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Pembrolizumab plus olaparib safe, active in docetaxel-pretreated men with prostate cancer
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SAN FRANCISCO — The combination of pembrolizumab and olaparib demonstrated activity in men with metastatic castration-resistant prostate cancer who previously received docetaxel and no more than two second-generation hormone treatments, according to results from the phase 1b/2 KEYNOTE-365 umbrella trial presented at Genitourinary Cancers Symposium.
“This is a heavily pretreated patient population; they receive a lot of different therapies, and although there are six FDA-approved therapies that prolong survival for metastatic, castration-resistant prostate cancer, once you’ve gotten past docetaxel chemotherapy, there really aren’t a lot of options,” Evan Y. Yu, MD, professor in the department of medicine, division of oncology, at University of Washington, and a medical oncologist with Seattle Cancer Care Alliance, said in an interview with HemOnc Today. “The hormone therapies have basically been exhausted. Our trial allowed patients to receive both docetaxel and cabazitaxel [Jetvana, Sanofi Genzyme]. So, many of the patients were in a setting where they basically received just about all therapies.”
Yu and colleagues evaluated 41 men (median age, 69 years; range, 47-80) in cohort A of the KEYNOTE-365 trial. This group included docetaxel-pretreated men with metastatic castration-resistant prostate cancer (27% PD-L1-positive; 42% visceral disease) that progressed within 6 months before screening, based on either PSA progression or radiographic progression in bone or soft tissue. The trial allowed men who received two or fewer second-generation hormone therapies and one previous chemotherapy treatment to enroll.
No men harbored the homologous recombination repair mutation.
Yu described the study cohort as a “truly molecularly unselected patient population.”
HemOnc Today. “We did whole-exome sequencing in 17 patients where we had some tissue available, and we didn’t definitively find a DNA repair alteration in any of those patients.”
Men received 200 mg IV pembrolizumab (Keytruda, Merck) every 3 weeks and 400 mg oral olaparib (Lynparza, AstraZeneca) twice daily.
Safety and PSA response rate — defined as confirmed PSA decrease of at least 50% — served as the primary endpoints. Objective response rate per RECIST version 1.1 criteria, disease control rate (complete response, partial response and stable disease for 6 months or longer) time to PSA progression, composite response rate, radiographic PFS and OS served as key secondary endpoints.
Median follow-up was 11 months.
Among 28 men with RECIST-measurable disease, 39% experienced a reduction in tumor burden, including eight men with a reduction of 30% or greater.
Results showed an ORR for the RECIST-measurable group of 7% (95% CI, 1-23), including two partial responses.
Among the overall cohort, researchers observed median radiographic PFS of 4.7 months (95% CI, 4-7.7), median OS of 13.5 months (95% CI, 7.7-not reached) and PSA response of 12% (n = 5).
Most patients (95%) experienced treatment-related adverse events, including anemia (37%), fatigue (34%) and nausea (34%).
Grade 3 to grade 5 treatment-related adverse events occurred in 21 (51%) men. Two men died, one due to an unknown treatment-associated cause.
he and his colleagues are expanding the current study into a phase 3 trial, KEYLYNK-010. The trial will enroll 100 patients with metastatic castration-resistant prostate cancer who have received previous docetaxel and either abiraterone or enzalutamide (Xtandi; Astellas, Pfizer Oncology).
“We’re excited to do that,” Yu said. “We don’t know yet if this will affect standard of care, but we’re going to find out.” – by Jennifer Byrne
Disclosure s : Yu reports a consultant role with and funding/research grants from Merck. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Donald L. “Skip” Trump, MD, FACP
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.
References:
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.
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