Tumor mutational burden may predict immunotherapy response in advanced prostate cancer
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Tumor mutational burden may help predict benefit of immune checkpoint inhibitor therapy for men with metastatic castration-resistant prostate cancer, according to retrospective study results.
“Immune checkpoint inhibitors haven’t made as big of an impact in prostate cancer as they have in renal cell carcinoma or even bladder cancer,” Peter D. Zang, MD, clinical resident/fellow in the department of medical oncology and experimental therapeutics at City of Hope, told Healio. “We wanted to better predict which men with metastatic castration-resistant prostate cancer would benefit from immune checkpoint inhibitor therapy.”
Researchers evaluated data from 23 men treated at City of Hope with the anti-PD-1 antibody pembrolizumab (Keytruda, Merck) between 2014 and 2023.
Investigators used next-generation sequencing to categorize patients as having low/medium or high tumor mutational burden (TMB).
A higher percentage of men in the high TMB group achieved objective response (50% vs. 0%), with two achieving complete response. Half of men in the high TMB group achieved PSA reduction of at least 50%, compared with none in the TMB low/medium group.
Investigators also reported significantly longer median PFS in the high TMB group (19.3 months vs. 2.5 months; HR = 0.08; 95% CI, 0.02-0.4).
Researchers observed a trend toward improved OS in the high TMB group but the difference did not reach statistical significance (HR = 0.37; 95% CI, 0.11-1.19).
Healio spoke with Zang about the study findings, their potential implications and the questions that must be answered in future research.
Healio: What inspired you to conduct this study?
Zang: Clinical trials using monotherapy with immune checkpoint inhibitors for metastatic castration-resistant prostate cancer have been negative, and even some of the combination trials have been negative. The only exception has been the CONTACT-02 trial, but we’re still waiting for the final OS data on that. We see patients in the clinic sometimes with microsatellite instability (MSI)-high status or TMB-high status, and they are able to get pembrolizumab approved for therapy. Some of these patients respond really well to pembrolizumab. Responses can be quite profound and fairly durable. We need to do a better job finding out which patients these are.
Healio: How did you conduct the study?
Zang: We identified 23 patients treated with pembrolizumab for metastatic castration-resistant prostate cancer. All received at least one cycle of pembrolizumab. It was a small sample size. Study participants either had MSI-high status or TMB-high status. Ten patients had TMB-high status and 13 had TMB-low/medium status. Of the 10 TMB-high patients, seven were microsatellite stable and three were MSI high.
Healio: What are the potential implications of your findings?
Zang: This is more of a hypothesis-generating study, but the hope is that perhaps we are seeing a link. MSI-high status can be a predictor of response but, because the majority of our patients with TMB-high status were microsatellite stable, perhaps TMB-high status by itself could be a predictor of response with immunotherapy. The hope is that we can conduct more research with a larger cohort. This will be challenging, but if we see the same findings, it could provide evidence that this could be a good predictor for response to checkpoint inhibitors. Other groups are looking at this. In fact, a recent publication from Mayo Clinic showed MSI-high status among these patients was a better predictor for response. There is a lot of work to be done in terms of clarifying our findings and other groups’ findings.
In general, I believe there should be more work done to better predict the patients who respond to checkpoint inhibitors with prostate cancer. Even if it’s a small percentage of patients, some really do get a huge benefit from these therapies, and this could be game-changing for them. That is [especially important] as we enter an era of increasingly personalized medicine.
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For more information:
Peter D. Zang, MD, can be reached at pzang@coh.org.
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