Prostate Cancer Vaccine Before Hormones May Boost Survival

By Crystal Phend
BETHESDA, Md., 11 july 2008-- For nonmetastatic castration-resistant prostate cancer, an investigational poxvirus-based PSA vaccine given before second-line hormone therapy, rather than the reverse approach, might confer a survival advantage, researchers here found.
In a small randomized trial, median overall survival for men given the vaccine at any point tended to be extended by almost two years compared with those given the antiandrogen drug nilutamide (Nilandron) alone (median 5.1 vs. 3.4 years, P=0.13), reported Jeffrey Schlom, Ph.D., of the National Cancer Institute here, and colleagues in the July 15 issue of Clinical Cancer Research.
But patients who got the vaccine first had significantly improved survival (median 6.2 versus 3.7 years, P=0.045).
No treatment has been shown to prolong survival or time to metastatic disease in this group of patients, and there is no standard of care for them, the researchers said.
An earlier report from the trial showed longer time to treatment failure with the vaccine alone compared with nilutamide alone (9.9 versus 7.6 months) as well as for those given the vaccine after nilutamide failure (total 25.9 months).
The phase II study included 42 men with rising PSA despite castrate levels of testosterone below 50 ng/dL and no radiographic evidence of metastasis.
Patients were randomized to initially receive nilutamide (300 mg/day then 150 mg/day after the first month) or the recombinant poxvirus-based PSA vaccine with monthly booster shots.
Patients who continued to have rising PSA levels after six months but still no evidence of metastasis were offered combination therapy, which 12 patients in the vaccine group and eight in the nilutamide group accepted.
The retrospective analysis of overall survival at a median 4.4 years of follow-up found a trend to longer overall survival in patients given the vaccine alone versus nilutamide alone (median 5.1 versus 3.4 years, P=0.13).
Vaccine-treated patients also had a higher probability of survival at three years compared with those who received nilutamide alone (81% versus 62%).
For patients who went on to receive combination therapy at PSA progression, survival probability at three years was greater when the vaccine was started before rather than after nilutamide (100% versus 75%).
Overall survival was significantly extended when the vaccine was given before nilutamide initiation (median 6.2 versus 3.7 years, P=0.045).
Overall survival from the time of treatment crossover showed the same significant benefit of vaccination before nilutamide initiation (4.8 versus 2.8 years, P=0.028).
Prostate cancer patients more likely to benefit from vaccine therapy were those with:
A Gleason score of 7 or less (median OS 5.9 versus 3.1 years, P=0.033).
A confirmed history of radiation therapy (median OS 5.9 versus 3.1 years, P=0.018).
An on-study PSA of less than 20 ng/dl (median OS 5.1 versus 2.6 years, P=0.013).
Both lower PSA and Gleason score are consistent with less pathologically aggressive disease and lower tumor volume, and prior radiation may act as an immune booster by increasing cross-presentation of tumor antigens to T cells, the researchers said.
This suggested, "vaccine-based therapy should be utilized in patients with a lower tumor burden that allows the immune system to mount an effective response," they wrote.
None of the participants had previously received chemotherapy, but Dr. Schlom and colleagues noted that a previous study of metastatic cancer showed less effective T-cell response to vaccine with more chemotherapy treatments.
The researchers cautioned, though, that the crossover findings were based on small, retrospectively determined cohorts. Including only a subset of patients retrospectively determined to have received crossover treatment may have biased the findings by selection for healthier patients and elimination of those with rapidly progressing disease.
"However, even accounting for these limitations it is clear that patients with tumor characteristics consistent with slow growth and small volume, and who received vaccine earlier in their treatment regimen, may exhibit improved overall survival," the researchers said.
The study was funded by the National Cancer Institute. The researchers provided no information on conflicts of interest.
Primary source: Clinical Cancer ResearchSource reference:Madan R, et al "Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy: implications for vaccine clinical trial design" Clin Cancer Res 2008.