Merck & Co has announced the discontinuation of its last remaining Phase 3 trial of Keytruda in prostate cancer, marking another setback in the company's efforts to expand the checkpoint inhibitor's reach into this challenging tumor type.
The KEYNOTE-641 trial, which evaluated Keytruda (pembrolizumab) in combination with Astellas/Pfizer's Xtandi (enzalutamide) for metastatic castration-resistant prostate cancer (mCRPC), failed to demonstrate improvements in both radiographic progression-free survival (rPFS) and overall survival (OS) compared to Xtandi alone. Both treatment arms included androgen deprivation therapy (ADT) as background treatment.
String of Immunotherapy Failures in Prostate Cancer
This latest disappointment follows a series of unsuccessful trials for Keytruda in prostate cancer. Just weeks earlier, Merck terminated the KEYNOTE-991 study in metastatic hormone-sensitive prostate cancer (mHSPC) for similar efficacy shortfalls. In 2022, two other Phase 3 trials - KEYNOTE-921 testing Keytruda plus chemotherapy and KEYLYNK-010 investigating a combination with the PARP inhibitor Lynparza - also failed to meet their primary endpoints.
Understanding the Challenge
The repeated failures of checkpoint inhibitors in prostate cancer reflect the unique biological characteristics of this malignancy. "Prostate cancer presents distinct challenges for immunotherapy," explains Dr. Eliav Barr, Merck's chief medical officer. "Science is rarely a straight line, and while we are disappointed in these study results, our research to investigate Keytruda in many difficult-to-treat types of cancer continues in earnest."
The disease typically exhibits fewer mutations compared to other cancers, providing limited targets for immune cell recognition. Additionally, prostate tumors are generally considered immunologically "cold," characterized by minimal immune cell infiltration into the tumor microenvironment.
Broader Implications for Immunotherapy Development
The pattern of disappointing results extends beyond Merck's program. Bristol-Myers Squibb's PD-1 inhibitor Opdivo (nivolumab) has similarly struggled to demonstrate efficacy in prostate cancer. One notable exception is the CheckMate 650 trial, which showed modest benefits combining Opdivo with the CTLA4 inhibitor Yervoy, though significant toxicity concerns led to dosing modifications.
Additional Setback in Lung Cancer
In a separate development, Merck also announced the discontinuation of KEYNOTE-789, which investigated Keytruda combined with Alimta (pemetrexed) and platinum-based chemotherapy in EGFR-mutated metastatic non-squamous non-small cell lung cancer. This unexpected failure occurred in patients whose disease had progressed on first-line tyrosine kinase inhibitors, representing a rare setback in what has traditionally been a strong therapeutic area for Keytruda.
