Decreased Survival for Prostate Cancers With dMMR

In Search of the Best Immunotherapy Candidates

Nick Mulcahy

September 10, 2018

For men with advanced prostate cancer who have certain genomic mutations, overall survival (OS) is roughly half that of patients who do not have the genetic anomalies, according to a new study that aims to refine the ways in which such mutations are identified.

The study was published online September 4 in the Journal of Clinical Investigation.

In the analysis, 8.1% of a cohort of 124 men with advanced disease had defective mismatch repair (dMMR) cancers, which means they may have benefited from immune checkpoint–inhibiting therapies, report Daniel Nava Rodrigues, MD, of the Institute of Cancer Research, London, United Kingdom, and international colleagues.

In the United States, the checkpoint inhibitor pembrolizumab (Keytruda, Merck) was approved in 2017 for use in all dMMR tumors and all tumors with a high degree of microsatellite instability (MSI-H). This approval was hailed as a milestone, as it was the first time that a drug was approved for use in a specific genetic mutation regardless of the site of the cancer. Such drugs are termed tissue-agnostic antitumor agents.

The dMMR amd MSI-H defects are found most commonly in colorectal, endometrial, and gastrointestinal cancers; they appear less commonly in other cancers, including those of the prostate.

In the new study, Rodrigues and colleagues sought to further characterize differences in clinical behavior between dMMR and non-dMMR prostate cancers (the latter are known as MMR-proficient [pMMR] cancers).

The team studied 127 biopsy specimens from 124 patients with advanced prostate cancer who underwent treatment at the Royal Marsden Hospital in London, United Kingdom. They determined dMMR status on the basis of either loss of mismatch repair protein expression or MSI, using polymerase chain reaction assay.

Ten men had dMMR cancers; the other 114 had pMMR cancers.

Advanced prostate cancer was defined as metastatic castration-resistant disease, meaning that the disease had progressed despite hormone therapy.

From time of diagnosis, the median OS was 8.5 years in the pMMR group vs 4.1 years in the dMMR group, per Kaplan-Meier survival analysis (log-rank test, P = .07). From the time of hormone therapy initiation, median OS was 7.0 years for the pMMR group vs 3.8 years for the dMMR group (log-rank test, P = .003).

The findings indicate that dMMR is a "clinically aggressive phenotype" and that such tumors "constitute a discrete subtype with decreased survival time," write the authors.

Furthermore, half of all men with dMMR cancers had high PD-L1 levels; by contrast, fewer than 10% of the men with pMMR cancers had high PD-L1 levels. Such high levels are a hallmark of tumors that are more likely to respond to immunotherapy with programmed cell death checkpoint inhibitors.

However, the authors point out that two issues exist in this setting with respect to diagnosis and treatment: first, dMMR cancers do not always respond to immunotherapy, and second, cancers that respond to immune checkpoint inhibitors are not necessarily dMMR cancers, as determined per conventional IHC and PCR assays.

To improve upon this situation, they hypothesized that a "multipronged approach is necessary to adequately stratify mCRPC [metastatic castration-resistant prostate cancer] patients who could potentially benefit from immunotherapy with immune checkpoint–blocking drugs."

After determining dMMR status, the team evaluated MSI by targeted panel next-generation sequencing (MSINGS) using biopsy specimens from the same Royal Marsden cohort and those from another group of 254 advanced prostate cancer samples from a Stand Up to Cancer/Prostate Cancer Foundation (SU2C/PCF) cohort.

The researchers conclude that "dMMR exome mutational signatures and high MSINGS scores are associated with complex immune mRNA profiles that may require further sub-classification based, for example, on the degree of myeloid cell infiltration, which can affect clinical behavior and responses to immune checkpoint therapies."

The new study builds on earlier work done by these same researchers, the results of which were presented in 2018 at the American Society of Clinical Oncology annual meeting.

As reported at the time by Medscape Medical News, a small proportion of men with advanced prostate cancer for whom other treatments had failed experienced a significant and ongoing benefit with pembrolizumab.

After 1 year of treatment, the immunotherapy was found to be beneficial in 11% of the 258 men with metastatic castration-resistant prostate cancer, including some in whom PD-L1 was not expressed.

The study was funded by Movember, Prostate Cancer UK, the Prostate Cancer Foundation, SU2C, and Cancer Research UK. Multiple study authors have disclosed financial ties to industry, including Merck. One study author has applied for a patent related to microsatellite instability testing.

J Clin Invest. Published online September 4, 2018. Full text

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