Coverage Policy Manual
Policy #: 2010028
Category: Pharmacy
Initiated: September 2010
Last Review: January 2024
  Sipuleucel-T (Provenge) for the Treatment of Prostate Cancer
Description:
Sipuleucel-T (Provenge®, Dendreon Corp.) is a new class of therapeutic agent used in the treatment of asymptomatic or minimally symptomatic, castrate-resistant (hormone-refractory), metastatic prostate cancer. It consists of specially treated dendritic cells obtained from the individual with leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic stimulating factors, and then reinfused back into the individual. The proposed mechanism of action is that the treatment stimulates the individual’s own immune system to resist spread of the cancer.
 
Prostate cancer is the second leading cause of cancer-related deaths among American men with an estimated incidence of 218,890 cases and an estimated number of 27,050 deaths in 2007. The majority of cases are diagnosed at a localized stage and are treated with prostatectomy or radiation therapy. However, some individuals are diagnosed with metastatic disease or recurrent disease after treatment of localized disease. Androgen ablation is the standard treatment for metastatic or recurrent disease. However, most individuals who survive long enough eventually develop androgen-independent prostate cancer. At this stage of metastatic disease docetaxel, a chemotherapeutic agent, has been demonstrated to confer a survival benefit of 1.9 to 2.4 months in randomized clinical trials (Berry, 2006) (Tannock, 2004).  Chemotherapy with docetaxel causes adverse effects in large proportions of patients, including alopecia, fatigue, neutropenia, neuropathy, and other symptoms. The trials evaluating docetaxel included both asymptomatic and symptomatic individuals, and results suggested a survival benefit for both symptomatic and asymptomatic individuals. Because of the burden of treatment and its side effects, most individuals therefore defer docetaxel treatment until the cancer recurrence is symptomatic.
 
Cancer immunotherapy has been investigated as a treatment which might be instituted at the point of detection of androgen-independent metastatic disease before significant symptomatic manifestations have occurred. The quantity of cancer cells in the individual during this time interval is thought to be relatively low, and it is thought that an effective immune response against the cancer during this time period could effectively delay or prevent progression. Such a delay could allow effective chemotherapy such as docetaxel to be deferred or delayed until necessary, thus providing an overall survival benefit. Sipuleucel-T (Provenge®, Dendreon Corp.) is a new class of therapeutic agent used in the treatment of asymptomatic or minimally symptomatic, castrate-resistant (hormone-refractory), metastatic prostate cancer. It consists of specially treated dendritic cells obtained from the individual with leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic stimulating factors, and then reinfused back into the individual. The cells are administered as 3 intravenous (IV) infusions, each infusion given approximately 2 weeks apart. The proposed mechanism of action is that the treatment stimulates the individual's own immune system to resist spread of the cancer.
 
Regulatory Status
 
On April 29, 2010, the U.S. Food and Drug Administration (FDA) approved Provenge® (sipuleucel-T, Dendreon Corp.) via a Biologics Licensing Application (BLA) for "the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (for autologous use only)." Approval was contingent on agreement of the manufacturer to conduct a post marketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 individuals with prostate cancer who receive sipuleucel-T.
 
Effective, July 1, 2011, the Centers for Medicare & Medicaid Services (CMS) has granted sipuleucel-T (PROVENGE) a temporary HCPCS code, Q2043. The leukapheresis procedure to obtain the individual’s dendritic cells would most likely be reported with CPT code 36511 (therapeutic apheresis; for white cells).
 
Coding
 
See CPT/HCPCS Code section.
 
Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Effective January 10, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Sipuleucel-T therapy meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of asymptomatic or minimally symptomatic, metastatic, castrate-resistant (hormone-refractory) prostate cancer if ALL the following criteria are met:
 
