When initial androgen-deprivation therapy (ADT) fails to control progression of metastatic prostate cancer, the disease is redefined as castration-resistant prostate cancer (CRPC). Studies have shown that using docetaxel and prednisone to treat men with CRPC only modestly extends median overall survival (OS) to ~19 months. In addition, only 18.6% of patients who receive this combination survive 3 years.1,2 Re cently, cabazitaxel (Jevtana), a novel taxane, was found to extend median OS in progressive metastatic CRPC following previous docetaxel, but only modestly compared with mitoxantrone (15.1 vs 12.7 months, P <.0001).3 Novel and more tolerable options are needed to manage prostate cancer in this population of mostly elderly men, who often have multiple comorbidities. Sipuleucel- T (Provenge), an autologous dendritic cell–based vaccine approved by the US Food and Drug Administration (FDA) in 2010, is one such option. Studies show that it prolongs OS in men with metastatic CRPC and is well tolerated.4
Rationale for Immunotherapy in Metastatic CRPC
Humoral (antibody) and cellular (T cells, natural killer cells, macrophages) immune responses are involved in combating malignancies, with cellular immunity thought to play a more prominent role. Antigen-presenting cells (APCs), which include dendritic cells, are able to activate T lymphocytes by efficiently presenting them to T-cell receptors. Activation of T cells subsequently enhances B-lymphocyte response. Prostate cancer provides an excellent opportunity for applying immunotherapy, because it is relatively indolent and expresses several essentially organ-specific tumor-associated antigens, such as prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA).
A Novel Vaccine
The sipuleucel-T vaccine, which consists of autologous APCs manufactured by processing the leukapheresis product and manipulating it to enhance the presentation of tumor antigens, has been evaluated extensively, culminating in FDA approval.5-7 The vaccine contains APCs pulsed with PA2024, a fusion protein of PAP-granulocyte macrophage colony-stimulating factor.8 In an initial small randomized trial enrolling 127 previously untreated men with asymptomatic, metastatic CRPC, sipuleucel-T prolonged median OS compared with placebo (25.9 vs 21.4 months, P = .01).9
Subsequently, the larger IMPACT (Immunotherapy Prostate Adenocarcinoma Treatment) trial randomized 512 men with asymptomatic metastatic CRPC at a 2:1 ratio to sipuleucel-T or placebo; the study’s primary end point of OS.4 Men with visceral metastasis were excluded. About 85% of patients were chemotherapy-naïve, and the 15% of men who received chemotherapy previously were required to have completed the treatment at least 3 months prior to enrollment. ADT was continued in all patients.
Treatment included 3 leukapheresis procedures (at weeks 0, 2, and 4). Approximately 3 days after each procedure, patients received a 60-minute infusion of sipuleucel-T or placebo following premedication with acetaminophen and an antihistamine. Even though the trial allowed patients assigned to placebo to crossover, median OS was still significantly improved in the sipuleucel-T arm compared with the placebo arm (25.8 vs 21.7 months, respectively; P = .02). The probability of 3-year survival was also better with sipuleucel-T than placebo (31.7% vs 23.0%, respectively). Approximately 55% of men in both groups received subsequent docetaxel at a median of 12 to 13 months after on-study therapy, but analyses did not suggest that the differences in the frequency of or time elapsed to docetaxel treatment could account for the differences in outcomes.
Notably, the time to disease progression was similar in the 2 groups and no clear early evidence of activity was observed. Confirmed PSA declines ≥50% were observed in only 8 of 311 (2.6%) patients in the sipuleucel-T group and in 2 of 153 (1.3%) patients in the placebo group. Sipuleucel-T was associated with mild and manageable grade 1 and 2 infusion-related adverse events, including fever (22.5%) and chills (51.2%). Antibody response against PAP or PA2024 (antibody titer exceeding 400) was observed in 66.2% of patients in the sipuleucel-T group and correlated with survival benefit. Tcell responses to the immunizing antigen also were observed but were not associated with survival.
Sipuleucel-T provides a modest extension of survival coupled with an excellent toxicity profile in generally chemotherapy-naïve and relatively asymptomatic patients without visceral metastases. Sipuleucel-T was highly tolerable, and no long-term and delayed adverse immune phenomena have been observed. Given the cost and a modest survival benefit, it is important to select patients appropriately based on the eligibility criteria used in the IMPACT trial.
Several other novel immunotherapeutic agents are being evaluated in clinical trials. Poxvirus-based vaccines and immune-checkpoint inhibitors of cytotoxic T-lymphocyte antigen 4 (CTLA- 4) and programmed death-1 (PD-1) appear promising. In addition, multiple emerging novel androgen-pathway inhibitors (abiraterone acetate, TAK700, MDV3100) are likely to expand the therapeutic armamentarium in the near future.10 Therefore, the proper sequence of therapeutic agents and appropriate selection of patients likely to benefit from specific agents will assume great importance.
Guru Sonpavde is a speaker for Dendreon Corp, and his institution receives research funding from Bellicum Pharmaceuticals. Toni K. Choueiri has nothing to disclose. Philip W. Kantoff is a consultant for Dendreon Corp, Bellicum Pharmaceuticals, and BN ImmunoTherapeutics Inc.
- Berthold DR, Pond GR, Soban F, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26:242-245.
- Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mito - xantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520.
- de Bono JS, Oudard S, Ozguroglu M, et al; for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154.
- Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.
- Sonpavde G, Slawin KM, Spencer DM, Levitt JM. Emerging vaccine therapy approaches for prostate cancer. Rev Urol. 2010;12:25-34.
- Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med. 2004;10:475-480.
- Drake CG. Prostate cancer as a model for tumour immunotherapy. Nat Rev Immunol. 2010;10:580-593. 8. Small EJ, Fratesi P, Reese DM, et al. Immunotherapy of hormone-refractory prostate cancer with antigenloaded dendritic cells. J Clin Oncol. 2000;18:3894-3903.
- Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24:3089-3094.
- De Bono J LC, Logothetis CJ, Fizazi K, et al; for the COU-AA-301 investigators. Abiraterone acetate plus low dose prednisone improves overall survival in patients with metastatic castration resistant prostate cancer who have progressed after docetaxel-based chemotherapy: results of COU-AA-301, a randomized double-blind placebo-controlled phase III study. Ann Oncol. 2010;21(suppl 8):LBA5