Rucaparib/nivolumab combo shows clinical activity in HRD-positive mCRPC

Combination therapy with the PARP inhibitor rucaparib (Rubraca) and the immunotherapy nivolumab (Opdivo) demonstrated clinical activity in patients with homologous recombination deficiency–positive metastatic castration-resistant prostate cancer (mCRPC) who had no prior chemotherapy, according to findings shared during the 2021 ESMO Congress.¹

Daniel P. Petrylak, MD

The findings from the CheckMate 9KD trial also showed noteworthy activity in individuals whose tumors harbored BRCA mutations. However, as study author Daniel P. Petrylak, MD, professor of medicine and urology at Yale School of Medicine and co-director of the Cancer Signaling Networks Research Program at Yale Cancer Center in New Haven, Connecticut, noted in his presentation of data, there was limited clinical activity with the combination in patients with HRD-negative tumors.

Among all cohorts of the phase 2 CheckMate 9KD trial (NCT03338790), patients had to have mCRPC, documented disease progression, an ECOG performance status of 0-1, available tumor tissue for HRD testing and no prior treatment with drugs that targeted T-cell co-stimulation or immune checkpoint pathways.

Here, Petrylak presented data from the final analysis of cohort A2 — which comprised 71 patients (median age, 73 years; range, 51-87 years) who had received 1 to 2 prior new hormonal therapies in the pre-chemotherapy setting. Patients in this cohort also did not receive any prior treatments with PARP inhibitors. Additionally, patients who made up the study population were ineligible for (or refused) immediate chemotherapy.

Nivolumab was administered at a 480-mg dose every 4 weeks (Q4W) and rucaparib was given at a 600-mg dose twice per day (BID). Treatment was given until a patient’s disease progressed or unacceptable toxicity was reached. Of note, nivolumab dosing was limited to a maximum of 2 years.

The primary endpoints assessed in this cohort were overall response rate (ORR) and PSA response rate (PSA-RR). Additional secondary endpoints included overall survival (OS), time to and duration of objective response, time to PSA progression, safety and radiographic progression-free survival (rPFS).

More than half (57.7%) of the patient population in the cohort had an ECOG performance status of 1. All other patients had an ECOG status of 0. HRD status was almost evenly split in the cohort:

• 47.9% of patients had HRD-positive tumors;
• 50.7% of patients had HRD-negative tumors, and
• 1.4% of patients had an undetermined HRD status.

In terms of prior treatment with new hormonal therapies, 60.6% of patients had received abiraterone monotherapy, 23.9% received enzalutamide monotherapy and 14.1% received a combination of those two.

The median treatment duration of nivolumab was 4.6 months and 5.5 months for rucaparib.

After a median follow-up of 17.5 months, the ORR among all evaluable patients (n = 39) was 15.4% (95% CI, 5.9-30.5). Confirmed ORR among the 20 patients with HRD-positive tumors was 25% (95% CI, 8.7-49.1). Moreover, the 9 patients whose disease harbored BRCA1/2-positive mutations achieved an ORR of 33.3% (95% CI, 7.5-70.1). However, ORR was unfavorable in the 19 patients who had HRD-negative or not evaluable tumors (5.3%; 95% CI, 0.1-26.0).

The trend of noteworthy clinical activity in patients with HRD-positive tumors and BRCA1/2-positive mutations continued in confirmed PSA-RRs. Among 66 evaluable patients, confirmed PSA-RR reached 27.3% (95% CI, 17.0-39.6). The confirmed PSA-RR rate among patients with HRD-positive tumors (n = 31) was 41.9% (95% CI, 24.5-60.9). And the 13 patients with BRCA1/2-positive mutations achieved a confirmed PSA-RR of 84.6% (95% CI, 54.6-98.1).

Petrylak also noted that the results showed survival outcomes favored patients with HRD-positive tumors. Among the overall population (n = 71), the median rPFS was 8.1 months (95% CI, 5.6-10.9). The median rPFS in those with HRD-negative tumors (n = 37) was 5.6 months (95% CI, 3.7-9.1) compared to 10.9 months (95% CI, 6.7-12.0) in those with HRD-positive tumors (n = 34).

Treatment with the combination was also associated with favorable OS results. The median OS among all patients was 20.2 months (95% CI, 14.1-22.8). The median OS in the 34 patients with HRD-positive tumors was 22.7 months (95% CI, 14.1 months-NE). Patients in the HRD-negative group (n = 37) had the least favorable median OS at 19.0 months (95% CI, 8.2-22.1).

Most of the study participants (n = 64) experienced a treatment-related adverse event (TRAE) of any grade. And, approximately half (n = 36) experienced a TRAE that was classified as grade 3 or 4.

Petrylak noted that the most common TRAEs included nausea, anemia, fatigue and increased liver enzymes. He also highlighted that there were no study deaths related to treatment.

Although the results showed favorable outcomes associated with the use of nivolumab and rucaparib in these patients, Petrylak expressed that more research is needed.

“Longer follow-up is needed to better characterize the clinical benefits of adding nivolumab to rucaparib for patients with HRD-positive, chemotherapy-naïve metastatic castration resistant prostate cancer,” he concluded.

Reference

1. Petrylak DP, et al. CheckMate 9KD cohort A2 final analysis: Nivolumab (NIVO) + rucaparib for chemotherapy (CT)-naïve metastatic castration-resistant prostate cancer (mCRPC). Presented at: 2021 ESMO Annual Congress. September 16-21, 2021. Abstract 579MO.