Immunotherapy drugs called checkpoint inhibitors are a promising cancer treatment, but so far only a minority of people respond to them. This has been especially notable in the treatment of prostate cancer, the most common cancer in men, after skin cancer. Researchers at Memorial Sloan Kettering Cancer Center (MSK) are trying to figure out ways to identify which prostate cancer patients will benefit from checkpoint inhibitor drugs in addition to developing more effective therapies.
By using in-depth genetic analysis of prostate cancer tumors from MSK patients, the scientists are clarifying how various genetic alterations can predict the response to checkpoint inhibitors. The scientists analyzed the tumors using MSK-IMPACT®, a genetic test developed at MSK that looks for cancer-related mutations.
This effort to make checkpoint inhibitor immunotherapy effective for prostate cancer is being led by two MSK physician-scientists. Medical oncologist Wassim Abida, MD, PhD, is an expert in prostate cancer genomics who treats prostate cancer patients and conducts clinical trials. He is the Director of Translational Research in Prostate Cancer and has published extensively on prostate cancer. Medical oncologist David Solit, MD, cares for people with genitourinary cancers, is Director of the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, and also has published extensively on prostate cancer.
We spoke with Dr. Abida to get updates on this research and what it means for the treatment of people with prostate cancer.
When should checkpoint inhibitor immunotherapy be used? For which genetic mutations?
Checkpoint inhibitors are approved for use in people whose cancer cells have certain genetic traits – including MMRd, TMB-H and MSI-H.
- A deficiency in repairing DNA is called mismatch repair (MMRd), which causes mutations to pile up. While a typical cancer cell has just a few dozen mutations, MMR-deficient cells can have hundreds or even thousands.
- Cancer cells with many mutations are classified as high tumor mutational burden (TMB-H).
- Tumors with an MMR deficiency often have a specific genetic alteration called microsatellite instability-high (MSI-H). Cells with MSI-H have repeated sequences of DNA, which means that something has gone awry in the repair process.
Checkpoint inhibitors are especially effective in people whose cancer cells are MSI-H. In 2017, the U.S. Food and Drug Administration (FDA) approved the checkpoint inhibitor pembrolizumab (Keytruda®) for MSI-H cancers. Pembrolizumab was the first drug approved based on a tumor’s genetic profile rather than where the cancer originated. Another FDA approval for pembrolizumab came in 2020 for patients with high tumor mutational burden, even if they did not have microsatellite instability but were instead microsatellite stable (MSS).
What have you learned about high microsatellite instability in prostate cancer, and why is this important?
In 2019, we published a study in JAMA Oncology in which we reported that, among slightly more than 1,000 prostate cancer patients, only about 3% had MSI-high tumors. So it was a small subset, but in this group, a significant number responded well to pembrolizumab or a similar immunotherapy drug — and the benefit was lasting.
In 2024, Dr. Solit and I published findings in Clinical Cancer Research that shed further light on microsatellite instability, tumor mutational burden, and how they affect response to checkpoint inhibitors in people with prostate cancer.
What were the findings of your latest study on microsatellite instability in late-stage prostate cancer?
The 2024 study analyzed tumors from 2,257 people with stage 3 or 4 prostate cancer — more than twice as large as the previous group. We found that 96 men (4.3%) had the type of genetic alterations that made their prostate cancer a candidate for checkpoint inhibitor immunotherapy — either high microsatellite instability or high tumor mutational burden.
Within this group:
- 63 men (2.8% of all patients) had microsatellite instability-high (MSI-H) tumors.
- 33 men (1.5% of all patients) had high tumor mutational burden, microsatellite-stable (TMB-H/MSS) tumors.
Prostate Cancer Checkpoint Inhibitor Treatment Results
Among the patients who received checkpoint inhibitors, people with MSI-H tumors responded much better to the treatment compared with those who had TMB-H/MSS tumors.
- In people with MSI-H prostate cancers, 45% of cases had a measurable decrease in tumor size or the amount of cancer in the body. Some people had a remarkable response, with disappearance of the tumors that persisted even years after stopping immunotherapy and even hormonal therapy.
- None of the TMB-H/MSS prostate tumors had a similar response.
Put simply, the study showed how critical microsatellite instability is to having a good response to checkpoint inhibitor immunotherapy. The study also showed a possible reason for this superior response: The MSI-H tumors had an especially high tumor mutational burden and additional genetic alterations that tend to draw the notice of the immune system — in turn making the immunotherapy work better.
How could this discovery change treatment for people with prostate cancer?
This study further supports the use of routine tumor sequencing of advanced (stage 3 or 4) prostate cancer patients to identify those with MSI-H tumors. At MSK, we are already using MSK-IMPACT to sequence tumors from all people with advanced cancers.
Although a response rate of about 45% is good for a cancer treatment, we need to investigate why checkpoint inhibitors don’t work for everyone with MSI-H prostate cancer. We need a better understanding of which other factors are driving the cancer.
We are also testing whether men with prostate cancer that is MSI-H that has not spread beyond the prostate (localized prostate cancer) can benefit from immunotherapy and avoid surgery and radiation. A clinical trial reported in the New England Journal of Medicine by gastrointestinal oncologist Andrea Cercek, MD, and gastrointestinal oncologist Luiz Diaz Jr., MD, has shown that this approach can be effective.
Does the presence of high microsatellite instability in someone with prostate cancer have any impact beyond immunotherapy treatment?
Yes. In our 2019 study, about a fifth of MSI-high patients also had a mutation in a gene associated with Lynch syndrome, an inherited condition that has been shown to increase the risk of developing certain types of cancer. In 2018, an MSK-led study estimated that people with high MSI had a 1 in 6 chance of carrying Lynch syndrome mutations. Testing for Lynch syndrome mutations should be considered for people with MSI-high prostate cancer because it can have implications for their family members as well.
We also found that the MSI-high characteristic occasionally did not appear until after the disease spread, so repeat biopsy testing, including “liquid biopsy” of blood samples is reasonable if the prostate cancer has progressed. We’ve learned MSI can occasionally emerge during the course of the disease.
Key Takeaways
- About 2.8% of people with prostate cancer have microsatellite instability-high (MSI-H), mismatch-repair deficient (MMRd) tumors.
- Checkpoint inhibitors, a type of immunotherapy, can be an effective treatment in nearly half of people with MSI-H, MMRd prostate cancer tumors.
- MSK uses MSK-IMPACT to do tumor genetic testing for all patients with advanced cancer, so MSK specialists can identify those most likely to benefit from checkpoint inhibitors.
- About one-fifth of people with MSI-H prostate cancer may have Lynch syndrome, which can run in families. Because Lynch syndrome can increase the risk of getting cancer, the families of patients with MSI-H prostate cancer should get tested for this condition.
- Because MSI-H characteristics may appear only once the cancer has spread, it’s reasonable to repeat DNA testing through a tumor biopsy or “liquid biopsy” of the blood.
Dr. Solit holds the Geoffrey Beene Chair.