New Agents for the Management of Castration-Resistant Prostate Cancer

Robert J Cersosimo PharmD BCOP


The Annals of Pharmacotherapy. 2012;46(11):1518-1528. 

In This Article


Mechanism of Action

Sipuleucel-T is indicated for the treatment of asymptomatic or minimally symptomatic metastatic CRPC.[11] Sipuleucel-T is the first vaccine approved for treatment of malignant disease. It consists of activated autologous peripheral blood mononuclear cells, including antigen-presenting cells that have been obtained from the patient by leukapheresis at an approved apheresis center.[7] After collection, these cells are sent to 1 of 3 processing centers (New Jersey, Georgia, or California) where they are activated with a recombinant human protein. This protein consists of prostatic acid phosphatase (PAP), an antigen found in prostate cancer tissue, that is linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), which serves as an immune cell activator. The final composition of sipuleucel-T depends on the composition of the patient's cells obtained during leukapheresis, but should consist of antigen-presenting cells, T cells, B cells, natural killer cells, and other cells. After activation, the product is sent to the provider for reinfusion into the patient. Leukapheresis should take place 3 days before the planned reinfusion date. Treatment with sipuleucel-T is a form of autologous cellular immunotherapy. Although the exact mechanism of action is unknown, it is designed to induce an immune response against PAP in prostate cancer cells. A Phase 2 study demonstrated that it may take 8 weeks for maximum T cell proliferation responses to develop.[12]


Sipuleucel-T is supplied as a 250-mL suspension that contains a minimum of 50 million autologous CD54 cells activated with PAP–GM-CSF in lactated Ringer's injection. The final product is supplied in a sealed, patient-specific infusion bag. A complete course of therapy consists of 3 doses, administered every 2 weeks. The infusion must begin prior to the expiration date and time indicated on the cell product disposition form and product label. The entire volume of the bag should be administered as an intravenous infusion over 60 minutes. The product should not be administered through a cell filter. The patient should be observed for at least 30 minutes following each infusion.[11]

Patients should be pretreated with acetaminophen and an antihistamine such as diphenhydramine 30 minutes prior to the infusion. Acute infusion reactions are commonly seen after administration and may include chills, fatigue, fever, nausea, and joint aches. Should an infusion reaction occur, the infusion should be slowed or interrupted, depending on the severity of the reaction. Treatment appropriate to the severity of the reaction should be administered. In controlled clinical trials the most commonly administered therapy was acetaminophen, intravenous histamine H1 and/or H2 blockers, and low-dose meperidine. If the reaction required the infusion to be stopped, the patient recovered, and it was deemed safe to resume the infusion, the manufacturer recommends not resuming the infusion if the bag was maintained at room temperature for more than 3 hours.[11] Patients who receive sipuleucel-T should have good immune systems. Since it takes a few months for the immune system to fully respond, those who receive sipuleucel-T should be patients who their physicians believe will have stable disease for several months after treatment.

Clinical Activity

Sipuleucel-T has been evaluated in 3 randomized Phase 3 trials of patients with asymptomatic metastatic CRPC (Table 2).[7,8,13,14] All patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and serum testosterone levels <50 ng/dL. Patients enrolled in the first 2 trials also had to have positive staining for PAP in 25% of tumor cells. Patients with cancer-related bone pain and visceral metastases were excluded. The first study, D9901, randomized 127 patients in a 2:1 ratio to receive 3 infusions of sipuleucel-T (n = 82) or placebo (n = 45) every 2 weeks.[13] The primary end point was time to progression, which was assessed by radiographic imaging, appearance of new cancer-related pain with radiographic anatomic correlation, or other evidence consistent with progression such as pathologic fracture, nerve root compression, or spinal cord compression. Prostate-specific antigen (PSA) was not used to determine disease progression. Although the study was not powered to detect a survival difference between the 2 groups, patients were followed for up to 36 months and survival data were reported. Upon progression, patients in the control arm were offered APC8015F, a product manufactured to the same specifications as sipuleucel-T but prepared from the patient's cells that were cryopreserved when the placebo was prepared. At the time of publication, 115 patients (90.5%) had experienced progression and 34 subsequently received APC8015F. After progression, 55.7% of patients receiving sipuleucel-T and 62.8% of patients receiving placebo received some type of chemotherapy.

