Immunointensification May Favorably Alter Survival in mCRPC

An immune checkpoint inhibitor combined with active immunotherapy has a potential positive effect on overall survival (OS) in the treatment of metastatic castration-resistant prostate cancer (mCRPC), announced Harpreet Singh, MD, at the 2015 Genitourinary Cancers Symposium.

“The rationale for combining immunotherapies, especially a vaccine with a checkpoint inhibitor, is that a vaccine is needed to prime the T cells and prepare the immune system for the checkpoint inhibitor to come in and recognize the [PSA-expressing] cancer cells,” said Singh, a clinical research fellow at the NCI, Bethesda, MD. “The thought that you can combine them also alludes to sequencing as well, ie, giving the vaccine first followed by the immune checkpoint inhibitor.”

A phase I study conducted at the NIH combining a fixed dose of PROSTVAC (recombinant pox-viral vaccine) with escalating doses of the checkpoint inhibitor ipilimumab produced encouraging survival results in 30 patients with mCRPC. In this study, the median OS was 31.3 months compared with a predicted median OS of 18.5 months by the Halabi nomogram.

Results from an updated analysis found a median OS of 37.2 months in those patients treated with 10 mg/kg of ipilimumab. At this dosage, 73.3% of the patients were alive at 24 months. Fourteen of 24 patients (58%) who were chemotherapy-naïve had a decline in their PSA, six of whom (25%) had a PSA decline >50%.

“The combination was well tolerated with not a lot of overlapping toxicity,” said Singh. These data suggest that therapeutic vaccines may make T cell-poor tumors into T cell-inflamed tumors that are responsive to immune checkpoint inhibition, she said.

PROSTVAC is a pox viral vaccine expressing prostate-specific antigen (PSA) and three T-cell co-stimulatory molecules. It is an “off the shelf” vaccine in that it is ready to use with minimal preparation and does not require individual patient blood cell collection. This vaccine has demonstrated PSA-specific immune responses and evidence of clinical benefit in phase I and phase II studies.

Phase II trials of PROSTVAC alone showed favorable OS in men with mCRPC. In a multicenter phase II trial of 125 men randomized in a 2:1 ratio to receive PROSTVAC or placebo, OS was 25.1 months in those randomized to PROSTVAC compared with 16.6 months in those randomized to placebo (HR: 0.56; 95% CI: 0.37-0.85). A second phase II trial of 32 patients treated with PROSTVAC, OS was 26.6 months compared with a predicted median OS of 17.4 months by the Halabi nomogram.

The ongoing phase III randomized, double-blind, placebo-controlled study will determine whether PROSTVAC alone or in combination with GM-CSF can prolong OS in chemotherapy-naïve asymptomatic or minimally symptomatic men with mCRPC. “This trial is randomizing patients to receive either vaccine with GM-CSF, which is thought to be immune-stimulating and to enhance the effects of the vaccine; the vaccine plus placebo; or GM-CSF plus an empty vector,” said Singh. The study completed accrual in January 2015.

Singh H, Madan RA, Dahut WL, et al. Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer. Presented at: 2015 Genitourinary Cancers Symposium; February 26-28, 2015; Orlando, FL. Abstract 172.

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