Pembrolizumab plus enzalutamide/ADT falls short in mHSPC


The double-blind phase 3 KEYNOTE-991 trial had enrolled 1251 patients.

The phase 3 KEYNOTE-991 trial (NCT04191096) exploring the combination of pembrolizumab (Keytruda), enzalutamide (Xtandi), and androgen deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) has been stopped by Merck (MSD) due to futility, the company announced in a press release.1

The immunotherapy pembrolizumab continues to be explored in other settings in prostate cancer.

The immunotherapy pembrolizumab continues to be explored in other settings in prostate cancer.

The discontinuation of the trial follows the recommendation of an independent Data Monitoring Committee, which reviewed findings from an interim analysis showing that the addition of pembrolizumab to enzalutamide and ADT did not improve the trial’s primary end points of overall survival and radiographic progression-free survival (rPFS) compared with enzalutamide and ADT alone. Although overall toxicity was worse in the pembrolizumab arm, there were no new safety signals reported with any of the drugs.

The double-blind phase 3 KEYNOTE-991 trial had enrolled 1251 patients. Merck plans to share the data from the study at an upcoming conference.

“There is a significant unmet need for patients with advanced prostate cancer, and the outcome of this study is an important reminder that this disease remains very difficult to treat,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, stated in the press release “We are grateful to the patients and investigators for their participation in this study, and we will continue to advance our clinical development program to evaluate Keytruda-based combinations and novel candidates for patients with prostate cancer.”

Merck continues to evaluate pembrolizumab in prostate cancer in several other clinical trials, including the phase 2 KEYNOTE-365 trial (NCT02861573) and the phase 3 KEYNOTE-641 trial (NCT03834493).

Pembrolizumab does not currently have an FDA-approved indication for patients with prostate cancer; however, the drug does have a tumor-agnostic approval for the treatment of patients with tumor mutational burden–high solid tumors.

Enzalutamide success in mHSPC

Enzalutamide is approved by the FDA for the treatment of patients with mHSPC. The approval is based on the international, double-blind ARCHES trial. The study enrolled 1150 patients with histologically verified metastatic castration-sensitive prostate cancer across North America, Europe, and the Asia-Pacific region. Patients were randomized to receive ADT plus either enzalutamide or placebo. Men with both low- and high-volume disease, as well as patients who received recent treatment with docetaxel but did not have disease progression were enrolled.

The study results reviewed by the FDA showed the median rPFS was not reached with enzalutamide plus ADT and was 19.45 months with placebo plus ADT, translating to a 61% reduction in risk of radiographic progression or death (HR, 0.39; P <.0001).2 Additionally, the addition of enzalutamide was also associated with an 81% reduction in the risk of time to PSA progression (HR, 0.19; P <.0001).


1. Merck Announces KEYNOTE-991 Trial Evaluating KEYTRUDA® (pembrolizumab) Plus Enzalutamide and Androgen Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer to Stop for Futility. Published online January 25, 2023. Accessed January 26, 2023.

2. Xtandi (Enzalutamide) approved by U.S. FDA for the treatment of metastatic castration-sensitive prostate cancer [news release]. Pfizer. Published December 16, 2019. Accessed December 16, 2019.

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