This randomized, controlled, and double-blinded phase II study was designed and powered for the short-term end point of PFS, and it failed to find an association between treatment arm and progression. However, a strong association between treatment arm and OS was observed. The magnitude of the effect (estimated hazard ratio of 0.56 and an observed difference in median survival of 8.5 months) suggests a clinically meaningful outcome. This study, with blinded control patients, strongly suggests that PROSTVAC-VF immunotherapy may produce an OS benefit. Thus PSA-targeted immunotherapy may offer a new complementary approach to treating prostate cancer.
In a search for alternative explanations for the differential survival outcome, analysis of known prognostic factors between arms was undertaken. There were no major differences between the groups that could explain the result. While the two treatment arms were reasonably well balanced considering the small size of the trial and the 2:1 randomization, there was a slight imbalance in favor of the PROSTVAC arm in mean and median laboratory values for PSA, hemoglobin, lactate dehydrogenase, and alkaline phosphatase. The magnitude of the differences is not likely to be clinically meaningful. Further, integration of these four highly correlated factors plus performance status in the Halabi nomogram revealed a 1-month mean and 2-month median difference in predicted survival (mean and median of 20.4 months for controls v mean of 21.4 months and median of 22.5 months for PROSTVAC; ). The observed survival difference of 8.5 months far exceeds that predicted by the Halabi nomogram. Finally, the effect modifier analysis, including the Halabi score, failed to find evidence of effect modification and, in fact, found suggestions of effect for all subgroups (). Thus, while there are some between-arm baseline differences, it does not seem plausible that these differences could be the explanation for the observed effect size for OS.
With the current PROSTVAC data, there are parallels with respect to other immunotherapy-based approaches to prostate cancer. Treatment of a similar group of metastatic prostate cancer patients with a good prognosis (median Halabi predicted survival of 21 months) with sipuleucel-T provided an improved median OS of 4.5 months (25.9 months for sipuleucel-T v
21.4 months for controls) and OS benefit (3-year OS of 33% v
11%), yet demonstrated only a trend toward delayed short-term disease progression.16
A larger phase III study with more than 500 patients has recently confirmed these results.17
These studies of immunotherapy in prostate cancer may represent an emerging theme of prolonged survival, without a demonstrable signal of tumor shrinkage or delay in short-term disease progression.
A potential limitation of this study of OS is the lack of treatment data after completion of the treatment phase of the trial. Imbalances due to chance may have occurred in treatments after progression. However, only docetaxel has been shown to affect survival in metastatic prostate cancer patients, and only by approximately 3 months.18
Thus, we think it unlikely that a potential imbalance in post-study chemotherapy treatment could explain the survival result.
The role of GM-CSF in the treatment effect is unclear. Murine data support its use as an adjuvant19
; however, clinical data are less definitive, and only small numbers of patients have been evaluated in poxviral vaccine trials with and without GM-CSF.9,20,21
While there has been single-agent activity of GM-CSF in prostate cancer (mainly PSA response), those studies used high doses (250 μg/m2
) for 14 days on and 14 days off and for multiple cycles, and effects on OS are not known.22
No detectable antibody titers to PSA were generated. This is consistent with prior observations with PSA-based poxviral vector vaccinations, where only 1 of 200 patients developed anti-PSA antibodies in previous clinical trials.1–4,7–9
Unfortunately, T-cell immune responses were not evaluated. However, in the recent phase II clinical study of PROSTVAC-VF in 32 patients conducted by the NCI, gamma-interferon ELISPOTs were analyzed.9
In that study, 13 of 28 evaluable patients had more than two-fold increases in PSA epitope-specific immune responses, and four of five high responders (more than a six-fold increase) survived > 40 months, while low or nonresponders had a median OS of 20 months.
In summary, PROSTVAC immunotherapy in this randomized, controlled, and blinded study was associated with an improved OS. The estimated hazard ratio is 0.56 (95% CI, 0.37 to 0.85), and the observed difference in median survival of 8.5 months suggests significant impact. Nonetheless, while these data are statistically and potentially clinically meaningful, these remarkable findings are regarded as hypothesis generating. PROSTVAC immunotherapy is a promising approach, and a larger pivotal phase III trial is planned.