Median time to progression was 11.7 weeks in patients who received sipuleucel-T and 10.0 weeks in patients who received placebo (p = 0.052). An intention-to-treat analysis revealed a median overall survival of 25.9 months in the sipuleucel-T group versus 21.4 months in the placebo group (p = 0.01). The estimated survival rate at 36 months was 34% in the sipuleucel-T group and 11% in the placebo group (p = 0.005, based on the number of survivors at 36 months). This analysis included the placebo patients who crossed over to sipuleucel-T. Sipuleucel-T maintained a significant impact on survival after adjustments were made for clinical variables that might affect survival (p < 0.002), including PSA, lactate dehydrogenase, number of bone metastases, body weight, and localization of disease.[13]

Another study, D9902, was a 2-stage double-blind, placebo-controlled Phase 3 trial. Both D9901 and D9902 were instituted at the same time.[14] Enrollment in the first stage, D9902A, was stopped after accrual of 98 patients when the results of D9901 revealed no significant benefit in time to progression with sipuleucel-T. Since a benefit was noted in patients with a Gleason score of 7 or less, the trial was amended to study only patients with Gleason scores of 7 or less. The first part of the study, in which patients with all Gleason scores were included, was designated as D9902A. The second part, in which only patients with Gleason scores of 7 or less were included, was designated as D9002B and was reported separately.[7,8]

An integrated analysis was performed of the data from D9901 and D9902A in which 225 patients were randomized to receive sipuleucel-T (n = 147) or placebo (n = 78).[14] In D9902A, the median time to progression was 10.9 months with sipuleucel-T and 9.9 months with placebo (p = 0.719). Integration of the data from the 2 trials revealed median times to progression of 11.1 months with sipuleucel-T and 9.7 months with placebo (p = 0.111). Respective median overall survival with sipuleucel-T versus placebo was 19.0 versus 15.7 months (p = 0.331) in D9902A and 23.2 versus 18.9 months (p = 0.011) in the integrated analysis. At 36 months, 33% of sipuleucel-T patients and 15% of placebo patients were still alive.

Study D9902B, the IMPACT (Immunotherapy for Prostate Adenocarcinoma Treatment) trial, randomized 512 men to receive sipuleucel-T (n = 341) or placebo (n = 171).[7] The study was later amended to include men with all Gleason scores and men with minimally symptomatic disease. Exclusion criteria included an ECOG performance status of 2 or greater, visceral metastases, spinal cord compression, and pathologic bone fractures. The primary end point was overall survival, with a secondary end point of time to progression. In the initial report, after 331 patient deaths, the median overall survival in the sipuleucel-T group was 25.8 months, versus 21.7 months in the placebo group (p = 0.032). A follow-up report after 349 deaths revealed no change.[7] The probability of surviving 36 months was 31.7% with sipuleucel-T and 23% with placebo. Sipuleucel-T therapy was associated with a 22% relative reduction in the risk of death. There was no significant difference in median time to progression between sipuleucel-T (14.6 weeks) and placebo (14.4 weeks).

Eighty-two percent of patients in the sipuleucel-T arm and 73% in the control arm received additional treatment after sipuleucel-T or placebo, including docetaxel, which was administered to 57.2% who received sipuleucel-T and to 50.3% who received placebo. The survival curves were similar for both groups with and without docetaxel therapy, suggesting that the results seen with sipuleucel-T were not affected by the poststudy addition of docetaxel. Upon progression, patients in the control arm were offered APC8015F. Eighty-four patients in the placebo group (49.1%) received APC8015F as their first treatment after completion of the study and 109 patients in the placebo group (63.7%) received it at some point. Median survival in those who received APC8015F was 23.8 months, versus 11.6 months in those who did not receive it. These results need to be confirmed in a randomized study. However, the authors reported that the survival benefit from sipuleucel-T persisted even after the administration of APC8015F to some of the placebo group. Immune response was assessed by measurement of antibody titers against the immunizing antigen PA2024 and against PAP and by T-cell proliferation responses to PA2024 and PAP at week 6. Sipuleucel-T patients who had an antibody titer greater than 400 against PA2024 or PAP at any time after baseline had a longer survival than those whose antibody titers were less than or equal to 400 (p < 0.001 and p = 0.08, respectively). There were no differences in survival among those who had T-cell proliferation responses to PA2024 or PAP and those who did not.[7]

One of the unusual outcomes with sipuleucel-T therapy is the lack of objective response criteria, other than the ultimate end point of survival. There was no objective evidence of a tumor response or time to progression benefit in any of these trials. It has been suggested that vaccines work in a different manner than conventional chemotherapy, where such monitoring parameters have traditionally been used.[15] Vaccines work by affecting the immune system, which takes time and may ultimately result in an impact on survival without affecting traditional outcome measures. Guidelines for the evaluation of immune therapy have been proposed.[16]