 ng/mL (range, 0.02-15,915).

Further Efficacy and Safety Data from the Analysis

Additional findings from the post-hoc analysis showed that patients in the high- and low-volume groups experienced a delayed time to mCRPC with darolutamide plus ADT vs placebo plus ADT, which was consistent with the benefit observed in the overall population (HR, 0.40; 95% CI, 0.32-0.51). Patients with high-volume disease in the investigational and control arms achieved a median time to mCRPC of NR (95% CI, 22.2-NR) vs 12.4 months (95% CI, 11.1-13.9), respectively (HR, 0.46; 95% CI, 0.36-0.60). In the low-volume group, the median time to mCRPC was NR (95% CI, NR-NR) vs 19.8 months (95% CI, 13.8-NR), respectively (HR, 0.21; 95% CI, 0.12-0.37).

The addition of darolutamide to ADT also led to a benefit compared with placebo plus ADT across all secondary end points examined. The greatest benefits were reported in time to initiation of subsequent systemic anticancer therapy in patients with low-volume disease (HR, 0.19; 95% CI, 0.08-0.43), time to PSA progression in patients with low-volume disease (HR, 0.19; 95% CI, 0.10-0.37), and time to PSA progression in patients with high-volume disease (HR, 0.34; 95% CI, 0.25-0.46).

“OS results were immature, but suggestive of a benefit with darolutamide vs placebo,” Saad noted.

Evaluable patients with high-volume disease in the darolutamide arm (n = 304) had undetectable PSA levels 24, 36, and 48 weeks after random assignment at rates of 44%, 48%, and 50%, respectively; 55% of these patients achieved undetectable PSA at any time. Comparatively, patients in the placebo arm (n = 148) achieved undetectable PSA at rates of 11%, 13%, 14%, and 16%, at the respective time points.

Patients with low-volume disease who received darolutamide (n = 121) also experienced undetectable PSA levels at higher rates compared with those who received placebo (n = 63) at the 24- (72% vs 17%, respectively), 36- (78% vs 19%), and 48-week (79% vs 19%) time points. Patients experienced undetectable PSA at any time at rates of 83% vs 25%, respectively.

In terms of safety, patients with high-volume disease who received darolutamide (n = 314) or placebo (n = 156) both experienced any-grade treatment-emergent adverse effects (TEAEs; 93.0% vs 91.7%, respectively), grade 3 or 4 TEAEs (31.2% vs 31.2%), serious TEAEs (28.3% vs 25.6%), and TEAEs leading to study drug discontinuation (7.3% vs 8.3%). Patients with low-volume disease in the darolutamide (n = 131) and placebo (n = 65) arms also experienced any-grade TEAEs (86.3% vs 86.2%), grade 3 or 4 TEAEs (29.8% vs 26.2%), serious TEAEs (12.2% vs 18.5%), and TEAEs leading to study drug discontinuation (3.1% vs 10.8%).

“Efficacy outcomes with darolutamide plus ADT were improved vs placebo plus ADT regardless of disease volume,” Saad said in conclusion. “Darolutamide plus ADT was well tolerated in both high-volume and low-volume subgroups with low treatment discontinuation rates consistent with the overall population and reconfirming the established tolerability of darolutamide. Patients with low-volume mHSPC had marked treatment efficacy with minimal treatment burden.”

References

1. Saad F, Shore N, Vjaters E, et al. Darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) by disease volume: subgroup analysis of the phase 3 ARANOTE trial. J Clin Oncol. 2025;43(suppl 5):151. doi:10.1200/JCO.2025.43.5_suppl.151
2. U.S. FDA accepts supplemental new drug application for Nubeqa (darolutamide) for the treatment of patients with metastatic hormone-sensitive prostate cancer. News release. Bayer. November 21, 2024. Accessed February 13, 2025. https://www.biospace.com/press-releases/u-s-fda-accepts-supplemental-new-drug-application-for-nubeqa-darolutamide-for-the-treatment-of-patients-with-metastatic-hormone-sensitive-prostate-cancer
3. Saad F, Vjaters E, Shore ND, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial. Ann Oncol. 2024;35(suppl 2):S1257-S1258. doi:10.1016/j.annonc.2024.08.2311