Early Evidence of Anti–PD-1 Activity in Enzalutamide-Resistant Prostate Cancer

Key Points

  • Three of the first 10 participants enrolled in the ongoing clinical trial experienced rapid reductions in prostate-specific antigen.
  • Subsequent imaging scans showed that tumors shrank in two of these three men, including metastatic liver tumors in one patient.
  • Two of the three participants who responded to the treatment gained relief from cancer pain and were able to stop taking opiate pain medication.

Restoring tumor-specific immunity is a treatment strategy that works well in melanoma and lung cancer patients. Now a new study out of the Oregon Health & Science University (OSHU) Knight Cancer Institute is reviving hope that the approach also may help men with life-threatening prostate cancer.

Prior results in men with aggressive, advanced-stage prostate cancer showed no evidence of antitumor activity with immune therapies that work by blocking programmed cell death protein 1 (PD-1) signals. In a study published by Graff et al in Oncotarget, 10 men with metastatic prostate cancer resistant to androgen-deprivation therapy and the androgen receptor antagonist enzalutamide (Xtandi) were treated with pembrolizumab (Keytruda).

Early Results

Three of the first 10 participants enrolled in the ongoing clinical trial experienced rapid reductions in prostate-specific antigen (PSA). Subsequent imaging scans showed that tumors shrank in two of these three men, including metastatic liver tumors in one patient. Two of the three participants who responded to the treatment gained relief from cancer pain and were able to stop taking opiate pain medication.

The research team led by Julie Graff, MD, said the data provide, for the first time, evidence of meaningful clinical activity with PD-1 blockade in men with metastatic prostate cancer that is 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 Dr. Graff, lead study author and an oncologist specializing in prostate cancer at the OHSU Knight Cancer Institute. “You don't get responses like this with almost any other treatment.”

Men in the study had been treated with the androgen-receptor inhibitor enzalutamide, but their cancers showed signs of progression in spite of this therapy.

The three participants who responded to PD-1 blockade started with serum PSA levels of 46, 71, and 2,503 ng/mL. These PSA levels plummeted to less than 0.1 ng/mL after treatment, and these three patients remain free of progression at 30, 55, and 16 weeks of follow-up, respectively.

Unanswered Questions

Important questions remain unanswered. It's not yet known whether PD-1 blockade can improve survival in men with metastatic, castration-resistant prostate cancer, and it's not possible to select which patients are likely to respond to the treatment.

Three of the 10 men in the study had stable disease at 30, 47, and 50 weeks, while the remaining 4 patients did not show evidence of clinical benefit. One of those four men died of prostate cancer.

In spite of the uncertainties, Dr. Graff and colleagues say the results in the men whose cancer responded to the treatment clearly stand out. Approved agents for metastatic, castration-resistant prostate cancer rarely produce PSA reduction to less than 0.2 ng/mL when enzalutamide has stopped working. Significant responses in liver metastases are also relatively uncommon with androgen receptor–targeting drugs or cytotoxic chemotherapies, they added.

The researchers had previously reported on two participants who were exceptional responders to immunotherapy and hypothesized that the immune-modifying actions of androgen receptor blockers such as enzalutamide might enhance immunotherapy. That prompted them to develop the phase II study to evaluate the efficacy of the PD-1 inhibitor pembrolizumab.

The authors cautioned that these results must be viewed as preliminary. The ongoing study, which is continuing to follow these men and has enrolled additional participants, will provide more robust answers about the potential benefits of PD-1 for men with metastatic prostate cancer, Dr. Graff concluded.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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