Successive therapies may extend survival in AIPC

February 1, 2007

New York-The administration of sipuleucel-T (Provenge), an investigational immunotherapy designed to stimulate a patient's immune response, followed by docetaxel chemotherapy prolonged survival in men with asymptomatic androgen-independent prostate cancer (AIPC), according to a recently released study. Median survival in these men was 14 months longer than would have been predicted by a prostate cancer survival nomogram, said Daniel Petrylak, MD, associate professor of medicine and director of genitourinary oncology at Columbia Presbyterian Medical Center in New York.

"Although the common wisdom has been that we can't give immunotherapy and chemotherapy at the same time because they are antagonistic, these data challenge that myth," Dr. Petrylak said.

Because docetaxel has been shown to improve survival in AIPC and immunotherapy is emerging as another strategy to improve survival in AIPC, "the real challenge is how best to integrate these treatments in the future," he added.

His rationale for combining chemotherapy and immunotherapy was that this combination decreases the number of regulatory/suppressor T cells, debulks the number of cancer cells for subsequent immune attack, modifies tumor tissue to make it more vulnerable to anti-inflammatory treatment, and reduces immunosuppressive factors. Further, preclinical evidence in murine tumors suggests that docetaxel is an immune stimulator that stimulates macrophage function and increases helper/inducer T-lymphocytes and natural killer cells. Sipuleucel-T is a novel treatment that activates dendritic cells ex vivo and reinfuses them back into the patient to attack tumor cells, Dr. Petrylak explained.

Exploratory analysis

The exploratory pooled analysis included data from two identical randomized, double-blind, placebo-controlled trials in 212 men with asymptomatic AIPC. The men were randomized 2:1 to study treatment with sipuleucel-T or placebo as follows: three cycles of sipuleucel-T every 2 weeks or three cycles of placebo every 2 weeks. At progression, patients in the sipuleucel-T arm were treated at the physician's discretion; patients in the placebo arm received salvage therapy with a frozen dendritic cell preparation every 2 weeks for three cycles. All patients were followed for survival.

Pre-specified 36-month analysis showed a survival benefit for those patients who received sipuleucel-T: a median benefit of 4.3 months compared with placebo. At 36 months, 36% of patients treated with sipuleucel-T were alive versus 15% in the placebo arm.

Dr. Petrylak said that if sipuleucel-T is approved by FDA, the question will be how to sequence these treatments: Should immunotherapy precede chemotherapy or the reverse? Should they be administered intermittently? This second question is especially important for asymptomatic patients, who may want to defer treatment as long as possible, he noted.

In the randomized trials, the majority of patients went on to docetaxel following progression on sipuleucel-T. Of 212 patients, 37% in the treatment arm and 41% in the placebo arm received docetaxel. Median time to chemotherapy was 4 to 6 months. Dr. Petrylak presented evidence showing continued immune activation for 3 to 6 months after treatment with sipuleucel-T, and suggested that this sustained immune response could potentially interact with subsequent chemotherapy.

The two studies demonstrated that subjects who received sipuleucel-T followed by docetaxel had prolonged survival. Fifty-one patients in the sipuleucel-T arm and 31 in the placebo arm received docetaxel. Unadjusted survival was significantly longer in those who received sequential immunotherapy followed by docetaxel, with a hazard ratio of 1.9 (p=.023, log rank). Analysis using the Halabi nomogram to adjust for heterogeneity of the disease showed a higher hazard ratio of 2.53 favoring the addition of docetaxel following sipuleucel-T (p=.006).

"This is supportive evidence for the interaction of sipuleucel-T and docetaxel," Dr. Petrylak said.

Median survival in patients who received docetaxel was 34.5 months in the sipuleucel-T arm, 14 months longer than predicted by Halabi nomogram, and 25.4 months in placebo arm, which is about 6 months longer than predicted. Patients who received docetaxel and placebo but who did not cross over to the frozen dendritic cell product had a median survival of 19.1 months, as predicted by the Halabi nomogram for this group of patients.