Combining androgen-deprivation therapy with immunotherapy may benefit patients with metastatic prostate cancer, contrary to previous beliefs. Researchers from the OHSU Knight Cancer Institute have demonstrated that the PD-1 inhibitor pembrolizumab (Keytruda) effectively reduced tumor size in some metastatic castration-resistant prostate cancer patients (mCRPC).
Their study, titled “Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer“, was published in Oncotarget.
PD-1 is a protein expressed at the surface of immune cells that functions as an immune checkpoint, impairing the anti-tumor activity of the cells. Inhibiting the protein has demonstrated great benefits in a some cancer types, including non-small cell lung carcinoma, renal cell carcinoma, bladder cancer, and melanoma.
In prostate cancer, previous studies had shown that the anti-PD1 agent nivolumab (Opdivo) did not enhance anti-tumor responses of CRPC patients. But two CRPC patients were reported to have exceptional responses to immunotherapy, which led researchers to hypothesize that androgen-receptor blockers, such as enzalutamide, could have immune modulatory actions that helped enhance immunotherapy impact.
Investigators developed a Phase 2 trial that included 10 mCRPC patients who progressed on enzalutamide therapy. Patients received four doses of pembrolizumab every three weeks, added to standard dose enzalutamine.
Among the 10 participants, three experienced rapid prostate specific antigen (PSA) reductions from 71, 46, and 2.5 ng/ml to levels lower than 0.2 ng/ml. Two of those patients revealed a decrease in tumor size with the immunotherapy, and one showed decrease in liver metastasis. The patients remained free of progression at 55, 30, and 16 weeks of follow-up, respectively.
“It’s pretty remarkable, especially in light of the fact that many people doubted this approach could work at all,” Julie Graff, the study’s first author and an oncologist specializing in prostate cancer at the OHSU Knight Cancer Institute, said in a press release. “You don’t get responses like this with almost any other treatment.”
Of the remaining seven participants, three had stable disease for 30, 47, and 50 weeks and still had not progressed. Four patients did not benefit; one of them died.
The findings are important because currently used therapies for mCRPC patients rarely induce such reductions in PSA levels to less than 0.2 ng/ml when patients no longer respond to enzalutamide. Significant responses in liver metastasis are also rare with cytotoxic chemotherapies or androgen receptor-targeting drugs, which suggests that pembrolizumab may surpass currently used therapies.
Further investigation is needed to determine if pembrolizumab can improve survival rates in mCRPC patients, and to identify patients who could benefit from the therapy. Plans are in the works for future studies.