Background

On April 29, 2010, the Food and Drug Administration approved sipuleucel-T (Provenge) for the treatment of advanced prostate cancer. This approval heralds the dawn of an entirely new era of generally safe treatments – immunotherapy – for patients with metastatic prostate cancer. The results of the pivotal Phase III clinical trial were published in The New England Journal of Medicine (July 29, 2010) by a team of investigators led by PCF-funded Philip W. Kantoff, MD, leader of the Dana-Farber/Harvard Cancer Center Prostate Cancer Program and a Provenge investigator. This trial involved 512 patients treated 2:1 with Provenge and placebo, respectively. Provenge-treated patients experienced a 22 percent reduction in the risk of death, which translates to a 4.1 month increased overall survival. Importantly, the increase in survival was not associated with a slowing of disease progression, i.e., PSA continued to rise and in some patients, radiologic scans of bone and soft tissue may have remained unchanged or even worsened. The uncoupling effect on survival and disease progression appears to be a common property of immunotherapy and might not be specific to Provenge.

Donald L. Trump, MD, president and CEO of the Roswell Park Cancer Institute, shared with HemOnc Today that “Provenge may be the only example of a cancer treatment wherein the standard measures of efficacy didn’t change. The PSA score didn’t decrease, patients with measurable lesions (tumor seen on X-rays or other scans) did not see those lesions change. None of the standard measures we use to say a treatment works were positive, and yet the overall survival improved.”

Provenge is an “autologous cellular immunotherapy” created by first collecting a patient’s white blood cells, which are sent to a specialized laboratory for processing. The laboratory “arms” these cells against prostate cancer treatment with a protein, prostatic acid phosphatase (PAP) and other immune-sensitizing agents. The “armed” cells are returned to the clinic where they are infused three times at two week intervals. The “armed” immune cells are thought to seek out prostate cancer and exert their ability to kill the tumor.

PCF has invested approximately $9.7 million (1993 – 2010) to support immunotherapy research and the discovery and development of therapeutic cancer vaccines and inter-related treatments to boost a patient’s immune response against his tumor. In the case of Provenge, PCF first provided funding to Dr. Eric Small in 1999 (a member of the 13 center Prostate Cancer Clinical Trials Consortium that is co-funded by PCF and the Department of Defense) to support clinical research around measuring immune responses in patients treated with Provenge. Dr. Small and his colleagues at UCSF provided important early data in patients for the development of Provenge by Dendreon Corporation, the corporate sponsor of Provenge. Dr. Small first published PCF-supported clinical testing of Provenge in the Journal of Clinical Oncology in July 2000.

Provenge and Patients

As with all new therapies, treating physicians are on a learning curve as to the best time in a patient’s disease course to administer Provenge.  Optimization of Provenge therapy with other anti-neoplastic agents is also in very early stages of development. Kantoff expects that the vaccine will be assigned to patients who are asymptomatic or minimally symptomatic and refractory to hormone therapy. We expect that numerous clinical trials will test Provenge in combination therapy. Studies of Provenge very early in the natural history of prostate cancer, as well as combination therapy with an immunostimulatory agent, Ipilimumab are underway.

The market launch of Provenge has sparked debate over the price of treatment. The treatment is not a simple pill; it is individually prepared, using each patient’s cells to produce the infusion product. This individual biological therapy is expensive. The entire cost of treatment is $93,000, resulting in a median of 4.1 months of prolonged survival, according to the study published in The New England Journal of Medicine. Pricing is based on Dendreon Corporation’s assumption that patients and their insurance companies are willing to pay around $23,000 for each additional month of life gained. Reimbursement will be a complex issue but is being managed effectively by private insurance companies as well as Medicare. We expect that those patients that might benefit from this therapy will receive coverage at some level.

Dendreon Corporation projects that they will only be able to produce enough Provenge for 2,000 patients during this initial year of commercialization. This capacity will increase by mid-2011. Even then, supply will be short and qualified providers will seek fair standards for patient selection. The key factor is the development of a laboratory method to predict patients most likely to respond. PCF is funding research to help in the decision process but these studies are at an early stage.

Ideally, for the more than 2.5 million American men living with prostate cancer, the use of Provenge should remain a personal decision, made by a patient and his physician without the added concern of cost. However, until production increases and we have a better understanding of how Provenge works, and why it works for some patients and not others, and how to optimally administer the therapy, the cost debate will likely persist. All controversy aside, Provenge is playing a vital role in validating the potential of immunotherapy and is offering new hope to patients and their families.  Further research on Provenge, and immunotherapy in general, is highly merited.