1. The individual has histologically confirmed adenocarcinoma of the prostate with metastatic disease in soft tissue and/or bone with evidence of disease progression determined at either of these sites or by serial measurement of prostate specific antigen (PSA)(NCCN 2A; EAU-ESTRO-SIOG Guidelines); AND
2. The individual had prior surgical castration or adequate hormonal therapies with castrate testosterone levels attained (FDA label, 2017);  AND
3. The individual has asymptomatic or minimally symptomatic prostate cancer with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (NCCN 2A); AND
4. The individual does not have visceral disease (liver, lung, or brain) metastases (NCCN 2A); AND
5. The individual does not have reported moderate to severe prostate cancer related pain and/or use of narcotics for cancer related pain (NCCN 2A); AND
6. The individual should have a life expectancy of greater than six months (NCCN 2A); AND
7. Will not be used in the following circumstances:
a. Individual has hormone-responseive prostate cancer; OR
b. Individual has moderate to severe symptomatic metastatic prostate cancer; OR
c. Individual has visceral (liver, lung or brain) metastatses; AND
8. Must be dosed in accordance with the FDA label.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended course of therapy for sipuleucel-T is 3 complete doses, given at approximately 2-week intervals.
 
Each dose of sipuleucel-T contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSP.
 
Dosing Limits
One course of therapy consisting of 3 doses per lifetime.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Sipuleucel-T therapy, for any indication or circumstance not described above, does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, Sipuleucel-T therapy, for any indication or circumstance not described above, is considered investigational. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
The tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  There is no information available regarding the risks or benefits of giving the two drugs together or in tandem (Hu et al, 2016).
 
For contracts without primary coverage criteria, the tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel is considered investigational.  
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective November 1, 2021 to January 9, 2024
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Sipuleucel-T therapy meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of asymptomatic or minimally symptomatic, metastatic, castrate-resistant (hormone-refractory) prostate cancer if ALL of the following criteria are met:
 
        • The patient has histologically confirmed adenocarcinoma of the prostate with metastatic disease in soft tissue and/or bone with evidence of disease progression determined at either of these sites or by serial measurement of prostate specific antigen (PSA)(NCCN 2A; EAU-ESTRO-SIOG Guidelines); and
        • The patient had prior surgical castration or adequate hormonal therapies with castrate testosterone levels attained (FDA label, 2017);  and
        • The patient has asymptomatic or minimally symptomatic prostate cancer with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (NCCN 2A); and
        • The patient does not have visceral disease (liver, lung, or brain) metastases (NCCN 2A); and
        • The patient does not have reported moderate to severe prostate cancer related pain and/or use of narcotics for cancer related pain (NCCN 2A); and
        • The patient should have a life expectancy of greater than six months (NCCN 2A)
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
    • Per FDA label guidelines.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Sipuleucel-T therapy does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in all other situations, including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases.
 
For contracts without primary coverage criteria, Sipuleucel-T therapy is considered investigational in all other situations, including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
The tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  There is no information available regarding the risks or benefits of giving the two drugs together or in tandem (Hu et al, 2016).
 
For contracts without primary coverage criteria, the tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel is considered investigational.  
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective January 17, 2019 to October 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Sipuleucel-T therapy meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of asymptomatic or minimally symptomatic, metastatic, castrate-resistant (hormone-refractory) prostate cancer if ALL of the following criteria are met:
 
        • The patient has histologically confirmed adenocarcinoma of the prostate with metastatic disease in soft tissue and/or bone with evidence of disease progression determined at either of these sites or by serial measurement of prostate specific antigen (PSA); and
        • The patient had prior surgical castration or adequate hormonal therapies with castrate testosterone levels attained; and
        • The patient has asymptomatic or minimally symptomatic prostate cancer with Eastern Cooperative Oncology Group (ECOG) performance status 0-1; and
        • The patient does not have visceral disease (liver, lung, or brain) metastases; and
        • The patient does not have reported moderate to severe prostate cancer related pain and/or use of narcotics for cancer related pain; and
        • The patient should have a life expectancy of greater than six months.
 
Dosage and Administration
 
    • Per FDA label guidelines.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Off Label:
    • NCCN 1, 2A, and 2B recommendations in accordance with Coverage Policy #2000030.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Sipuleucel-T therapy does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in all other situations, including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases.
 
For contracts without primary coverage criteria, Sipuleucel-T therapy is considered investigational in all other situations, including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
The tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  There is no information available regarding the risks or benefits of giving the two drugs together or in tandem.
 
