Nivolumab plus rucaparib for metastatic castration-resistant prostate cancer: results from the phase 2 CheckMate 9KD trial

Abstract

BackgroundCheckMate 9KD (NCT03338790) is a non-randomized, multicohort, phase 2 trial of nivolumab plus other anticancer treatments for metastatic castration-resistant prostate cancer (mCRPC). We report results from cohorts A1 and A2 of CheckMate 9KD, specifically evaluating nivolumab plus rucaparib.MethodsCheckMate 9KD enrolled adult patients with histologically confirmed mCRPC, ongoing androgen deprivation therapy, and an Eastern Cooperative Oncology Group performance status of 0–1. Cohort A1 included patients with postchemotherapy mCRPC (1–2 prior taxane-based regimens) and ≤2 prior novel hormonal therapies (eg, abiraterone, enzalutamide, apalutamide); cohort A2 included patients with chemotherapy-naïve mCRPC and prior novel hormonal therapy. Patients received nivolumab 480 mg every 4 weeks plus rucaparib 600 mg two times per day (nivolumab dosing ≤2 years). Coprimary endpoints were objective response rate (ORR) per Prostate Cancer Clinical Trials Working Group 3 and prostate-specific antigen response rate (PSA50-RR; ≥50% PSA reduction) in all-treated patients and patients with homologous recombination deficiency (HRD)-positive tumors, determined before enrollment. Secondary endpoints included radiographic progression-free survival (rPFS), overall survival (OS), and safety.ResultsOutcomes (95% CI) among all-treated, HRD-positive, and BRCA1/2-positive populations for cohort A1 were confirmed ORR: 10.3% (3.9–21.2) (n=58), 17.2% (5.8–35.8) (n=29), and 33.3% (7.5–70.1) (n=9); confirmed PSA50-RR: 11.9% (5.9–20.8) (n=84), 18.2% (8.2–32.7) (n=44), and 41.7% (15.2–72.3) (n=12); median rPFS: 4.9 (3.7–5.7) (n=88), 5.8 (3.7–8.4) (n=45), and 5.6 (2.8–15.7) (n=12) months; and median OS: 13.9 (10.4–15.8) (n=88), 15.4 (11.4–18.2) (n=45), and 15.2 (3.0–not estimable) (n=12) months. For cohort A2 they were confirmed ORR: 15.4% (5.9–30.5) (n=39), 25.0% (8.7–49.1) (n=20), and 33.3% (7.5–70.1) (n=9); confirmed PSA50-RR: 27.3% (17.0–39.6) (n=66), 41.9 (24.5–60.9) (n=31), and 84.6% (54.6–98.1) (n=13); median rPFS: 8.1 (5.6–10.9) (n=71), 10.9 (6.7–12.0) (n=34), and 10.9 (5.6–12.0) (n=15) months; and median OS: 20.2 (14.1–22.8) (n=71), 22.7 (14.1–not estimable) (n=34), and 20.2 (11.1–not estimable) (n=15) months. In cohorts A1 and A2, respectively, the most common any-grade and grade 3–4 treatment-related adverse events (TRAEs) were nausea (40.9% and 40.8%) and anemia (20.5% and 14.1%). Discontinuation rates due to TRAEs were 27.3% and 23.9%, respectively.ConclusionsNivolumab plus rucaparib is active in patients with HRD-positive postchemotherapy or chemotherapy-naïve mCRPC, particularly those harboring BRCA1/2 mutations. Safety was as expected, with no new signals identified. Whether the addition of nivolumab incrementally improves outcomes versus rucaparib alone cannot be determined from this trial.Trial registration numberNCT03338790.

Advances in PARP Inhibitors for Prostate Cancer

“…PSA or radiologic progression occurred in 53% of patients [ 95 ]. CHeckMate 9KD [ 100 ] is a phase II trial assessing the safety and efficacy of nivolumab, a PD-1 inhibitor, in combination with rucaparib, docetaxel or enzalutamide in patients with mCRPC. Patients in cohort A received nivolumab 280 mg administered intravenously (IV) every 4 weeks with rucaparib 600 mg PO BID.…”

Development of PARP inhibitors in advanced prostate cancer

“…While most studies are still ongoing, the trials reported to date have shown limited antitumor activity from the combination of PARPi with cediranib, 44 pembrolizumab, 51 or nivolumab 52 in mCRPC patients without detectable HRR alterations and for those with HRR defects it is unclear whether the combinations add any benefit to PARPi in monotherapy. The most promising results have been reported from trials investigating the combination of PARPi with ARSi, with several lines of work showing a close interplay between the AR pathway and the DDR machinery, supporting the synergistic effect of ARSi and PARPi.…”

Progression in immunotherapy for advanced prostate cancer

“…PARP inhibitors have been shown to have synergistic effects with PD-1/PD-L1 or CTLA-4 blockade (126,127). A recent study of rucaparib in combination with nivolumab for mCRPC reported its results: regardless of previous chemotherapy (128), the CheckMate 9KD study showed significantly improved ORR and PSA response rates with combination therapy in the HRD+ cohort, particularly in patients with BRAC1/2 mutations; in terms of OS and rPFS, the median OS for the A2 cohort without chemotherapy was 20.2 months (95% CI 14.1-22.8 months) and the median rPFS was 8.1 months (95% CI 5.6-10.9 months). Regarding safety, common TRAEs observed following combination therapy were nausea, fatigue, anemia, and loss of appetite, with G3-G4 TRAEs occurring in half of the patients in both cohorts, and neutropenia warranting focus during treatment.…”