PD-1 Signal Blocker Shows Efficacy in Prostate Cancer

Despite prior results that indicate PD-1 signal blocking therapy does not produce anti-tumor activity in men with aggressive, advanced-stage prostate cancer, a new study in Oncotarget found that PD-1 antibodies may help these patients after all.

In an ongoing clinical trial, researchers enrolled 10 men with metastatic prostate cancer who were resistant to androgen deprivation therapy, as well as the androgen receptor antagonist enzalutamide. Participants were administered the monoclonal antibody pembrolizumab, a drug that binds to the PD-1 receptor.

The results of the study found that 3 of the first 10 participants experienced rapid reductions in prostate specific antigen (PSA). Using subsequent imaging scans, researchers found that the tumors shrank in 2 of the 3 men, which included 1 patient with metastatic liver tumors. There were 2 of 3 men who responded to the treatment who experienced pain relief from the cancer, and were able to stop taking opiate pain medication.

The 3 responding participants started with serum PSA levels of 46, 71, and 2503 ng/ml. After treatment, the PSA levels ended up plummeting to less than 0.1 ng/ml, and 3 patients remained progression free at 30, 55, and 16 weeks of follow-up, respectively.

Men who were treated with enzalutamide showed signs of cancer progression in spite of the therapy. The findings are the first time that evidence of meaningful clinical activity was found for PD-1 blockade in men with metastatic prostate cancer who are resistant to androgen deprivation.

“It’s pretty remarkable, especially in light of the fact that many people doubted this approach could work at all,” said lead study author Julie Graff, MD. “You don’t get responses like this with almost any other treatment.”

Although the findings show promise, researchers still don’t know whether PD-1 blockade can improve survival in men with metastatic, castration-resistant prostate cancer. Furthermore, they are still unable to select which patients are most likely to respond to treatment.

Three of the 10 men achieved stable disease at 30, 47, and 50 weeks, while the other 4 patients did not show evidence of any clinical benefit. One of the 4 men ended up dying of prostate cancer.

Authors noted that men who did respond to treatment stand out, despite the uncertainties. In fact, it is rare that approved agents for this form of prostate cancer are able to reduce PSA to less than 0.2 ng/ml when enzalutamide stopped working.

Researchers hypothesize that the immune-modifying actions of androgen receptor blockers, such as enzalutamide, may enhance immunotherapy. This hypothesis was a result of previous research that showed 2 participants who were exceptional responders to immunotherapy.

This knowledge prompted researchers to develop a phase 2 study to examine pembrolizumab’s efficacy.

“There are considerable data showing that androgen-ablation may augment an anti-tumor immune response,” the study authors wrote. “Enzalutamide therapy represents a more potent form of androgen suppression and may therefore associated with previously underappreciated immune modulatory effects.”