Pembrolizumab/Olaparib Trial Ended After Showing No OS Benefit in mCRPC

A trial of pembrolizumab (Keytruda) plus olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC) has been discontinued after it failed to show overall survival (OS) benefit at an interim analysis, according to a press release from Merck.¹

The phase 3 KEYLYNK-010 trial (NCT03834519) did not demonstrate OS benefit over chemotherapy plus either abiraterone acetate (Zytiga) or enzalutamide (Xtandi). At a previous interim analysis, it did not meet its other primary end point of improvement in radiographic progression-free survival (rPFS). The combination also showed higher incidence of serious adverse events (AEs) than the control arms.

KEYLYNK-010 investigators combined pembrolizumab, a PD-1 inhibitor, with olaparib, a PARP inhibitor, following data from the phase 1b/2 KEYNOTE-365 study (NCT02861573), which showed clinical activity in patients with docetaxel-pretreated mCRPC.² Patients in the KEYLYNK-010 study were eligible if they had received docetaxel-based chemotherapy and either abiraterone or enzalutamide for mCPRC.¹

There were 793 patients randomized 2:1 to receive 200 mg pembrolizumab intravenously every 3 weeks plus 300 mg olaparib orally twice daily versus chemotherapy plus either 1000 mg abiraterone once daily with 5 mg prednisone/prednisolone twice daily or 160 mg enzalutamide daily, depending on which they had not received before.

Responses were assessed by CT/MRI and radionuclide bone imaging every 9 weeks in the first year and every 12 weeks afterward, and treatment was to continue for up to 2 years.³ In addition to the primary end points of OS and rPFS, secondary end points included objective response rate, duration of response, and safety.

The trial was discontinued based on recommendation from the data monitoring committee after not meeting its OS goal.¹ Data from this trial will be presented at an upcoming conference, according to the press release.

“Merck continues to evaluate the combination of Keytruda and Lynparza in a range of cancers, and to research other Keytruda-based combinations for patients with advanced prostate cancer,” Roy Baynes, MD, PhD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, said in a statement. “We are grateful to the patients, their families and the investigators who made this study possible.”

Other trials that are studying the combination of pembrolizumab and olaparib include the KEYLYNK-008 (NCT03976362) trial for patients with advanced lung cancer, the KEYLYNK-001 trial (NCT03740165) for those with ovarian cancer, the KEYLYNK-009 trial (NCT04191135) for triple-negative breast cancer, and the KEYLYNK-007 trial (NCT04123366) of homologous recombination repair mutation (HRRm) and/or homologous recombination deficiency (HRD)-positive solid tumors. Olaparib with abiraterone for prostate cancer is being evaluated in the phase 3 PROpel trial (NCT03732820) as first-line therapy for mCRPC.

“There remains a significant unmet need for patients diagnosed with advanced prostate cancer, who have a poor prognosis after not responding to initial therapy,” Baynes said.

_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. Merck. Published March 15, 2022. Accessed March 16, 2022. https://bit.ly/3N0vzGA}

_{2. Yu EY, Piulats JM, Gravis G, et al. KEYNOTE-365 cohort A updated results: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(suppl 6):100. doi:10.1200/JCO.2020.38.6_suppl.100}

_{3. Yu EY, Xu L, Kim J, Antonarakis ES. KEYLYNK-010: Phase III study of pembrolizumab (pembro) plus olaparib (OLA) vs enzalutamide (ENZA) or abiraterone (ABI) in ENZA- or ABI-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who had progression on chemotherapy (CTx). Ann Oncol. 2019;30(suppl 5):V351-V352. doi:10.1093/annonc/mdz248.050}