Clinical Development of Prostate Cancer Vaccines Continues

Mark Stein, MD

The field of prostate cancer vaccines remains an area of active exploration, with clinical trials into sipuleucel-T (Provenge) continuing even amid a corporate restructuring and a phase III study into PROSTVAC reaching full enrollment. Research into emerging compounds also is under way, including an early study that pairs a vaccine candidate with pembrolizumab (Keytruda).

Sipuleucel-T, an autologous dendritic cell vaccine, remains the only therapeutic prostate cancer vaccine with regulatory approval. Earlier this year, the Canadian company Valeant Pharmaceuticals obtained approval in US Bankruptcy Court to purchase Provenge manufacturer Dendreon Corporation for $495 million.

Among vaccines under study in prostate cancer, PROSTVAC is a front-runner in the field. Manufactured by Bavarian Nordic, the vaccine has yielded promising trial data and falls into the injectable class, involving an initial shot of recombinant poxvirus and several booster shots of recombinant fowlpox.

Both sipuleucel-T and PROSTVAC share a common drawback in that clear biomarkers for which patients would benefit most from the therapies have not yet been validated, although this is an area of active investigation, according to Mark Stein, MD, of Rutgers Cancer Institute of New Jersey. Stein is a medical oncologist at the institute and assistant professor of Medicine at Rutgers Robert Wood Johnson Medical School. He was involved in a recently concluded phase II PROSTVAC trial.¹

Sipuleucel-T and PROSTVAC Trials

Stein believes that further research on sipuleucel-T bears watching and that it could well develop that combining the drug with other therapies will demonstrate additional value. Ongoing clinical trials include phase II studies in combination with enzalutamide (Xtandi) in men with metastatic castration-resistant prostate cancer (mCRPC)² and with ipilimumab (Yervoy) in chemotherapy-naïve mCRPC.³

For PROSTVAC, results of a large, multicenter phase III trial are pending on whether it makes any “definitive” contribution to overall survival (OS) in advanced prostate cancer, Stein said. Nearly 1300 men have enrolled in the global PROSPECT study, which is designed to investigate whether PROSTVAC alone or in combination with granulocyte-macrophage colony-stimulating factor is effective in prolonging OS in men with few or no symptoms from metastatic, castration-resistant prostate cancer (mCRPC).⁴

The drug’s prospects have generated huge interest from Bristol-Myers Squibb, which has extended a nearly $1 billion licensing and distribution contract to Bavarian Nordic in order to capitalize on the potential market for the drug.⁵ A phase II study that would combine PROSTVAC with ipilimumab, which Bristol-Myers developed, is in the planning stages.⁵

Listeria Vaccines

Vaccines based on the Listeria bacterium also hold promise and constitute another prong in this field of advancement. Currently, Plainsboro, NJ-based Advaxis Inc is combining its Listeria monocytogenes immunotherapy agent ADXS-PSA, which has been modified to target prostate-specific antigen, with Merck’s checkpoint inhibitor pembrolizumab.6 The phase I/II KEYNOTE-046 trial aims to enroll 51 patients with previously treated mCRPC.⁶

Live attenuated Listeria-based vaccines can generate immune system responses that destroy tumor cells, and they have already been studied in pancreatic cancer and mesothelio- ma. These drugs can help to stimulate the im- mune responses necessary to facilitate the use of checkpoint inhibitors, which block proteins that are negatively regulating immune system responses in cancer.

“Listeria-based vaccines are a compelling platform,” Stein said. “It seems to be very immunogenic, safe, and may overcome some of the mechanism that tumors use to hide from the immune system.”

References

1. DiPaola RS, Chen YH, Bubley GJ, et al. A national multicenter phase 2 study of prostate-specific antigen (PSA) pox virus vaccine with sequential androgen ablation therapy in patients with PSA Progression: ECOG 9802 [published online December 18, 2014]. Eur Urol. pii:S0302-2838(14)01265-2. doi:10.1016/j. eururo.2014.12.010.
2. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identfier: NCT01981122.
3. NIH Clinical Trials Registry. www.ClinicalTrials.gov. Identfier: NCT01804465.
4. PROSPECT phase 3 clinical study. Bavarian Nordic website. http://ci.bavarian-nordic.com/pipeline/prostvac/prospect- phase-3-clinical-study.aspx. Accessed April 29, 2015.
5. Bristol-Myers Squibb signs exclusive agreement with Bavarian Nordic for PROSTVAC®, a prostate-specific antigen-targeting cancer immunotherapy [press release]. Kvistgaard, Denmark, and New York, NY: Bavarian Nordic and Bristol-Myers Squibb Company; March 4, 2015.
6. Advaxis and Merck announce initiation of enrollment in the phase 1/2 study of ADXS-PSA in combination with anti-PD-1 therapy, Keytruda (pembrolizumab), for the treatment of advanced prostate cancer [press release]. Princeton, NJ and Kenilworth, NJ: Advaxis Inc and Merck; April 8, 2015.