Raoul S. Concepcion, MD, FACS
Nearly a decade ago, sipuleucel-T (Provenge) became the first FDA-approved personalized cancer vaccine, a harbinger of the current era of immunotherapy. After the autologous cellular vaccine gained approval in April 2010, its entry into the clinic was accompanied by expectations that it would see significant uptake by men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).
The trajectory of this groundbreaking therapy, however, has been far different from the rapid adoption now underway with checkpoint blockade immunotherapy. Sipuleucel-T did find a place in the prostate cancer toolkit, particularly among urologists, but it was not widely adopted. Although it extends survival and is well tolerated, a combination of factors has led to limited use of the therapy, according to experts. These factors include a delayed initial approval, incomplete understanding of the new therapeutic mechanism, a lack of biomarkers to measure efficacy, cost barriers, the complexity of administration, and the subsequent approval of competing drugs. It was dogged by controversy and its manufacturer, Dendreon, declared bankruptcy and changed ownership 3 times.1
Yet advocates for sipuleucel-T point out that the public has become more aware of and interested in immunotherapy now, and they believe the product has the potential to benefit a larger group of patients. Dendreon last year began a new effort to expand its market by launching ProVent (NCT03686683), a phase III randomized trial testing the effectiveness of sipuleucel-T versus active surveillance in decreasing histologic progression of low-grade prostate cancer (Figure
ProVent “has a lot of potential, depending on how quickly it can accrue. Obviously, that is a very, very big space. There’s lots of interest in newly diagnosed, low-grade prostate cancer patients on active surveillance,” said Raoul S. Concepcion, MD, director of The Comprehensive Prostate Center and clinical associate professor at Vanderbilt University School of Medicine, both in Nashville, Tennessee. He has served as a physician adviser to Dendreon.
Several other trials are testing combinations or sequencing of sipuleucel-T with radiotherapy, checkpoint inhibitors, and other therapies. “It will maintain itself as a go-to medication for metastatic castrate-resistant prostate cancer, but the future is in combination therapy— learning how to mix it not only with chemotherapy, but with androgen-receptor pathway blockers or with other immunotherapeutic agents that might enhance the overall response to sipuleucel- T,” said Leonard G. Gomella, MD, director of the Kimmel Cancer Center Network at Thomas Jefferson University Hospital in Philadelphia.
Impact on PSA
Sipuleucel-T treatment begins with leukapheresis, typically at a physician’s office or blood-collection center. The harvested white blood cells, most importantly dendritic antigen-presenting cells, are sent to a manufacturing facility. They are incubated with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP), an antigen that is highly expressed in most prostate cancer cells, and granulocyte-macrophage colony-stimulating factor.
Three or 4 days after the initial blood draw, the activated cells are reinfused into the patient, activating an immune system response against PAP-expressing prostate cancer cells. The procedure is conducted 3 times over a period of 6 weeks.3
Attitudes toward sipuleucel-T have been heavily shaped by the fact that the therapy has not demonstrated significant impacts on lowering PSA levels and on slowing disease progression in radiographic imaging studies. The first phase III trial, D9901 (N = 127), did not achieve a statistically significant improvement in the primary endpoint of median time to progression; PSA progression was not included in the primary endpoint.4
The study was not powered for overall survival (OS), but investigators were surprised to find the sipuleucel-T group had a median survival advantage of 4.5 months over the placebo group (25.9 vs 21.4 months; log-rank P
= .01). The estimated survival rate at 36 months was 34% for sipuleucel-T and 11% for placebo (P
The data were pooled with findings from another phase III trial, D9902A, and the integrated results showed a similar median survival benefit of 4.3 months (HR, 1.50; 95% CI, 1.10-2.05; log rank P
Yet the failure to meet the original endpoint and the lack of evidence of direct antitumor effect, along with other concerns, sowed skepticism among some members of the FDA advisory committee reviewing the data. In 2007, the agency rejected sipuleucel-T and asked for more data.6