For contracts without primary coverage criteria, the tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel is considered investigational.  
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 2010 - January 16, 2019
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Sipuleucel-T therapy meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of asymptomatic or minimally symptomatic, metastatic, castrate-resistant (hormone-refractory) prostate cancer if ALL of the following criteria are met:
 
    • The patient has histologically confirmed adenocarcinoma of the prostate with metastatic disease in soft tissue and/or bone with evidence of disease progression determined at either of these sites or by serial measurement of prostate specific antigen (PSA); and
    • The patient had prior surgical castration or adequate hormonal therapies with castrate testosterone levels attained; and
    • The patient has asymptomatic or minimally symptomatic prostate cancer  with Eastern Cooperative Oncology Group (ECOG) performance status 0-1; and
    • The patient does not have visceral disease (liver, lung, or brain) metastases; and
    • The patient does not have reported moderate to severe prostate cancer related pain and/or use of narcotics for cancer related pain; and
    • The patient should have a life expectancy of greater than six months.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Sipuleucel-T therapy does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in all other situations,  including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases.
 
For contracts without primary coverage criteria, Sipuleucel-T therapy is considered investigational in all other situations, including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
The tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  There is no information available regarding the risks or benefits of giving the two drugs together or in tandem.
 
For contracts without primary coverage criteria, the tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage
 
Effective August 2010 – September 2010
 
Sipuleucel-T therapy meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of asymptomatic or minimally symptomatic, metastatic, androgen-independent (hormone-refractory) prostate cancer.
 
Sipuleucel-T therapy does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in all other situations,  including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases.
 
For contracts without primary coverage criteria, Sipuleucel-T therapy is considered investigational in all other situations, including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
The tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  There is no information available regarding the risks or benefits of giving the two drugs together or in tandem.
 
For contracts without primary coverage criteria, the tandem (or concomitant) administration of Sipuleucel-T (Provenge) and cabazitaxel is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective May 2010 – July 2010
 
Sipuleucel-T therapy meets member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the  treatment of asymptomatic or minimally symptomatic, metastatic, androgen-independent (hormone-refractory) prostate cancer.
  
Sipuleucel-T therapy does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes  in all other situations,  including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases.
  
For contracts without primary coverage criteria, Sipuleucel-T therapy is considered investigational in all other situations, including but not limited to treatment of hormone-responsive prostate cancer, treatment of those with moderate to severe symptomatic metastatic prostate cancer, and those with visceral (liver, lung or brain) metastases. Investigational services are contract exclusions in most member benefit certificates of coverage.
 
  
Rationale:
Sipuleucel-T has been studied most definitively in a series of double-blind, placebo-controlled studies. Results of 2 of these studies have been published by Small and co-workers (Small, 2006) and Higano et al. (Higano, 2009), and extensively presented in a briefing document available from the U.S. Food and Drug Administration (FDA).  The third and largest trial is not published, but results were presented at the American Urological Association meeting in April 2009 and summarized in an FDA press release in April 2010.  Patients enrolled in these trials all had androgen-independent metastatic prostate cancer, were asymptomatic or mildly symptomatic, in good physical health characterized by ECOG performance status 0 or 1, and had tumors with positive staining for prostatic acid phosphatase.
 
In the two early identically designed studies (9901A and 9902A), patients with asymptomatic metastatic prostate cancer were randomized to receive either sipuleucel-T or a control infusion of untreated dendritic cells (Small, 2006) (Higano, 2009). The principal outcome of these studies was time to disease progression, defined as the time from randomization to the first observation of disease progression. Disease progression could be defined as radiologic progression (based on several imaging criteria), clinical progression (based on prostate cancer-related clinical events such as pathologic fracture), or pain progression (based on onset of pain corresponding to anatomic location of disease).
 
The studies were not designed to establish efficacy based on overall survival. Upon progression of cancer, patients were allowed to have additional treatment as needed including chemotherapy. Patients originally assigned to placebo were allowed to “cross over” by receiving their own dendritic cells pulsed with PA2024, but prepared from frozen dendritic cells harvested from their initial leukapheresis procedures.
 
Results of study 9901A for the principal outcome of time-to-progression did not show a significant difference between vaccine and control. Median time to progression was 11.7 weeks for the vaccine group and 10.0 weeks for the control group.
 
