CANCER VACCINE-EFFECT ON SURVIVAL WITHOUT RESPONSES?

July 28, 2010 — Details of the pivotal clinical trial with the prostate cancer vaccine sipuleucel-T (Provenge; Dendreon), which showed an improvement in overall survival and led to the recent FDA approval of the product, have now been published in the New England Journal of Medicine.

Although the improvement in overall survival seen is "important," the lack of any measurable antitumor effect was "surprising," and the high cost of this new product is a "concern," comments Dan Longo, MD, in an accompanying editorial.

The pivotal trial, known as IMPACT, was sponsored by the manufacturer and headed by Philip Kantoff, MD, from the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. It was conducted in 512 men with metastatic castration-resistant prostate cancer who were randomly assigned 2:1 to receive the vaccine or placebo.

The vaccine reduced the relative risk for death by 22% (hazard ratio, 0.78; P = .03), with overall survival improved to 25.8 months vs 21.7 months in the placebo group (4.1-month improvement).

This survival benefit is the best that has been reported in such patients to date.

Dr. Kantoff and colleagues note that in other recent phase 3 trials in metastatic castration-resistant prostate cancer, the median survival has ranged from 12.2 to 21.7 months, and the only approved therapy that has been shown to prolong survival, docetaxel, improved survival by 2 to 3 months compared with mitoxantrone and prednisone.

The reduction in the risk for death seen with the vaccine in these patients with metastatic disease "is an important step," comments editorialist Dr. Longo. However, he also raises a number of questions about some of the other findings in this study.

Lack of Antitumor Effect Is "Surprising"

"The improvement in survival came without evidence of a measurable antitumor effect," Dr. Longo points out. There was no significant effect on the time to tumor progression, and only 1 of 341 patients in the vaccine group showed a partial tumor response. In addition, only 3% of patients in the vaccine group showed a reduction in prostate specific antigen (PSA) of at least 50% on 2 visits at least 4 weeks apart.

This lack of antitumor is "surprising," Dr. Longo comments. "It is hard to understand how the natural history of a cancer can be affected without some apparent measurable change in the tumor, either evidence of tumor shrinkage or at least disease stabilisation reflected in a delay in tumor progression."

It also "raises the concern that the results could have been influenced by an unmeasured prognostic variable that was accidentally imbalanced in the study-group assignments," Dr. Longo writes.

However, this has been seen before, he points out. Another prostate cancer vaccine under development, PROSTVAC-VF (under development by Therion Biologics), also improved overall survival (by 8.5 months) without improving progression-free survival in a randomized phase 2 study (J Clin Oncol. 2010;28:1099-1105). This product is now in phase 3 clinical trials.

However, a third prostate cancer vaccine, known as GVAX (BioSante Pharmaceuticals), was unsuccessful in phase 3 testing, Dr. Longo notes.

High Cost is a Concern

"Another concern with sipuleucel-T treatment is the cost," Dr. Longo comments. The current cost of care for men with prostate cancer has been estimated at around $1800 per month. The vaccine costs $93,000, which works out at $23,000 per month of survival advantage.

"The high cost may affect use," Dr. Longo comments.

This has recently been discussed in a Medscape videoblog, entitled "Provenge Approved: Now How Much is a Life Worth?"

"It is also uncertain what role sipuleucel-T will ultimately play in the treatment of prostate cancer, given other promising treatments in development," Dr. Longo comments, specifically mentioning abiraterone (Cougar Biotechnology) and MDV3100 (Medivation). Both of these drugs are in phase 3 trials with survival as an end-point, as reported by Medscape Medical News.

The trial was supported by Dendreon.

N Engl J Med. 2010;265;411-422, 479-481.