Phase 3 KEYLYNK-010 Trial Examining Pembrolizumab/Olaparib in mCRPC to Stop for Futility

The phase 3 KEYLYNK-001 trial (NCT03834519) evaluating the combination of pembrolizumab (Keytruda) and olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progressed following chemotherapy and either abiraterone acetate (Zytiga) or enzalutamide (Xtandi) will be discontinued for futility.¹

The decision follows a recommendation issued by an independent Data Monitoring Committee (DMC) after a review of findings from a planned interim analysis. The doublet was not found to provide an overall survival (OS) benefit vs abiraterone acetate or enzalutamide in this population, missing 1 of the primary end points of the trial.

Additionally, results from an earlier interim analysis showed that pembrolizumab plus olaparib also did not significantly improve radiographic progression-free survival (rPFS) vs the control agents in these patients, thus missing the other primary end point of KEYLYNK-001.

Although the toxicity profile of each individual agent proved to be consistent with what had been observed in prior studies, the combination was linked with a higher incidence of adverse effects that were grades 3 to 5 in severity, as well as treatment-related serious toxicities, compared with the control arm.

“There remains a significant unmet need for patients diagnosed with advanced prostate cancer, who have poor prognosis after not responding to initial therapy,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, as well as chief medical officer at Merck Research Laboratories, stated in a press release. “Merck continues to evaluate the combination of [pembrolizumab] and [olaparib] in a range of cancers, and to research other [pembrolizumab]-based combinations for patients with advanced prostate cancer. We are grateful to the patients, their families, and the investigators who made this study possible.”

Previously, data from the phase 1b/2 KEYNOTE-365 trial (NCT02861573) showed that the combination of pembrolizumab plus olaparib produced encouraging activity in patients with mCRPC who had been molecularly unselected and previously received docetaxel and second-generation hormone therapy.

The global, open-label, phase 3 KEYLYNK-010 enrolled patients with histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology who were at least 18 years of age and who had evidence of metastatic disease.² At the time of screening, these patients had to have evidence of prostate-specific antigen (PSA) progression per PCWG3 criteria, radiographic disease progression in soft tissue per PCWG3 RECIST v1.1 criteria, or radiographic disease progression in the bone per PCWG3 criteria.

Moreover, patients needed to have previously received treatment with either abiraterone acetate or enzalutamide but could not have received both agents. They must have experienced disease progression on abiraterone acetate for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC, or on enzalutamide for mCRPC for at least 8 weeks in the soft tissue. Additional eligibility criteria included: progression during or following docetaxel for mCRPC, ongoing androgen deprivation with serum testosterone of less than 50 ng/dL, acceptable organ function, and an ECOG performance status of 0 or 1.

If patients previously received olaparib or another PARP inhibitor, apalutamide (Erleada) or darolutamide (Nubeqa) for nonmetastatic CRPC, apalutamide or enzalutamide for mHSPC, radium-223 (Xofigo) or another radiopharmaceutical agent, PD-1/PD-L1/PD-L2 or another agent directed to another stimulatory or coinhibitory T-cell receptor, or a small molecule inhibitor or monoclonal antibody within 4 weeks of randomization, they were excluded. Patients also could not have known active central nervous system metastases and/or carcinomatous meningitis.

The trial set out to enroll approximately 780 patients who were randomized 2:1 to receive either pembrolizumab at 200 mg every 3 weeks plus olaparib at 300 mg twice daily (n = ~520) vs enzalutamide at 160 mg once daily or abiraterone acetate at 1000 mg once daily with prednisone or prednisolone at 5 mg twice daily (n = ~260).

Key stratification factors included prior therapy received (enzalutamide vs abiraterone acetate) and the presence of measurable disease (yes vs no).

The primary end points of the trial were OS and rPFS per PCWG3-modified RECIST v1.1 criteria and blinded independent central review (BICR). Key secondary end points included time to the initiation of the first subsequent anticancer therapy or death, time to PSA progression, objective response rate, and duration of response per PCWG3-modified RECIST v1.1 criteria and BICR, as well as safety and tolerability. Biomarker analysis served as an exploratory end point.

Merck shared that study investigators will be informed of the recommendation issued by the DMC and to advise patients on the study to talk to their physician about treatment.

Data from KEYLYNK-010 will be shared at an upcoming medical meeting.

References

1. Merck announces KEYLYNK-010 trial evaluating KEYTRUDA (pembrolizumab) in combination with LYNPARZA (olaparib) in patients with metastatic castration-resistant prostate cancer to stop for futility. News release. Merck; March 15, 2022. Accessed March 15, 2022. https://bit.ly/3wqemRl
2. Yu EY, Sook SH, Huang Y-H, et al. Phase III study of pembrolizumab (pembro) plus olaparib versus enzalutamide (enza) or abiraterone acetate (abi) in patients (pts) with metastatic castration-resistant prostate cancer who progressed on chemotherapy: KEYLYNK-010. J Clin Oncol. 2020;38(suppl 6):TPS256. doi:10.1200/JCO.2020.38.6_suppl.TPS256