Dr. Charles G. Drake recently joined New York-Presbyterian/ Columbia University Medical Center as the Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center.
Prostatepedia spoke with him about current trends in immunotherapy for prostate cancer
What are some of the more promising approaches to immunotherapy being investigated now?
Dr. Drake: I’m not 100% sure that everybody in the prostate cancer community is aware of this, but investigators at Merck did what is called a basket trial. They looked at patients with cancers that have a defect in what is called mismatch repair. Cancers that have a defective mismatch repair accumulate many mutations. Those mutations serve as antigens, or targets, for the immune system. It was first shown by Drs. Luis Diaz and Dung Le at Johns Hopkins that in colorectal cancer, where mismatch repair is common, checkpoint blockade with anti-PD-1 is very effective. It turns out that there are mismatch repair patients with every kind of cancer, including prostate cancer.
Based on this large basket trial, the anti-PD-1 antibody Keytruda (pembrolizumab) was recently approved for patients’ cancers that have mismatch repair defects. Across multiple tumor types, there have been really dramatic responses reported in the literature. This means that prostate cancer patients who have mismatch repair defects now have a second immunotherapy option. What percentage of prostate cancer patients have mismatch repair? It’s probably on the lower side, likely in the 3 to 5% range, but since prostate cancer is so common, that is actually a lot of patients.
I think that is fairly exciting and that perhaps the entire community is not completely aware that it is happening. True mismatch repair is rare in prostate cancer, but a significant fraction of patients have other mutations that lead to DNA damage repair defects. Those defects are different and are called DNA damage repair mutations. There have been some studies suggesting that this is actually pretty common in men with metastatic disease—as high as 10 to 20%. Those patients have been shown in a landmark paper by Dr. Johann de Bono published in the New England Journal of Medicine to respond to PARP inhibitors, which are reasonably well-tolerated oral drugs. There are now several ongoing trials testing this.
It is possible that these same patients might also respond to immunotherapy. I was part of a trial that Dr. Julie Graff published last summer that showed that out of the first 10 patients treated with Keytruda (pembrolizumab) who are progressing on Xtandi (enzalutamide), about three had a really beautiful response. Only one had true mismatch repair, but it could be that the other patients have mutations in DNA damage repair. That is important because that would extend the number of patients with prostate cancer who might be eligible for, or likely to respond to, anti-PD-1 or anti-PD-L1 agents.