KEYNOTE-991 Trial of Pembrolizumab Plus Enzalutamide/ADT in mHSPC to Stop for Futility

Merck is discontinuing the phase 3 KEYNOTE-991 trial (NCT04191096) evaluating pembrolizumab (Keytruda) plus enzalutamide (Xtandi) and androgen deprivation therapy (ADT) vs placebo plus enzalutamide/ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) due to futility, according to an announcement from the company.¹

An independent data monitoring committee recommended stopping the trial following a planned interim analysis. Findings showed that pembrolizumab plus enzalutamide/ADT did not improve overall survival (OS) or radiographic progression-free survival (rPFS) compared with enzalutamide/ADT alone.

Merck plans to present full data from the trial at an upcoming medical meeting.

“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 of clinical research at Merck Research Laboratories, stated in a news 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.”

Patients in the randomized, double-blind KEYNOTE-991 trial were required to have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology, an ECOG performance status of 0 or 1, and adequate organ function.²

Key exclusion criteria included a known additional malignancy that was progressing or required active treatment in the last 3 years; active autoimmune disease that required systemic treatment in the past 2 years; a diagnosis of immunodeficiency or chronic systemic steroid therapy; major surgery within 28 days prior to randomization and lack of adequate recovery from toxicities and/or complications; active infection requiring systemic therapy; a history of non-infectious pneumonitis that required steroids or current pneumonitis; or known or suspected central nervous system metastases and/or carcinomatous meningitis.

Investigators randomly assigned 1251 patients to 200 mg of intravenous pembrolizumab every 3 weeks for up to 2 years plus 160 mg of daily enzalutamide and standard-of-care ADT or placebo plus enzalutamide and ADT. Patients were allowed to receive enzalutamide and ADT until criteria for discontinuation were met.

OS and rPFS per Prostate Cancer Working Group-modified RECIST v1.1 criteria as assessed by blinded independent central review served as the trial’s co-primary end points. Secondary end points included objective response rate, duration of response, and safety.

Although the safety profile of pembrolizumab was consistent with previous studies and no new safety signals were observed, the pembrolizumab-based combination was associated with a higher incidence of grade 3 to 5 adverse effects (AEs) and serious AEs compared with enzalutamide and ADT alone.

References

• 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. http://bit.ly/3j21nkp
• Efficacy and safety of pembrolizumab (MK-3475) plus enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus enzalutamide plus ADT in participants with metastatic hormone-sensitive prostate cancer (mHSPC) (MK-3475-991/KEYNOTE-991). ClinicalTrials.gov. Updated August 19, 2022. Accessed January 25, 2023. https://clinicaltrials.gov/ct2/show/NCT04191096