A survival analysis of study 9901A was presented in the FDA briefing document, with the caveats that the study was not powered to show a survival effect, and that a primary method of survival analysis was not prespecified in the protocol. The median survival times for vaccine-treated patients was 25.9 months and for placebo-treated patients was 21.4 months, which was statistically significant. At 36 months, the survival rate was 34% for vaccine-treated patients and 11% for placebo-treated patients.
 
The FDA briefing document shows analyses of possible confounders regarding the survival analysis. After disease progression, patients in both groups received chemotherapy, but the rate of chemotherapy was slightly higher in the placebo-treated groups (48% versus 36%). Examination of the causes of death did not reveal any obvious spurious elevation of non-cancer causes of death in the placebo group. The published version of study 9901A (Small, 2006) analyzed the survival data after adjusting for prognostic factors and found a significant association of sipuleucel-T treatment and survival.
 
Because study 9901A did not meet its principal outcome endpoint for efficacy, enrollment for its partner study 9902A was suspended. Its sample size was therefore smaller and the study subsequently had lower statistical power. Results for study 9902A showed a median time-to-progression of 10.9 weeks in the vaccine group versus 9.9 weeks in the placebo group, which was not statistically significant. A survival analysis of study 9902A showed that vaccine-treated patients had a median survival of 19 months and control patients had a median survival of 15.7 months, which was also not statistically significant.
 
The two studies’ survival data was pooled in the study by Higano et al (Higano, 2006).  The pooled analysis showed a 33% reduction in the risk of death. The association was robust to adjustments in imbalances in baseline prognostic factors and post-progression chemotherapy use.
 
Because these earlier studies did not meet criteria for success for their principal endpoints, the FDA did not approve sipuleucel-T in 2007. A larger Phase III trial of similar design called IMPACT enrolling 512 patients was designed with a principal endpoint of overall survival (Kantoff, 2010). Analyses reported at the American Urological Association in April 2009 and used to support FDA approval reported a 22% reduction in overall mortality in the patients treated with sipuleucel-T. Treatment extended median survival by 4.1 months compared to placebo (25.8 months versus 21.7 months) and improved 3-year survival by a relative 38% compared to placebo (31.7% versus 23.0%). Results adjusted for subsequent docetaxel use and timing, as well as analyses examining prostate cancer-specific survival showed similar magnitude and statistical significance of the survival benefit. Of note, 14% of enrolled subjects in this trial had received prior docetaxel treatment.
 
Regarding the safety of sipuleucel-T, most adverse effects were grade 1 and 2 and resolved within 48 hours. The rate of serious adverse events was not statistically different between vaccine- and placebo-treated patients. However, one difficulty in assessing the potential adverse effects by comparing sipuleucel-T to placebo is that the placebo consisted of infusion of untreated dendritic cells, which may cause some adverse effects. There was concern expressed in the FDA review regarding a possible association with cerebrovascular events, as 8/147 vaccine-treated patients experienced cerebrovascular-related adverse events, compared to zero placebo-treated patients in the 2 early trials.  In the latest available report of adverse effects reported in the full prescribing information documents (Dendreon Corporation), the stroke rate was 3.5% in the sipuleucel-T group and 2.6% in the control group, but these figures appear to include data from trials evaluating a different indication. In the FDA review summarizing cerebrovascular event rates from studies 9901A, 9902A, and interim data from IMPACT, the rate was 4.9% in the sipuleucel-T-treated subjects, and 1.7% in placebo-treated subjects. The FDA review called the cerebrovascular event rate a “potential safety signal” and included as part of the approval, a post marketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 patients with prostate cancer who receive sipuleucel-T.
 
Summary
The results of 3 randomized, controlled trials of sipuleucel-T given in the setting of asymptomatic or mildly symptomatic androgen-independent metastatic prostate cancer show an improvement in median survival of 4 months. The 2 early studies of sipuleucel-T were not specifically designed to demonstrate a difference in overall mortality, but showed survival effects consistent with the third study which was designed to demonstrate a mortality difference. All 3 studies are also consistent in demonstrating that sipuleucel-T treatment does not delay time to measurable progression of disease. In all studies, many patients had further chemotherapy treatment at the discretion of their physician; thus, the survival benefit accrues in the context of additional treatment as needed for symptomatic recurrence.
 
