The KEYNOTE-365 trial is designed to assess the safety and efficacy of pembrolizumab in four different combinations in phase 1b/phase 2 studies of patients with metastatic castration-resistant prostate cancer. Results from cohort A, combining pembrolizumab and olaparib, are reported here. Three other combinations to be evaluated in KEYNOTE-365 are pembrolizumab plus docetaxel and prednisone; pembrolizumab and enzalutamide; and pembrolizumab plus abiraterone (Zytiga, Janssen) and prednisone. Seventy patients were intended to be entered in each arm.
The scientific rationale for this trial is based on the possibility that checkpoint inhibitor therapy will be safe and effective with other therapies in metastatic castration-resistant prostate cancer.
In cohort A, this hypothesis may be particularly important in that fraction of men with metastatic castration-resistant prostate cancer whose tumors contain defects in DNA repair genes. In 10% to 12% of men with metastatic prostate cancer, such defects may be detected and lead to tumors responsive to poly(ADP) ribose polymerase (PARP) inhibitors, such as olaparib. Notably, Mateo and colleagues reported homozygous deletions, deleterious mutations or both in DNA repair genes such as CHEK-2, Fanconi anemia genes, and BRCA1 or BRCA2 in 16 men with metastatic castration-resistant prostate cancer (33% of those evaluable for mutations). Among these patients, 14 (88%) had a response to olaparib (all seven with BRCA2 loss responded).
In addition, conceptually, tumors with DNA repair defects may express mutated proteins, which could serve as neoantigens, potentially making them more responsive to checkpoint inhibitors.
Karzai and colleagues studied 17 men and found the combination of durvalumab (Imfinzi, AstraZeneca) and olaparib to be safe, with evidence of response observed.
In the current study, Yu and colleagues found no prohibitive toxicity of the combination of 200 mg IV pembrolizumab on day 1 of each 3-week dosing cycle with 400 mg oral olaparib twice daily. However, this was not an innocuous combination: grade 3 to grade 5 treatment-related adverse events occurred in 51% of 41 men. There were two deaths, including one that was treatment-related (cause unknown). Criteria for study entry did not require the presence of DNA repair defects or specific tumor expression levels of PD-1/PD-L1.
Researchers reported a PSA response rate of 13% and objective response rate per RECIST version 1.1 criteria of 7%. The disease control rate, which combines classic response and stable disease, was 29%. PD-L1 expression was detected in 27% of patients, whereas homologous recombination repair mutations were not detected in any patient.
This study confirms that pembrolizumab and olaparib are feasible in combination, but not without toxicity in pretreated men with metastatic castration-resistant prostate cancer. The response rates and survival in this small group of patients is not encouraging. However, additional work with this and similar populations enriched for expression of biomarkers that would be predicted to be associated with response is keenly awaited.
Karzai F, et al. J Immunother Cancer. 2018;doi:10.1186/s40425-018-0463-2.
Mateo J, et al. N Engl J Med. 2015;doi: 10.1056/NEJMoa1506859.
Donald L. “Skip” Trump, MD, FACP
HemOnc Today Editorial Board MemberInova Schar Cancer Institute
Disclosures: Trump reports no relevant financial disclosures.