Is there going to be a competitor to Provenge once it is approved? This is a very interesting question as a second investigational vaccine has shown a significant survival advantage in men with asymptomatic metastatic castration-resistant prostate cancer.

There were just released updated results from a phase II trial of PROSTVAC-VF/Tricom vaccine. The trial had a sample of 122 men and its results showed a median overall survival of 25.1 months for men receiving, compared with 16.6 months for those receiving placebo (hazard ratio, 0.56; P = .006). The results were reported by Dr. Philip Kantoff at the annual meeting of the American Society of Clinical Oncology.

This 8.5-month improvement in survival with the poxvirus-based vaccine comes just months after investigators with the phase III IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial reported a 4.1-month survival advantage with the controversial cell-based vaccine sipuleucel-T, also known as Provenge.

What remains unclear with both trials is what is driving this extended survival, as neither vaccine significantly delays disease progression.

The updated primary end point of progression-free survival was not significantly different at 3.8 months with PROSTVAC-VF/Tricom vs. 3.7 months with placebo (HR, 0.88), confirming a previous finding reported 3 years ago at ASCO. In the Provenge trial, time to disease progression was also not significantly different between the vaccine and placebo (HR, 0.95), Dr. Kantoff said.

“While the PROSTVAC experience is very early in comparison to the Provenge experience, these studies raise the question of how survival can be prolonged in the absence of significant objective responses and changes in early progression rates,” said Dr. Kantoff, chief clinical research officer and chief of the solid tumor oncology division at Dana-Farber Cancer Institute in Boston.

This paradox is confusing as it still remains unclear how immunotherapy actually extends lives without delaying disease progression. We do not have any other experience with cancer vaccines to look at. One of the theories for this is that the vaccine builds up the immune response slowly over time, so one observes a delayed effect, said Dr. Mario Eisenberger, who was invited to discuss the results. It’s also possible that the survival advantage is due to post-vaccine chemotherapy, to controls getting worse in the absence of standard docetaxel (Taxotere) treatment, or to some other post-vaccine variable. Based on a back-of-the-envelope analysis he outlined, neither vaccine offers a survival advantage when compared with matched historical populations who were treated with docetaxel or mitoxantrone (Novantrone) in the TAX 327 trial.

Dr. Eisenberger suggested that future trials should be designed to include the tail of the curve for overall and progression-free survival, and should adjust survival outcomes based on prognostic factors such as prostate-specific antigen or PSA-doubling time at progression, which can profoundly affect survival from that point on. If such an adjustment had been performed in the recently terminated VITAL-1 (Vaccine Immunotherapy With Allogeneic Prostate Cancer Cell Lines) trial evaluating the GVAX vaccine, the negative survival results may have been different “and we would have a nice vaccine for us,” said Dr. Eisenberger, the R. Dale Hughes professor of oncology and urology at Johns Hopkins University in Baltimore.

Baseline characteristics of patients in both arms of the PROSTVAC-VF/Tricom trial were similar, Dr. Kantoff said. The vaccine appeared to be beneficial in all subsets, with perhaps a tendency to benefit those with better prognostic disease. Interestingly, the majority of benefit was observed in HLA A2-positive patients, although these results can be considered only hypothesis-generating in light of the negative primary end point, he said.

Because of progression, only 25% of the 82 patients randomized to PROSTVAC-VF/Tricom received all seven vaccinations, which were co-administered with granulocyte-macrophage colony-stimulating factor and given over a 5-month period. Post trial chemotherapy use is not known, Dr. Kantoff said.

Just like with the Provenge trials the incidence of serious side effects were low in this study. Two patients treated with vaccine withdrew because of a grade 2 injection-site reaction and recurrent lip swelling. Two possible drug-related serious adverse events were reported: one grade 2 pyrexia in the control arm, and one thrombotic thrombocytopenic purpura in the vaccine arm, Dr. Kantoff reported.

The investigators disclosed financial ties with BN ImmunoTherapeutics Inc., a Mountain View, Calif.-based subsidiary of Baviarian-Nordic A/S in Kvistgård, Denmark. The company completed the follow-up for survival status, and has announced plans for a phase III study in collaboration with the National Cancer Institute. Dr. Eisenberger disclosed financial ties with Bristol-Myers-Squibb Co., GenVec Inc., the Ipsen Group, Medarex Inc., Sanofi-Aventis, and Cougar Biotechnology Inc.

Basic story from Elsevier Global Medical News. 2009 Jun 25, P Wendling

It certainly looks as though we are on the brink of seeing cancer vaccines becoming a part of the treatment of the disease. With what we hope will be the FDA approval of Provenge next year and possibly a successful phase III trial leading also to the approval of Prostvac in the near future we might soon be able to add to our minimal array of weapons to fight advanced prostate cancer multiple Immunotherapy options.

On the economic side, having a second approved cancer vaccine will introduce a little competition and help control the cost of Provenge to the patient.

Of course, on the possible would not it be great side of the equation, it might come to pass that combining these potential therapies might also extend life even more. Wouldn’t that be great?

Joel T Nowak MA, MSW