A multicohort phase 2 trial of androgen deprivation therapy (ADT), docetaxel (DOCE), and nivolumab (NIVO) in patients (pts) with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) enriched for inflamed tumors and DNA damage repair (DDR) alterations.

183 Background: This multicenter phase 2 investigator-initiated trial evaluated ADT, DOCE, and NIVO in pts with de novo mHSPC. Cohorts were prospectively allocated by the presence of DDR alterations (C1), PD-L1 and CD8 positivity (C2), or absence of biomarkers (C3). Primary results from all cohorts are reported. Methods: Pts with newly diagnosed mHSPC (ECOG 0-2 and PSA >4.0ng/mL before ADT) were enrolled, allowing up to 140 days of prior ADT. Pts received continuous ADT, DOCE 75mg/m 2 and NIVO 360mg Q3W for 6 cycles, followed by NIVO 480mg Q4W for up to 2 years. Primary endpoint (PEP) was PSA < 0.2ng/mL at 7mo and considered promising if 2-sided 80% CI exceeded 20%. Secondary endpoints included PSA < 0.2ng/mL before next therapy, objective response rate (ORR), time to castration resistance (TTCRPC), overall survival (OS) and adverse events (AE). Planned enrollment was 60 pts (20/cohort). Biomarkers were centrally assessed. Results: 47 pts were enrolled between 5/2020-3/2024 (C1: 8, C2: 19, C3: 20). Due to evolving treatment landscape, abiraterone was permitted post-7mo in 1/2022, and enrollment was subsequently stopped early. Across cohorts, median age was 65y (IQR 60-72) and median PSA at ADT start 98ng/mL (IQR 36-477). 41 (87%) pts had high-volume metastases with 11 (23%) visceral disease. Median follow-up was 42mo. Pts received a median of 6 DOCE and 11 NIVO cycles. PSA < 0.2ng/mL at 7mo occurred in 3 (38%, 80% CI: 15%-66%) pts in C1, 3 (16%, 5.9%-32%) pts in C2, and 3 pts (15%, 5.6%-30%) in C3; 6 pts (2 in C2, 4 in C3) lacked data due to early discontinuation for AE or physician decision. Rate of PSA < 0.2ng/mL before next therapy was 4 (50%) in C1, 4 (21%) in C2, and 4 (20%) in C3. ORR was 0% (0/2) in C1, 50% (4/8) in C2, and 50% (6/12) in C3. Abiraterone was started by 11 (23%) pts on study, with median time from C1D1 of 11mo (range: 7-19). Survival outcomes are summarized in Table. Grade 3-4 treatment-related AEs occurred in 28 (60%) pts, most frequently neutropenia (30%) and leukopenia (11%). Conclusions: C2 and C3 did not meet the 7mo PSA response PEP, and C1 was underpowered for assessment. Pts with PD-L1 and/or CD8 high tumors tended to have longer TTCRPC and OS; however, the study was not designed for cross-cohort comparisons. Safety was consistent with individual profiles of each agent. With the expanding therapeutic arsenal for mHSPC, future studies should further explore biomarker-driven combination strategies to optimize treatment selection and pt outcomes. (NCT04126070). Clinical trial information: NCT04126070 . Cohort 1 (DDR altered, N=8) Cohort 2 (PD-L1/CD8 high, N=19) Cohort 3 (Biomarker negative, N=20) TTCRPC, median (95% CI) 8.8 (6.2-NR) 14.3 (5.3-38.6) 7.9 (5.1-NR) 3yr OS rate, % (95% CI)* 55 (14-83) 72 (46-87) 59 (33-78) *Median OS not reached in each cohort.