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

Abstract

Background: CheckMate 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.

Methods: CheckMate 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.

Results: Outcomes (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.

Conclusions: Nivolumab 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 number: NCT03338790.

Keywords: Clinical Trials, Phase II as Topic; Immunotherapy.

Figure 1

Kaplan-Meier plots of rPFS and OS in all treated patients and based on HRD status for cohort A1 (A, B) and cohort A2 (C, D). HRD, homologous recombination deficiency; NE, not evaluable; OS, overall survival; rPFS, radiographic progression-free survival.

Figure 2

Waterfall plots of maximum change from baseline in tumor size (A) and PSA (B) based on HRD-related genetic mutations for cohort A1. *Patients with a measurable target lesion at baseline and at least one on-treatment tumor assessment; seven patients did not have available tumor change data. †Represents patients categorized as HRD-positive but with missing information on the specific genetic mutation(s). ‡Patients with baseline PSA and at least one postbaseline PSA assessment. Horizontal reference lines indicate a 30% reduction consistent with a PCWG3 response (A) or a 50% reduction consistent with a PSA response (B). Open squares indicate truncation of percent change at +100%. +Symbol represents a confirmed objective response; ▲ Symbol represents a confirmed PSA response. HRD, homologous recombination deficiency; MSI-H, microsatellite instability-high; NA, not available; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PSA, prostate-specific antigen.

Figure 3

Waterfall plots of maximum change from baseline in tumor size (A) and PSA (B) based on HRD-related genetic mutations for cohort A2. *Patients with a measurable target lesion at baseline and at least one on-treatment tumor assessment; one patient did not have available tumor change data. †Represents patients categorized as HRD-positive but with missing information on the specific genetic mutation(s). ‡Patients with baseline PSA and at least one postbaseline PSA assessment. Horizontal reference lines indicate a 30% reduction consistent with a PCWG3 response (A) or a 50% reduction consistent with a PSA response (B). Open squares indicate truncation of percent change at +100%. +Symbol represents a confirmed objective response; ▲ Symbol represents a confirmed PSA response. HRD, homologous recombination deficiency; NA, not available; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PSA, prostate-specific antigen.