PD-1 Blockade Shows Promise for mCRPC

In a small study, some men whose cancer progressed while on enzalutamide had a profound PSA response to pembrolizumab.
In a small study, some men whose cancer progressed while on enzalutamide had a profound PSA response to pembrolizumab.

For the first time, a study has provided evidence of meaningful clinical activity for programmed death 1 (PD-1) blockade in men with metastatic castration-resistant prostate cancer (mCRPC), according to a new report.

In an ongoing phase II study, a team led by Julie N. Graff, MD, of the Oregon Health & Science University (OHSU) Knight Cancer Institute in Portland, observed robust responses to treatment with pembrolizumab—a monoclonal antibody that binds to the PD-1 receptor—among 3 of the first 10 men with enzalutamide-resistant mCRPC enrolled in the study. All 3 experienced rapid drops in PSA level to below 0.1 ng/mL after treatment, Dr Graff and her colleagues reported in Oncotarget. At enrollment, the men had PSA levels of 46, 71, and 2503 ng/mL.

 

The investigators noted that currently approved agents for mCRCP generally do not produce PSA reductions to 0.2 ng/mL or below after enzalutamide is no longer effective.

Imaging scans showed that tumors shrank in 2 of the patients, including metastatic liver tumors in 1 patient. In addition, 2 of the men had relief from cancer-related pain and were able to discontinue opiate therapy. The patients remained free of progression at 16, 30, and 55 weeks of follow-up.

“It's pretty remarkable, especially in light of the fact that many people doubted this approach could work at all,” Dr Graff said in an OHSU press release. “You don't get responses like this with almost any other treatment.”

Of the remaining 7 patients, 3 had stable disease at 30, 47, and 50 weeks. Four patients showed no evidence of clinical benefit, with 1 dying from prostate cancer.

Three of the 10 patients experienced significant immune-related adverse events. Grade 2 myositis occurred in 1 patient, grade 3 hypothyroidism in 1 patient, and grade 2 hypothyroidism in 1 patient.

To be included in the study, patients needed to have at least 1 distant metastatic lesion, castrate levels of testosterone (less than 50 ng/dL), a PSA response to enzalutamide (defined as a PSA decrease of 50% or less), and, at the time of enrollment, must have had progression on enzalutamide. Additionally, they could not have received chemotherapy for castration-resistant cancer, but previous chemotherapy for castration-sensitive cancer was allowed. Patients were continued on enzalutamide 80–160 mg orally per day; pembolizumab was given as a dose of 200 mg intravenously every 3 weeks for a total of 4 doses.

In a previous report published in The New England Journal of Medicine (2012;366:2443-2454),  researchers reported the findings of a phase I study showing that PD-1 inhibition with nivolumab showed activity in melanoma, renal cell cancer, and non–small-cell lung cancer. The researchers observed no objective responses in the 17 patients with CRPC. In subsequent phase III studies, PD-1 blockade has demonstrated improved survival for non–small-cell lung cancer, renal cell carcinoma, melanoma, and bladder cancer.

 

 

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