Prostate cancer treatment with pembrolizumab and olaparib yields promising outcomes: Study

USA: According to a research published in the European Urology journal, pembrolizumab plus olaparib exhibited an antitumor effect and predicted safety in patients suffering from metastatic castration-resistant prostate cancer.

With numerous therapy options available for both hormone-sensitive and metastatic castration-resistant prostate cancer, the standard of care for the disease is continuously evolving. In the open-label phase 1b KEYNOTE-028 and phase 2 KEYNOTE-199 clinical studies, pembrolizumab, an inhibitor of the programmed cell death protein 1 (PD-1) has shown some early promise as a monotherapy. The US Food and Drug Administration has authorized olaparib, a PARP inhibitor, for a group of patients with harmful or suspected germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer whose disease has advanced on abiraterone or enzalutamide therapy.

"For individuals with metastatic castration-resistant prostate cancer, recent therapeutic advances have increased survival and quality of life. Yet the median overall survival for individuals with metastatic illness receiving newer therapy is only about 2.8 years, highlighting the need for novel drugs that might enhance patient outcomes," the authors wrote.

The goal of the study was to assess the effectiveness and safety of pembrolizumab + olaparib in metastatic castration-resistant prostate cancer.

KEYNOTE-365 is a multicohort, nonrandomized, multicenter, open-label phase 1b or 2 trial. Individuals with molecularly unselected, docetaxel-pretreated mCRPC who developed disease within 6 months of screening were recruited in cohort A in eight nations (Australia, Canada, France, Germany, New Zealand, Spain, UK, and USA). Patients received olaparib 400 mg capsules (for the first 40 patients enrolled) or 300 mg tablets twice daily until confirmed disease progression, intolerable toxicity, or withdrawal of consent. Patients also received pembrolizumab 200 mg intravenously every 3 weeks (Q3W) for up to 35 cycles (roughly 24 mo). The primary objectives were safety, confirmed PSA response rate, and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, by blinded independent central review. Radiographic progression-free survival (rPFS) and overall survival (OS) were the secondary outcomes.

Key highlights of the trial:

• 24 months was the median amount of time between the first dose and database cutoff (IQR, 22–47). 15% of PSAs were verified as being responded to.
• Patients with detectable illness had a verified ORR of 8.5% (five partial responses).
• While the median overall survival was 14 mo (95% CI, 10.4-18.2), the median rPFS was 4.5 mo (95% confidence range [CI], 4.0-6.5).
• For both the homologous recombination repair mutation and programmed death ligand 1 (PD-L1)-positive groupings, clinical activity was constant. 93 individuals (91%) experienced treatment-related adverse events. 49 individuals (48%) had grade 3-5 treatment-related adverse events.
• Six deaths (5.9%) resulted from adverse events, and two of these (a myocardial infarction and a death from an undetermined cause) were linked to the medication.

The authors concluded that molecularly unselected, docetaxel-pretreated metastatic castration-resistant prostate cancer patients who had previously received treatment showed antitumor activity in response to pembrolizumab + olaparib, which had a safety profile commensurate with the profiles of the individual drugs.

REFERENCE

Yu EY, Piulats JM, Gravis G, Fong PCC, Todenhöfer T, Laguerre B, Arranz JA, Oudard S, Massard C, Heinzelbecker J, Nordquist LT, Carles J, Kolinsky MP, Augustin M, Gurney H, Tafreshi A, Li XT, Qiu P, Poehlein CH, Schloss C, de Bono JS. Pembrolizumab plus Olaparib in Patients with Metastatic Castration-resistant Prostate Cancer: Long-term Results from the Phase 1b/2 KEYNOTE-365 Cohort A Study. Eur Urol. 2022 Aug 30:S0302-2838(22)02554-4. doi: 10.1016/j.eururo.2022.08.005. Epub ahead of print. PMID: 36055895.