Revised View Enhances Provenge OS Data

Leonard G. Gomella, MD

The Bernard W. Godwin Jr. Professor of Prostate Cancer Chairman, Department of Urology Director, Clinical Affairs Kimmel Cancer Center Thomas Jefferson University Philadelphia, PA

A further analysis of clinical trial data for sipuleucel-T (Provenge) suggests that the therapeutic prostate cancer vaccine may have delivered a greater overall survival (OS) benefit than previously described in the study that paved the way for its approval nearly two years ago, according to a leading researcher.

In fact, the analysis indicated that the survival benefit may be significantly higher than the 4.1-month advantage reported in the IMPACT study when the experiences of patients in the control arm who crossed over to a cryopreserved form of the vaccine are considered, said Leonard G. Gomella, MD, chairman of the Department of Urology and director of Clinical Affairs at the Kimmel Cancer Center, Thomas Jefferson University, in Philadelphia, Pennsylvania.

Gomella discussed his hypothesis at the 5th Annual Interdisciplinary Prostate Cancer Congress (IPCC) March 31 in New York City, for which he served as a program director. The research was presented at the 2012 Genitourinary Cancer Symposium sponsored by the American Society of Clinical Oncology (ASCO) in February and at the 2011 ASCO Annual Meeting.

Gomella’s comments come amid continuing controversy over sipuleucel-T, including a recent commentary in the Journal of the National Cancer Institute that maintained previously unpublished data cast doubt on the vaccine’s survival benefit partly because of factors involving patients in the placebo arm.

The FDA approved Provenge on April 29, 2010 for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant, hormone-refractory prostate cancer based on clinical trial data demonstrating that patients who took the vaccine experienced a median OS of 25.8 months versus 21.7 months for those who received a placebo.

Sipuleucel-T is custom-manufactured for each patient from antigen-presenting cells that are harvested from the patient through the process of leukapheresis, then cultured to activate immunogenicity, and infused into the patient. The treatment course consists of three intravenous infusions.

In his analysis, Gomella looked more closely at participants in the control arms of three randomized, double-blind sipuleucel-T studies. Of 249 people in the control arms, 216 participants who experienced disease progression had the option of receiving APC8015F, an autologous immunotherapy with the same potency as sipuleucel-T that was made for each patient and cryopreserved at the time the placebo was prepared.

For the 155 patients from the control arm who received APC8015F, the median OS was 23.6 months from randomization and 20.0 months following disease progression, which compared favorably with the median OS in the sipuleucel-T arms of 25.4 months from randomization and 20.7 months after progression.

In contrast, the 61 participants from the control arm who experienced disease progression but did not cross over to APC8015F had a median OS of 12.7 months from randomization and 9.8 months following disease progression.

“The survival difference was dramatically different,” Gomella said during his IPCC presentation. “So in a way, the sipuleucel-T trials shot themselves in the foot because the frozen product was included. If you exclude the frozen product, you actually get a much more dramatic and a much more robust response of about 10 to 12 months.”

In an interview, Gomella added, “From my viewpoint, the benefit of sipuleucel-T has been understated because many of the patients who received the frozen product who were on the control arm actually enjoyed a longer survival, decreasing the difference between the control arm and the treatment arm.

“In fact, if you look at our analysis of the patients who received a frozen product on the control arm and those who did not receive it, there was a significant survival advantage to those patients who did receive the frozen product,” said Gomella. “It made the difference between the control arm and the actual treatment arm much closer. And if you take out those patients who did not receive the frozen product on the control arm, that survival difference actually approaches 10 to 11 months.”

Gomella’s analysis stands in sharp contrast to the contentions of Huber et al, who argue that previously unpublished trial data show worse OS in older versus younger patients in the placebo groups, and that the difference may stem from the study design.

Patients on placebo who were younger than age 65 experienced an 11-month median survival advantage when compared with those over age 65 (28.2 months vs 17.2 months, respectively), the authors said. They contend that the placebo intervention itself may have adversely affected older patients in the placebo arm and therefore enhanced the sipuleucel-T survival advantage.

“Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival ‘benefit,’” the authors said.

In his IPCC presentation, Gomella said researchers are debating the impact of extracting immune cells, but that a study pending publication indicates the “number of immune cells you pull out of the body with leukapheresis is clinically insignificant.”

Meanwhile, Dendreon Corporation, the Seattle, Washington, company that developed Provenge, is continuing to investigate the vaccine for patients with earlier-stage disease.

Key Research

• Gomella LG, Nabhan C, Whitmore JB, et al. Post-progression treatment with APC8015F may have prolonged survival of subjects in the control arm of sipuleucel-T phase III studies. Poster presented at: 2011 ASCO Annual Meeting; June 3-7, 2011; Chicago, IL. Abstract 4534.
• Huber ML, Haynes L, Parker C, et al. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer [published online ahead of print January 9, 2012]. J Natl Inst.
• Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
• Nabhan C, Gomella LG, DeVries T, et al. An analysis to quantify the overall survival (OS) benefit of sipuleucel-T accounting for the crossover in the control arm of the IMPACT study. J Clin Oncol. 2012;30(suppl 5;abstract 144).