Daniel Petrylak, MD, Yale Cancer Center, New Haven, CT, shares results from the phase 3 KEYNOTE-921 study, which he presented at the 2023 ASCO Genitourinary Cancers Symposium. This study evaluated the efficacy and safety of pembrolizumab plus docetaxel among patients with metastatic castration-resistant prostate cancer who had previously been treated with.

Dr Petrylak stated, that while this combination did not meet the coprimary end points of progression-free survival or overall survival, “this does not mean that we should not be looking for microsatellite instability in patients with castration-resistant disease.”

Transcript:

Hello, my name is Dr. Daniel Petrylak. I'm professor of Medicine and Urology at the Smilow Cancer Center, Yale University.

At this year's ASCO Genitourinary Cancers Symposium, we presented our data with KEYNOTE-921, which was a randomized study that compared docetaxel combined with pembrolizumab to docetaxel alone in patients with castration-resistant prostate cancer. There have been observations made that second-generation hormones, such as abiraterone and enzalutamide, actually may make patients less sensitive to docetaxel. In fact, the median survival from a number of different studies of docetaxel in castration-resistant prostate cancer is about 19 months. And there was a small publication that looked at patients who had been on abiraterone, followed by docetaxel, and found survival from the start of docetaxel treatment was about 13 months. The thought was there may have been some cross-resistance between the 2 different drugs.

Pembrolizumab, of course, is a checkpoint inhibitor, and it's being evaluated in a number of different situations in prostate cancer. In a phase 2 study there was about a 6-month improvement in overall survival in those patients who received pembrolizumab combined with docetaxel, compared to that historical control. Based upon that, as well as some other scientific observations about the interaction between chemotherapy and immune therapy, it was decided to go forth with the phase 3 study, comparing docetaxel plus prednisone, plus pembrolizumab to docetaxel prednisone alone.

The trial randomized more than 1000 patients with castration resistant prostate cancer, and the co-primary endpoints were progression-free survival as well as overall survival. Unfortunately, there was no difference in either progression-free survival or overall survival in the two different arms. In fact, the median was about 19 months for both. We look at some of the key secondary endpoints, such as objective response rates as well as the time to the next treatment. Those also were no different in the docetaxel combined with pembrolizumab, versus the docetaxel alone arm.

There were no real differences in safety, except of course, additive toxicity seen between immunotherapy and chemotherapy. There was a higher rate of pneumonitis, but that's about what we see for the combined combination of the 2 different drugs.

In summary, the combination of docetaxel and pembrolizumab, at least in unselected patients, really does not warrant further evaluation, and does not change the results of this trial, does not change the standard of care for castration-resistant prostate cancer. This does not mean that we should not be looking for microsatellite instability in patients with castration-resistant disease. That represents about 2% of patients with metastatic castration-resistant prostate cancer. And of course, pembrolizumab is FDA-approved for that particular indication across a variety of different tumors.

But we do need to understand more about the signature for those patients who do respond to docetaxel. And understand why we didn't see the survival difference when pembrolizumab is added to docetaxel and prednisone. This may come from evaluating molecular signals from this trial.

Source:

Petrylak DP, Ratta R, Matsukara N, et al. Pembrolizumab plus docetaxel for patients with metastatic castration-resistant prostate cancer (mCRPC): Randomized, double-blind, phase 3, KEYNOTE-921 study. J Clin Oncol. 2023;41(6_suppl):19. doi:10.1200/JCO.2023.41.6_suppl.19