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, including KEYNOTE-991 and KEYNOTE-641. The KEYNOTE-991 study evaluated the combination of pembrolizumab and enzalutamide for treating mCRPC, while KEYNOTE-641 study evaluated the same combination plus ADT in mHSPC patients. 

As presented in a Mini Oral Session, the data showed that KEYTRUDA-XTANDI regimen did not demonstrate an improvement in overall survival (OS) or radiographic progression-free survival (rPFS) compared to placebo-XTANDI in either of the trial. Secondary efficacy endpoints also did not show marked enhancements with the addition of pembrolizumab to enzalutamide. Furthermore, the combination was associated with a greater occurrence of Grade 3─5 adverse events compared to the control arm.

Both trials were grounded in the scientific hypothesis that primary androgen deprivation therapy (ADT) boosts immune cell presence within tumors, and this effect could be amplified through the use of immune-modulating agents like enzalutamide, potentially leading to improved responses to immunotherapy. However, the outcomes of both studies yielded unfavorable results.

Based on these disappointing results, Merck terminated both the trials, KEYNOTE-991 and KEYNOTE-641, due to futility of combination therapy in January 2023 and February 2023 respectively. The decision to halt these Phase III trials was based on the recommendation of an independent data monitoring committee.

KOL insights

“Although the results from this trial were negative, hopefully there are still lessons we can learn. We know that a small number of patients respond very well to immunotherapy and some of these harbor tumor mismatch repair deficiency or microsatellite instability. Beyond these patients, the challenge now will be to understand if there are other novel combinations that can sensitize to immunotherapy and identify the patients who may benefit from these treatments. ” – Medical Oncologist, United States.

Conclusion 

The data from the Phase III trials, KEYNOTE-991 and KEYNOTE-641 showed that the combination of pembrolizumab and enzalutamide did not result in better overall survival (OS) or radiographic progression-free survival (rPFS) when compared to placebo in both mHSPC and mCRPC patients. In addition, the group who received pembrolizumab in combination with enzalutamide experienced more treatment-related adverse events of Grade 3 or higher, as well as serious adverse events that led to discontinuation of study treatment. The studies were halted due to a lack of benefit displayed at the first scheduled interim analysis.

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. 

The exact role of immune checkpoint inhibition in the treatment of prostate cancer remains uncertain, and further research is necessary to identify the patient populations most likely to benefit from this approach. 

As per DelveInsight’s estimates, in 2022, the total prevalent population of mHSPC and mCRPC was around ~104,700 and ~128,000, respectively in the 7MM. For more insight into the Prostate cancer types including metastatic CRPC, metastatic CSPC, non-metastatic CRPC and non-metastatic CSPC, their respective geographical patient burden, treatment, and changing market landscape-related advancements,

For more detailed insights, refer to the following reports:

• Metastatic Prostate Cancer Market Forecast
• Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Market Forecast
• Non-metastatic Prostate Cancer (nmPC) Market Forecast 
• Metastatic Castration-Resistant Prostate Cancer (mCRPC) Market Forecast