The PSA-targeted immunotherapy PROSTVAC was deemed unlikely to demonstrate an improvement in overall survival (OS) compared with placebo for patients with metastatic castration-resistant prostate cancer (CRPC), according to a preplanned interim analysis of the phase III PROSPECT trial conducted by an independent Data Monitoring Committee (DMCB).
The DMCB recommended discontinuation of the PROSPECT study, which enrolled 1297 patients with asymptomatic or minimally symptomatic mCRPC under a special protocol assessment from the FDA. The trial was designed to detect an 18% reduction in the risk of death with PROSTVAC versus placebo. Bavarian Nordic, the company developing the immunotherapy with the National Cancer Institute, has not yet released exact numbers from the study.
"We are extremely disappointed for patients that this study of PROSTVAC as monotherapy was not successful," Paul Chaplin, president & chief executive officer of Bavarian Nordic, said in a statement. "While this is certainly not the desired outcome, we remain steadfast believers in the power of combination treatments, including immunotherapies, to transform the future of cancer therapies."
The PROSTVAC-V/F immunotherapy consists of 2 parts: rilimogene galvacirepvec (V) and rilimogene glafolivec (F). The first consists of a recombinant vaccinia virus encoding prostate specific antigen (PSA) and 3 costimulatory molecule transgenes collectively known as TRICOM (B7.1, ICAM-1, and LFA-3). The second utilizes a recombinant fowlpox virus encoding PSA and TRICOM.
The phase III trial finished enrollment in January 2015, with patients participating from 200 sites in 15 countries. In the investigational arms, rilimogene galvacirepvec was administered upfront followed by booster shots of rilimogene glafolivec with an adjuvant dose of GM-CSF or placebo. A third comparator arm administered a placebo alone.
All patients in the trial had progressive disease following treatment with a GnRH agonist or antagonist (unless surgically castrated). Additionally, patients were chemotherapy naive and were required to have received a previous smallpox vaccination. The study began enrollment in 2011, prior to the approval of immune checkpoint inhibitors.
"I am sad that we didn't see an OS signal; however, I remain convinced that the advanced cancer vaccine alone will not be the optimal approach," said lead investigator James L Gulley, MD, PhD, Director, Medical Oncology Service at National Cancer Institute (NCI), following the announcement of the results. In terms of potential vaccine combination candidates, Gulley said "it depends on what is going on in the tumor microenvironment but PD-(L)1 inhibition, IL-15, TGF-beta inhibition, and IDO inhibition would rank high."
A phase I/II study is currently exploring PROSTVAC with the PD-1 inhibitor nivolumab and/or the CTLA-4 inhibitor ipilimumab for men with prostate cancer (NCT02933255). Additionally, separate phase II studies are examining PROSTVAC with ipilimumab (NCT02506114) or docetaxel (NCT02649855).
In a phase I study, PROSTVAC was combined with escalating doses of ipilimumab in 30 patients with metastatic CRPC. Ipilimumab doses ranged from 1 mg/kg up to 10 mg/kg (a dose of 3 mg/kg is being administered in the currently enrolling phase II study). All patients were chemotherapy-naive and androgen insensitive. The estimated OS for these patients was 18.5 months.
Overall, 58% experienced a decline in PSA after treatment, with a PSA decline of greater than 50% for 25% of patients. In those treated with the 10 mg/kg dose of ipilimumab, the median OS was 37.2 months. In those receiving a <10 mg/kg dose, the median OS was 31.3 months. With the single agent alone in phase I and II trials the median OS was 26.6 and 25.1 months, respectively.
With PROSTVAC alone in the phase I trial, 53% of patients were alive at 24 months. For the combination 73.3% of patients remained alive after 24 months. Additionally, approximately 20% of patients treated with PROSTVAC plus ipilimumab at 10 mg/kg remained alive at 80 months, representing a potential "tail on the curve."
The ongoing phase II study exploring PROSTVAC with ipilimumab plans to recruit 75 participants. The estimated completion date for the study is December 2020, with a primary endpoint focused on immune response. The phase I/II study of PROSTVAC with nivolumab with or without ipilimumab is recruiting 65 patients with a primary endpoint of safety and changes in T-cell infiltration. The estimated study completion date is August 2021.
Singh H, Madan RA, Dahut WL, et al. Combining active immunotherapy and immune checkpoint inhibitors in prostate cancer. J Clin Oncol. 2015;33(suppl 7; abstr 172).