Although rare overall, about half of patients with prostate cancer with a specific determinant of immunotherapy response — microsatellite instability (MSI)-high/mismatch repair-deficient (dMMR) phenotype — had meaningful clinical benefit from treatment with checkpoint inhibitors, a new study found.
Among 1,551 tumor samples taken from 1,346 patients with prostate cancer, about 3% — or 32 patients — had MSI-high/dMMR disease. 11 of these patients had castration-resistant prostate cancer (CRPC) and received an anti-PD-1/PD-L1 therapy, with more than half achieving a greater than 50% decline in prostate-specific antigen (PSA) levels, according to Wassim Abida, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, and colleagues.
And a small number of patients acquired the MSI-high phenotype later in the course of the disease, after it had metastasized, as reported in JAMA Oncology.
“Although MSI may have been subclonal in the earlier samples and thus missed owing to tumor heterogeneity, this result indicates that it was not a truncal event and would have been missed if only an older archival sample had been profiled,” the authors wrote. “These data suggest that metastatic tissue may represent the optimal material for assessment of MSI status.”
The study included tumor samples taken from patients undergoing treatment for prostate cancer at Memorial Sloan Kettering Cancer Center from 2015 to 2018. Samples were analyzed using a targeted sequencing assay. Patients were assigned MSIsensor scores of high, indeterminate, or low.
There were 1,033 patients with adequate tumor quality to undergo analysis for MSI status. Analyses revealed that 3.1% of patients had MSI-high/dMMR prostate cancer with 2.2% having high MSIsensor scores. Nine patients had indeterminate scores with evidence of dMMR.
About one in five (21.9%) patients with MSI-high/dMMR disease had a pathogenic germline mutation in a Lynch syndrome-associated gene. These included five patients with mutations in MSH2, one with a mutation in MSH6, and one with a mutation in PMS2.
As of May 2018, 11 of the 32 patients with MSI-high/dMMR disease had undergone treatment with an anti-PD-1 or anti-PD-L1 therapy for metastatic CRPC. Duration of therapy ranged from 4.6 to 89 weeks. Decline in PSA levels >50% occurred in 54.5% of patients and four patients had declines >99%. In addition, four patients achieved radiographic objective response. Overall, 45.5% of the 11 patients had a durable clinical benefit from anti-PD-1/PD-L1 therapy.
These results confirm a previous study that established the anti-PD-1 inhibitor pembrolizumab (Keytruda) as a pan-solid tumor treatment in patients with MSI-high/dMMR disease. However, half of patients with MSI-positive tumors did not respond, indicating that “the presence of MSI alone is not sufficient for treatment response,” wrote Zachery R. Reichert, MD, PhD, of the University of Michigan Rogel Cancer Center in Ann Arbor, and colleagues in an accompanying editorial.
Reichert’s group also pointed out that not all patients with prostate cancer that respond to anti-PD-1/PD-L1 therapy have the MSI-high/dMMR phenotype, demonstrating that its presence is not necessary for response.
“Indeed we now know that CDK12 mutations are present in 6.9% of patients with CRPC, and these CDK12 mutations are linked with increased neoantigen burden and T-cell infiltration,” they wrote. “Prospective clinical trials will be necessary to determine whether patients whose tumors harbor CDK12 mutations — such as those whose tumors harbor MSI — are significantly more likely to respond to checkpoint inhibitor therapy.”
Abida and colleagues reported ties to various industry entities.
Alumkal reported consulting or an advisory role with Astellas Pharma, Bayer, and Janssen Biotech Inc., and institutional research funding from Aragon Pharmaceuticals Inc., Astellas Pharma, Novartis, Zenith Epigenetics Ltd, and Gilead Sciences Inc.
Urrutia and Reichert had no conflicts of interest.