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Prostate Cancer Study Suggests Patients With DNA Repair Mutations May Benefit From Immunotherapy

CHICAGO (GenomeWeb) – A team led by the Institute of Cancer Research in the UK has used exome sequencing in an effort to tease out prostate cancer molecular features that are associated with a response to the checkpoint blockade immunotherapy drug pembrolizumab (Merck's Keytruda).

At the American Society of Clinical Oncology meeting here this week, Johann de Bono, director of the ICR's drug development unit, shared data from the Keynote-199 study, a Phase II trial comparing pembrolizumab response in 258 metastatic prostate cancer cases with or without tumor expression of PD-L1.

Just a subset of the patients responded to the drug, de Bono said. But some of those who did respond had pronounced and ongoing benefits, prompting the exome sequencing analysis of responders — an approach that has already unearthed alterations affecting several mismatch repair genes, including BRCA2 and ATM.

"[U]p to now, no one had demonstrated a benefit in men with prostate cancer," de Bono said in a statement. "Our study has found that immunotherapy can benefit a subset of men with advanced, otherwise untreatable prostate cancer, and these are most likely to include patients who have specific DNA repair mutations within their tumors."

The team's analysis focused on men with metastatic, castration-resistant prostate cancer (mCRPC) who had exhausted conventional treatment options, failing to respond to docetaxel chemotherapy followed by one or more rounds of endocrine therapy.

The patients in the study fell into three cohorts: 131 individuals in a Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease cohort with PD-L1 expression, a measurable disease cohort of 67 individuals without PD-L1 expression, and a cohort of 60 advanced cases with non-measurable disease by RECIST, but predominant bone metastases.

The investigators tracked these difficult, treatment-refractory cases on pembrolizumab every nine weeks for the first year and every 12 weeks thereafter, as long as treatment was tolerated and until disease progression, if it occurred.

One in 10 of the patients had evidence of disease control or response after six months on pembrolizumab, de Bono reported, with 9 percent to 12 percent of those treated remaining on the study across the cohorts. Though a response occurred in just a subset of patients, he noted, this group included some individuals with particularly deep responses.

However, PD-L1 expression did not distinguish responders from non-responders. This is in contrast to other tumor types, such as advanced lung cancer, where high PD-L1 expression tends to correspond to better progression-free survival or overall survival following treatment with checkpoint inhibitors alone or in combination with chemotherapy.

The team did see hints that response may coincide with DNA mismatch repair (MMR) mutations in the advanced prostate tumors, though. Such alterations are expected to produce the type of rampant DNA mutations that bump up levels of neoantigens recognized by the immune system once immune brakes come off on checkpoint blockade treatment.

De Bono recalled treating in his own clinic a 70-year-old prostate cancer patient with a large bulky pelvic mass who responded well, who had a notably high tumor mutational burden but a tumor microsatellite instability score that did not meet the threshold for MSI-high classification.

To explore such cases further, the researchers used exome sequencing to search for alterations affecting MMR or other DNA damage-related genes in six of the responders from Keynote-199, uncovering changes affecting BRCA2, ATM, CDK12, and other genes with ties to homologous recombination.

In an abstract accompanying the ASCO presentation, de Bono and co-authors wrote that pembrolizumab "shows anti-tumor activity and disease control with acceptable safety in [patients] with docetaxel-refractory mCRPC, regardless of PD-L1 status, in both RECIST-measurable and non-measurable disease."

Based on their tumor sequencing results for a handful of those patients who did respond, the investigators called for additional trials of pembrolizumab in advanced prostate cancer patients, particularly those with homologous recombination-defective tumors.

"We are planning a new clinical trial, specifically in men with prostate cancer whose tumours have mutations in DNA repair genes, to see if immunotherapy can become a standard part of their treatment," de Bono said in a statement. "It's exciting that immunotherapy could offer some men more time with their loved ones where they have such advanced disease that they have run out of existing treatment options." 

Mutations affecting genes from DNA repair and other pathways turned up in an exome sequencing meta-analysis of more than 1,000 prostate cancer cases that de Bono co-authored in Nature Genetics in April of this year — an analysis that included both primary and metastatic prostate cancer cases.

Despite the range of alterations present in such tumors, uncovering biomarkers that reliably predict response to chemotherapy or hormone treatments for advanced prostate cancer cases has been difficult.