ESMO 2023 is on the horizon, and prominent pharmaceutical entities like Amgen, Novartis, Janssen, and Merck are poised for the conference, ready to unveil data readouts and conclusive analyses. In 2022, the total prevalent population of metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) was around ~104,700 and ~128,000, respectively in the 7MM. This content focuses on Merck’s discontinued Phase III trials of pembrolizumab in mCRPC and mHSPC. 

Prostate Cancer Highlights

• Abstract Number – 1771MO and 1772MO 
• Abstract Type - Mini Oral session
• Indication – mHSPC and mCRPC

Title: Two Phase III pembrolizumab trials (KEYNOTE-991 and KEYNOTE-641) showed lack of benefit in prostate cancer

Executive Summary - Merck discontinued two Phase III studies, KEYNOTE-991 and KEYNOTE-641, evaluating KEYTRUDA in combination with enzalutamide and androgen deprivation therapy (ADT) in mHSPC and mCRPC, respectively, as they failed to demonstrate significant benefit in prostate cancer.

Main Content: 

KEYTRUDA, a PD-1 blocking antibody has failed in four Phase III trials that comprised an aggressive prostate cancer program launched by Merck in 2019. In January 2023, Merck terminated KEYNOTE-991 study due to futility of combination therapy in metastatic mHSPC, and in the following month, the company discontinued another trial, coded Keynote-641, evaluating KEYTRUDA in combination with enzalutamide and ADT for the treatment of patients with metastatic castration-resistant prostate cancer mCRPC. The decision to halt these Phase III trials was based on the recommendation of an independent data monitoring committee which reviewed data from a planned interim analysis. The data showed that KEYTRUDA-XTANDI-ADT regimen did not demonstrate an improvement in overall survival (OS) or radiographic progression-free survival (rPFS) compared to placebo-XTANDI-ADT in mHSPC as well as in mCRPC.  In addition, the combination was associated with a greater occurrence of Grade 3─5 adverse events compared to the control arm.

With a series of discouraging studies in recent years, KEYTRUDA is struggling to make headway for its checkpoint inhibitor in prostate cancer. The challenge is that it is difficult for PD-1/PD-L1 antibody therapy to work well in an immunologically cold tumor like prostate cancer which does not have many infiltrating T cells. Thus, targeting PD-1 or PD-L1 in a microenvironment where there are few T cells expressing these pathways may not lead to antitumor responses. 

In addition, a comparable lack of success could also be seen with Bristol Myers Squibb’s PD-1 inhibitor, OPDIVO, where the results from the discontinued Phase III CheckMate -7DX trial evaluating OPDIVO in combination with docetaxel for mCRPC did not meet the primary endpoints of rPFS at final analysis, nor OS at an interim analysis. 

However, despite the disappointing results of KEYTRUDA in prostate cancer, Merck still plans on releasing data from the interim analysis at the upcoming medical conference.

List of Abstracts to be presented in ESMO 2023