Subgroup analysis evaluates darolutamide in previously treated mCRPC

Darolutamide (Nubeqa) demonstrated modest antitumor activity in molecularly defined subgroups of patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with androgen receptor pathway inhibitors (ARPIs), according to findings from the phase 2 CCTG IND.234: PC_BETS trial presented at the 2025 American Society of Clinical Oncology Annual Meeting in Chicago, Illinois.¹

Michael Ong, MD

“Darolutamide is structurally distinct from other AR antagonists (enzalutamide [Xtandi], apalutamide [Erleada]), and possibly retains antitumor activity despite prior ARPI,” wrote the investigators, led by Michael Ong, MD, associate professor and medical oncologist at the Ottawa Hospital in Ottawa, Ontario, Canada. The phase 2 CCTG Group IND.234: PC_BETS study registered patients with mCRPC to undergo ctDNA-based genomic screening. “A molecular tumor board assigned patients to substudies based on prespecified biomarker (BM) criteria: BM-positive (BM+), or by randomization if BM-negative (BM–),” the investigators wrote. Treatment with darolutamide was evaluated in 3 cohorts: AR gain (amplification, cohort 1), AR mutation (cohort 2), or BM– (cohort 3) in 2 stages.

Patients were included in the analysis if they had mCRPC, an ECOG Performance Status of 0-1, evaluable disease, biochemical and/or radiological disease progression, and had received a prior ARPI. Patients were excluded if they had received prior chemotherapy. The primary end point was clinical benefit rate (CBR; defined as 50% reduction in prostate-specific antigen level [PSA50], RECIST complete response/partial response, or SD ≥12 weeks). Secondary end points included time to PSA progression and overall survival (OS).

The investigators used a prostate cancer-specific panel² to conduct deep targeted sequencing of plasma ctDNA and matched leukocyte DNA. If a patient had a ctDNA rate of less than 1% they were ineligible for inclusion unless they carried a germline DDR gene alteration. All patients in the study received darolutamide 600 mg twice daily.

A total of 27, 26, and 19 patients comprised cohorts 1-3, respectively. Median patient age was 72 (range, 53-88 years), 76 (range, 61-87 years), and 74 (range, 63-84 years), respectively. Eight patients in both cohort 1 and 2 had received prior chemotherapy; no patient had received prior chemotherapy in cohort 3. Prior enzalutamide/apalutamide was given in 15/0 (56%), 12/2 (54%), and 10/2 (63%) patients, respectively. Prior abiraterone acetate was reported in 12 (44%), 12 (46%), and 7 (37%), respectively. Lung metastases were reported in 5 (19%), 2 (8%), and 2 (11%) patients, respectively. Liver metastases were reported in 3 (11%), 0 (0%), and 2 (11%) patients, respectively. No bone metastases were reported in 4 (15%), 1 (4%), and 0 (0%) patients, respectively. Fewer than 10 bone metastases were reported in 6 (22%), 14 (54%) and 6 (32%) patients, respectively. Ten or more bone metastases were reported in 17 (63%), 11 (42%), and 13 (68%) patients respectively. ECOG Performance Status was 0/1 in 15/12 (100%), 10/16, and 11/8 patients, respectively.

CBR was observed 5 (27%) patients in cohort 1, 7 (27%) patients in cohort 2, and 2 (11%) patients in cohort 3. PSA50 was observed in 3 (11%) patients in cohort 1, 4 (15%) patients in cohort 2, and 1 (5%) patient in cohort 3. Median time to PSA progression was 2.8 months (95% CI: 1.8-3.7) in cohort 1, 2.8 months in cohort 2 (95% CI: 1.9-4), and 1.9 months in cohort 3 (95% CI: 1.8-2.8). Median OS was 12.9 months (95% CI: 6.6-19.9) in cohort 1, 16.4 months in cohort 2 (95% CI: 12.9-29), and 15.5 months in cohort 3 (95% CI: 12.2-NA).

“CBR was higher with SPOP mutations (3/5, 60%) and all CBR pts had [more than] 10 AR copies. [Cohort 2] CBR was seen with L702H (3/7, 43%) and T878A (4/7, 57%) but not F877L, W724C/L, or V716M,” wrote the investigators in their abstract.

Regarding safety across the study population, any all-grade adverse events (AEs) were observed in 46 (64%) patients. Six (8.3%) patients had a grade 3 or higher AE. AEs reported included fatigue (all-grade incidence, 38%; ≥ grade 3 incidence, 3%), diarrhea (all-grade incidence, 18%; ≥ grade 3 incidence, 1%), nausea (all-grade incidence, 15%; ≥ grade 3 incidence, 0%), and anorexia (all-grade incidence, 11%; ≥ grade 3 incidence, 0%).

“Darolutamide demonstrates modest activity for unselected mCRPC following AR pathway inhibitors. ctDNA analysis enriched for patients more likely to benefit from darolutamide including those with SPOP alterations, AR amplification, and AR mutations L702H or T878A,” the investigators concluded.

REFERENCES

1. Ong M, Chi K, Hotte S, et al. Substudy C of the Canadian cancer trials group (CCTG) IND.234: PC_BETS (Prostate Cancer Biomarker Enrichment and Treatment Selection)—A phase II study of darolutamide (DARO) selected by androgen-receptor (AR) circulating tumor DNA (ctDNA) in patients (PTS) with metastatic castration-resistant prostate cancer (mCRPC) after prior AR pathway inhibitors (ARPIs). J Clin Oncol. 2025;43(suppl 17):5056. doi:10.1200/JCO.2025.43.16_suppl.5056

2. Fonseca NM, Maurice-Dror C, Herberts C, et al. Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer. Nat Commun. 2024;15(1):1828. doi:10.1038/s41467-024-45475-w