KEYNOTE-991 Study Halted Due to Futility of Combination Therapy in mHSPC

The KEYNOTE-991 trial assessing the use of pembrolizumab in combination with enzalutamide and androgen-deprivation therapy has been halted as it failed to reach its primary end points.

prostate cancer, KEYNOTE-991, pembrolizumab, ADT

The KEYNOTE-991 trial (NCT04191096) investigating the combination of pembrolizumab (Keytruda) and enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC) was discontinued due to futility, according to Merck.1

Merck, the manufacturer of pembrolizumab, explained in a press release that the decision to halt the phase 3 trial was based on a recommendation of the independent data monitoring committee after results showed the study was not reaching its primary end points.

The committee reviewed data from a planned interim analysis of KEYNOTE-991 and found that the combination of the anti-PD-1 therapy and antiandrogen drug with ADT did not improve patients’ overall survival (OS) or radiographic progression-free survival (rPFS), the co-primary end points of the study, when compared with placebo plus enzalutamide and ADT.

The randomized double-blind trial enrolled 1,251 adult patients with mHSPC who had 2 or more bone lesions or visceral disease, no prior treatment with next-generation hormone agents, adequate organ function, and an ECOG performance score of 0 or 1. Enrolled patients were further stratified by whether or not they had prior docetaxel therapy and if they had a presence of high-volume disease.

Patients were randomized 1:1 to either 160 mg of enzalutamide given daily orally plus ADT and 200 mg of pembrolizumab given intravenously every 3 weeks, or the same amount of enzalutamide and ADT but with the addition of placebo. Their responses were then assessed by either CT or MRI and radionuclide bone imaging based on Prostate Cancer Working Group 3 criteria and modified RECIST v1.1 criteria done by blinded independent central review 12 weeks from the date of randomization.2

Key secondary end points of the trial included time to first subsequent anticancer therapy and time to symptomatic skeletal-related event. Other end points were progression after next line of therapy or death, the prostate-specific antigen (PSA) response rate, time to PSA progression, PSA undetectable rate, objective response rate, duration of response, time to soft tissue, and radiographic bone progression. None of these end points were met as the trial was halted due to not hitting the primary end points of OS and rPFS.

Safety was also evaluated for the pembrolizumab combination, but researchers found the safety profile of the agent to be consistent with previously reported outcomes. No new safety signals were identified with the combination, but researchers noted that it was associated with a higher incidence of grade 3-5 adverse events (AEs) when compared with patient AEs in the placebo arm. This also extended to serious AEs being more notable in the treatment arm compared with the control arm.

“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,” said Scot Ebbinghaus, MD, vice president, clinical research at Merck Research Laboratories, 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 [pembrolizumab]-based combinations and novel candidates for patients with prostate cancer.”

Merck announced that it is informing investigators of their decision to halt the trial and to advise patients in the study to speak with their physicians on next steps for treatment. The company still plans on releasing data from the interim analysis at a future medical conference.


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. News release. Merck. January 25, 2023. Accessed January 25, 2023.

2. Gratzke C, et al. 346 KEYNOTE-991: phase 3 study of pembrolizumab plus enzalutamide and androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Journal for ImmunoTherapy of Cancer. 2020;8. doi:10.1136/jitc-2020-SITC2020.0346

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