Beyond Provenge: The Next Steps With Immunotherapy in Prostate Cancer

Jason M. Broderick @jasoncology
Published: Friday, May 17, 2013
Dr. Susan F. Slovin

Susan F. Slovin, MD, PhD

Following the 2010 approval of sipuleucel-T (Provenge), the excitement surrounding immunotherapy in prostate cancer reached a fever pitch. However, despite some tantalizing prospects, there has yet to be another FDA-approved immunotherapy for the disease. At the 2013 IPCC, Susan F. Slovin, MD, PhD, Memorial Sloan-Kettering Cancer Center, provided an overview of the most promising immunotherapeutic follow-ups to sipuleucel-T.

Ipilimumab Shows Promise

Slovin was the lead researcher in a study that examined the anti-CTLA-4 immune checkpoint inhibitor ipilimumab (Yervoy) in prostate cancer. The agent was approved in 2011 to treat patients with metastatic melanoma.

In March, results from Slovin et al’s phase I/II study of ipilimumab with or without radiotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC) were published online in the Annals of Oncology (doi:10.1093/annonc/mdt107).

In the second part of this dose escalation study, 50 patients received monotherapy with 10 mg/kg of ipilimumab (4 doses every 3 weeks; n = 16) or ipilimumab at the same dosage combined with radiotherapy (8 Gy/ lesion; n = 34).

Four patients in each treatment group had PSA declines ≥50%. One patient in the monotherapy group and five in the combination arm had stable disease. Additionally, one patient in the ipilimumab-alone arm had complete response. “This patient remains in complete remission with a PSA of less than 0.05,” said Slovin.

Although toxicities in the study were considered manageable, Slovin noted the importance of monitoring the serious immunomodulatory adverse events (AEs) that can be triggered by CTLA-4 blockade. Among the 50 patients treated with 10 mg/kg of ipilimumab ± radiotherapy, common immune-related AEs included diarrhea (54%), colitis (22%), rash (32%), and pruritus (20%). Colitis (16%) and hepatitis (10%) were the most common grade 3/4 immune-related AEs. There was one treatment-related death.

“This phase I/II trial led the way for the development of two [phase III] randomized, placebo-based, multinational trials using ipilimumab in [mCRPC],” said Slovin. The first is comparing ipilimumab with placebo in patients with asymptomatic or minimally symptomatic chemotherapy-naïve mCRPC (http://1.usa.gov/ZKqSlg). The other is examining ipilimumab versus placebo after radiotherapy in patients with CRPC previously treated with docetaxel (http://1.usa.gov/146x4Hv). Slovin said she hopes that results from these studies will be available in the next 6 months.

PD-1 Inhibitor Disappoints

Similar to ipilimumab, the anti–PD-1 antibody nivolumab (formerly BMS-936558) is a checkpoint inhibitor that “takes the breaks off the immune system.” A phase I study by Topalian et al presented at the 2012 ASCO Annual Meeting and subsequently published in The New England Journal of Medicine (2012;366:2443-2454) examined nivolumab in 296 patients with various cancers, including 17 with CRPC.

Slovin, who worked with three of the CRPC patients in the study, said she had hoped that “Maybe [the results with] PD-1 would be better than our work with ipilimumab.” Unfortunately, the prostate data were not positive. While objective response rates as high as 28%, 27%, and 18% were observed in patients with melanoma, renal cell carcinoma, and non–small cell lung cancer, respectively, no objective responses were observed in patients with prostate cancer.

Slovin did not report any next steps with PD-1 inhibition in prostate cancer.

PROSTVAC

Another immunotherapeutic agent being investigated in prostate cancer is the vaccine PROSTVAC. According to Slovin, “PROSTVAC is a…vaccine that has three costimulatory molecules [B7-1, ICAM-1, and LFA-3] that really ‘zest up’ the immune system and has shown some benefit in terms of delaying time to treatment, but not yet overall survival [OS].” This may change, however, with the results of an ongoing phase III study of PROSTVAC that has a primary OS endpoint.

The phase III international, PROSPECT trial (http://1.usa.gov/12ZU6NF) is examining PROSTVAC in men with asymptomatic or minimally symptomatic mCRPC. The three-arm study will assess OS versus placebo for both PROSTVAC alone and PROSTVAC plus GM-CSF. The targeted enrollment for the trial is 1200 patients.

PROSPECT was launched following a positive phase II study in which treatment with PROSTVAC plus GM-CSF improved OS by 8.5 months versus placebo in patients with minimally symptomatic mCRPC (J Clin Oncol. 2010;28[7]:1099-1105).


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