Use of Sipuleucel-T Refined

Eric J. Small, MD

Studies that continue to shed light on the optimal use of sipuleucel- T in men with prostate cancer were presented at the 2013 Genitourinary Cancers Symposium.

Sipuleucel-T, the first-approved vaccine for the treatment of prostate cancer; is an autologous cellular immunotherapy designed to stimulate an immune response to prostate cancer. Studies have shown that it takes approximately 6 months for the treatment effect to become evident.

IMPACT Trial

Results of trials presented at this year’s GU Cancers Symposium evaluated the effect on cancer-related pain, as measured by time to first opioid administration (TFOA), in patients on sipuleucel- T; effect of the vaccine in different age groups and in patients with and without prior docetaxel; and the optimal sequencing of sipuleucel-T and androgen-deprivation therapy (ADT) in men with biochemically recurrent prostate cancer.IMPACT was the pivotal trial leading to the FDA approval of sipuleucel-T in patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). An exploratory analysis of the IMPACT trial suggests that sipuleucel-T has a clinical impact in this patient population that goes beyond its known effect on improving overall survival, according to Eric J. Small, MD, deputy director of Clinical Sciences at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, California, and coauthors [Abstract 74].

IMPACT randomized 512 men with asymptomatic or minimally symptomatic mCRPC to a 2:1 ratio to treatment with sipuleucel-T versus placebo. Sipuleucel-T was associated with a significant improvement in overall survival (OS) compared with controls (P = .03, absolute difference of 4.1 months favoring the vaccine).

The analysis Small presented found that TFOA for cancer-related pain was significantly delayed in patients on the vaccine versus placebo (P <.041). Median TFOA was 11.9 months for sipuleucel-T versus 8.3 months for placebo.

At 12 months, 48.7% of the sipuleucel-T group and 39.7% of the placebo group were opioid-free, and the difference between the two groups was evident at 6 months, which may reflect the delayed treatment effect, Small commented.

Subanalyses of PROCEED

Shorter TFOA was significantly associated with higher PSA and alkaline phosphatase levels, younger age, an ECOG performance status of 1, a Gleason score of 8 or higher, increased weight, previous primary radiotherapy, and a higher number of bone metastasis.Two separate analyses of the PROCEED trial showed that patients aged 80 years or older derive the same benefit from sipuleucel-T as younger patients, and that patients previously exposed to docetaxel derived a similar benefit from the vaccine as those who were docetaxel-naïve.

PROCEED is an ongoing, multicenter, phase IV registry enrolling patients who are receiving sipuleucel- T in the real-world setting.

Chadi Nabhan, MD

The first analysis presented by lead author Chadi Nabhan, MD, director, Division of Hematology/Oncology at Advocate Lutheran General Hospital in Park Ridge, Illinois, compared product parameters in 111 patients who were aged 80 years or older (20%) versus 449 patients younger than age 80 [Abstract 131]. All 560 patients had completed sipuleucel-T treatment as of September 2012.

A lower proportion of PROCEED patients were 80 years or older. Among this group, fewer patients had ECOG performance status of 0, Gleason scores of 8 or higher, and 10 or more bone metastases compared with those in the younger cohort. Both age groups had comparable total nucleated count (TNC) and antigen presenting cell (APC) activation, showing that the older patients exhibited similar immune activation compared with younger patients, with evidence of immunologic prime-boosting.

The second analysis of the same patient population compared the immunologic effects of the vaccine in patients previously exposed to docetaxel versus those who were docetaxel-naïve upon entry to the registry [Abstract 30]. These data were presented by Oliver Sartor, MD, professor of Medicine and Urology at Tulane University School of Medicine, New Orleans, Louisianna.

Sartor noted that in the IMPACT trial, the use of docetaxel was prohibited within 3 months prior to registration, but there was no restriction on docetaxel use in the real-world PROCEED registry.

Of the 560 patients enrolled in the study, 82 (15%) previously had received docetaxel and 474 (85%) had received no docetaxel; the docetaxel stop date was not available for 4 patients. Of the patients who had received docetaxel, 14 patients received docetaxel for 90 days or less before initiation of sipuleucel-T, and 68 patients received docetaxel more than 90 days before initiation of the vaccine.

Oliver Sartor, MD

Baseline demographics and disease characteristics were different in patients with and without prior docetaxel exposure. Product parameters of sipuleucel-T, including APC and TNC counts and APC activation, were comparable in both groups independent of prior docetaxel use.

Optimal Sequencing of Sipuleucel-T

and Androgen Ablation

“Sipuleucel-T stimulated a robust immune response that is consistent with immune prime-boost independent of prior docetaxel exposure,” the authors wrote, but said that only a small number of patients received docetaxel less than 90 days before sipuleucel-T, so further evaluation is warranted in this group of patients.The optimal sequencing of sipuleucel-T and androgen ablation is still under study. A randomized phase II trial of 68 patients with biochemically recurrent prostate cancer provides preliminary evidence that ADT should be administered first to improve antitumor immune response [Abstract 34]. The lead author on the study was Emmanuel Antonarakis, MB BCh, assistant professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland.

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Dr. Emmanuel Antonarakis on Sequencing ADT and Sipuleucel-T

The combination of sipuleucel-T and ADT was well tolerated in patients with biochemically recurrent prostate cancer in this analysis. Immune activation of the vaccine was independent of the timing of ADT. Measurement of serum cytokines, including IFN-gamma, suggested that ADT may enhance T cell activity when administered before sipuleucel-T.

Further study is needed to establish with certainty optimal sequencing of these two modalities in men with biochemically recurrent prostate cancer.

• Small EJ, Higano CS, Kantoff PW, Whitmore JB, Frohlich MW, Petrylak DP. Relationship of sipuleucel-T with time to first use of opioid analgesics in patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer on the IMPACT trial. J Clin Oncol. 2013;31(suppl 6; abstr 74).
• Nabhan C, Sartor AO, Cooperberg MR. Real-world experience with sipuleucel-T in patients ≥80 years old with metastatic castration-resistant prostate cancer: Data from PROCEED. J Clin Oncol. 2013;31(suppl 6; abstr 131).
• Sartor AO, Cooperberg MR, Vogelzang NJ. Real-world experience with sipuleucel-T in patients with metastatic castration-resistant prostate cancer who received prior docetaxel: Data from PROCEED. J Clin Oncol. 2013;31(suppl 6; abstr 30).
• Antonarakis ES, Kibel A, Tyler RC. Randomized phase II trial evaluating the optimal sequencing of sipuleucel-T and androgen-deprivation therapy in patients with biochemically recurrent prostate cancer. J Clin Oncol. 2013;31(suppl 6; abstr 34).