Nivolumab plus rucaparib shows ‘noteworthy activity’ in subset of men with prostate cancer
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Nivolumab plus rucaparib demonstrated activity among men with chemotherapy-naive metastatic castration-resistant prostate cancer, according to results of cohort A2 of the CheckMate 9KD trial presented during the virtual ESMO Congress 2021.
“In this cohort of patients ... the combination of nivolumab [Opdivo, Bristol Myers Squibb] and rucaparib [Rubraca, Clovis Oncology] showed clinical efficacy in patients with HRD-positive tumors, with noteworthy activity in those patients harboring BRCA mutations,” Daniel P. Petrylak, MD, professor of medicine and urology at Smilow Cancer Hospital at Yale School of Medicine, said during a presentation. “Clinical activity of the combination was limited in patients with HRD-negative tumors.”
Petrylak and colleagues reported final results of cohort A2, which included 71 men (median age, 73 years) with chemotherapy-naive metastatic castration-resistant prostate cancer who received ongoing androgen deprivation therapy and previous therapy with abiraterone, enzalutamide (Xtandi, Pfizer) or apalutamide (Erleada, Janssen Oncology) for metastatic disease but not poly(ADP)-ribose polymerase (PARP) inhibitor treatment. Most of the men (54.9%) had measurable disease, 50.7% had homologous recombination deficiency (HRD)-negative tumors and 23.9% had visceral metastases.
The men received 480 mg nivolumab every 4 weeks plus 600 mg rucaparib twice daily until disease progression or unacceptable toxicity.
Objective response rate and PSA response rate (PSA-RR) among all treated men and those with HRD-positive tumors served as co-primary endpoints. Radiographic PFS, OS and safety served as secondary endpoints.
Median follow-up was 17.5 months. Median treatment duration was 4.6 months with nivolumab and 5.5 months with rucaparib.
Sixty-five men (91.5%) had stopped treatment by the time of the final database lock March 21, most because of disease progression.
Results showed a confirmed ORR of 15.4% (95% CI, 5.9-30.5) and PSA-RR of 27.3% (95% CI, 17-39.6) overall. Men with HRD-positive vs. HRD-negative disease had higher ORR (25% vs. 5.3%) and PSA-RR (41.9% vs. 14.3%). BRCA1/BRCA2 were the most common mutations in the cohort and were associated with improved outcomes (ORR = 33.3%; PSA-RR = 84.6%).
Median radiographic PFS was 8.1 months (95% CI, 5.6-10.9) and median OS was 20.2 months (14.1-22.8), and both were numerically longer among patients with HRD-positive vs. -negative tumors.
Safety results appeared consistent with the profiles of each individual agent. About half (50.7%) of men experienced grade 3 to grade 4 treatment-related adverse events, including anemia (14.1%) and increased alanine aminotransferase (12.7%). Any-grade treatment-related adverse events occurred among 90.1% of patients and led 23.9% of patients to discontinue therapy. No treatment-related deaths occurred.
“Longer follow-up is needed to better characterize the clinical benefits of adding nivolumab to rucaparib for patients with HRD-positive, chemotherapy-naive metastatic castrate-resistant prostate cancer,” Petrylak said. “The PSA response rate of 84.6% in patients with BRCA-positive tumors justifies further evaluation of this combination in patients with BRCA1 or BRCA2 mutations.”
Perspective
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Yung Lyou, MD, PhD
On May 15, 2020, the FDA granted accelerated approval for use of the PARP inhibitor rucaparib among men with metastatic castration-resistant prostate cancer with a deleterious BRCA1/BRCA2 mutation (germline and/or somatic) who previously had been treated with an anti-androgen and taxane-based chemotherapy. The FDA approval was based on data from the TRITON2 study, a single-arm, open-label phase 2 clinical trial that showed rucaparib had a confirmed ORR by blinded independent review of 44%. This FDA approval was significant in that it added another available PARP inhibitor that could be used in the treatment of men with advanced metastatic castration-resistant prostate cancer with deleterious BRCA1/BRCA2 mutations.
In this study presented by Petrylak and colleagues, the investigators asked this question: If a combination of nivolumab and rucaparib could be given safely in an earlier chemotherapy treatment-naive setting, would it show some hints of effectiveness? As expected, the investigators found men who had HRD-positive disease and, in particular, deleterious BRCA1/BRCA2 mutations derived the greatest benefit from this combination. Although these results cannot be directly compared with the TRITON2 clinical trial due to differences in study design and patient population, the ORR in HRD-positive patients with BRCA1/BRCA2 mutations is encouraging enough to merit a broader phase 2 clinical trial with a larger sample size if this combination can, indeed, be beneficial in an earlier treatment setting for these patients.
Another question from this study that merits future investigation would be to determine how much clinical benefit nivolumab adds in addition to rucaparib when used in prostate cancer treatments.
Reference:
Abida W, et al. J Clin Oncol. 2020;doi:10.1200/JCO.20.01035.
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Petrylak DP, et at. Abstract 579MO. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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