medwireNews: The presence of the microsatellite instability (MSI)-high/mismatch repair-deficient (dMMR) phenotype could help select advanced prostate cancer patients who are likely to derive durable clinical benefit from treatment with checkpoint inhibitors, say researchers.
They note that the molecular phenotype appears to be “uncommon yet therapeutically meaningful” in this setting.
Of the 1346 men with prostate cancer who were treated at the Memorial Sloan Kettering Cancer Center in New York, USA, between January 2015 and January 2018, samples from 1033 were of sufficient quality to undergo testing for MSI status.
A total of 23 men were classified as having MSI-high disease on the basis of an MSIsensor score of at least 10, while nine men had an indeterminate MSIsensor score (≥3 and <10) but with evidence of MMR deficiency, which was defined as the presence of a deleterious germline or somatic mutation in an MMR gene or loss of MMR protein on immunohistochemical analysis.
Altogether, 3.1% of the study participants were therefore considered to have MSI-high/dMMR prostate cancer.
Eleven of these 32 patients were treated with an inhibitor of programmed cell death protein 1 (PD-1) or its ligand (PD-L1) – either given as monotherapy or alongside another immunomodulatory agent – for a duration of 4.6 to 89.0 weeks.
A decline in prostate-specific antigen levels of more than 50% was observed in just over half (54.5%) of the treated patients. Four patients achieved a partial radiographic response and one had stable disease for around 6 months, while three men experienced disease progression and three were not evaluable.
One patient who initially had progressive disease remained on immunotherapy and derived clinical benefit from the treatment, meaning that nearly half (45.5%) of the 11 patients had “durable clinical benefit,” report Wassim Abida and the team from the Memorial Sloan Kettering Cancer Center.
They continue: “Because approximately half of patients with MSI-H/dMMR had no response to immunotherapy, future studies should explore mechanisms of resistance in this population, which may involve alterations in the tumor antigen–presenting machinery and tumor-extrinsic factors, including inadequate T-cell activation.”
And the study authors conclude in JAMA Oncology: “Given the potential for durable responses to anti–PD-1/PD-L1 therapy, these findings support the use of prospective tumor sequencing to screen all patients with advanced prostate cancer for MSI-[high]/dMMR.”
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