Other Indications
A phase III trial of sipuleucel-T in the setting of androgen-dependent, nonmetastatic prostate cancer has completed enrollment (Provenge for the Treatment of Hormone Sensitive Prostate Cancer [PROTECT], NCT00779402) and has released some preliminary findings. No published studies are yet available from this study. According to news reports, preliminary findings include an increase in prostate-specific antigen doubling time in sipuleucel-T-treated subjects compared to placebo-treated subjects, and a statistically nonsignificant delay in detecting metastasis. According to the ClinicalTrials.gov website, this study is no longer recruiting participants.
 
2012 Update
A search of the MEDLINE database through September 2012 did not reveal any new randomized controlled trials or other information that would prompt a change in the coverage statement.
 
Sipuleucel-T is being studied for the treatment of indications other than prostate cancer. A Phase III trial of sipuleucel-T in the setting of androgen-dependent, nonmetastatic prostate cancer was published in 2011  (Beer, 2011). Patients with prostate cancer detectable by PSA following radical prostatectomy received 3 to 4 months of androgen suppression therapy and were then randomized (2:1) to receive sipuleucel-T (n=117) or control (n=59). The primary endpoint was time to biochemical failure. There was no difference in this endpoint between groups; median time to biochemical failure was 18.0 months for sipuleucel-T and 15.4 months for control (HR: 0.936, p=0.737). Sipuleucel-T patients had a 48% increase in PSA doubling time following testosterone recovery (155 vs. 105 days, p=0.038). Sixteen percent of patients developed distant failure. The treatment effect favored sipuleucel-T but was not statistically significant (HR: 0.728, p=0.421).
 
Ongoing trials
Other indications are currently being investigated in clinical trials in progress or recruiting patients. A trial to determine whether sipuleucel-T and androgen deprivation therapy augment each other in patients with recurrent but non-metastatic prostate cancer is currently in progress. Concurrent versus sequential sipuleucel-T plus a newly approved drug abiraterone is also being investigated. Finally, sipuleucel-T as neoadjuvant therapy for patients with localized prostate cancer undergoing prostatectomy is being investigated.
 
2013 Update
A search of the MEDLINE database through August 2013 did not reveal any new published results of randomized controlled trials that would prompt a change in the coverage statement.
 
2014 Update
 
A literature search conducted through June 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Sipuleucel-T has been studied most definitively in a series of double-blind, placebo-controlled randomized controlled trials (RCTs) (Dendreon, 2014).  These studies were published by Small et al (2006),( Small, 2006), Higano et al (2009),(Higano, 2009), and Kantoff et al (2010),(Kantoff, 2010) and were extensively presented in a briefing document available from the U.S. Food and Drug Administration (FDA).  Patients enrolled in these trials all had androgen independent metastatic prostate cancer, were asymptomatic or mildly symptomatic, in good physical health characterized by Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, and had tumors with positive staining for prostatic acid phosphatase (PAP).
 
In retrospective, prespecified, multivariate subgroup analysis, several baseline factors were associated with overall survival: PSA, lactate dehydrogenase, hemoglobin, ECOG performance status, alkaline phosphatase, and Gleason score (Schellhammer, 2013). Analysis of PSA by quartiles showed that men in the lowest quartile had the greatest survival benefit with sipuleucel-T: 49% reduced mortality compared with 26% reduced mortality in the second quartile, 19% in the third quartile, and 16% in the highest quartile.
 
In men with metastatic, hormone-resistant prostate cancer, concurrent versus sequential sipuleucel-T plus abiraterone is under study (NCT01487863), as is sipuleucel-T in combination with enzalutamide (NCT01981122), radiotherapy (NCT01807065, NCT01818986, and NCT01833208), the chemotherapeutic agents indoximod (NCT01560923) and cyclophosphamide (NCT01420965), the investigational agent tasquinimod (NCT02159950), and recombinant interleukin-7 (NCT01881867).
 
For patients who do not meet the above criteria, evidence does not demonstrate an improvement in health outcomes. One RCT of patients with androgen-dependent, nonmetastatic prostate cancer showed no statistical difference between sipuleucel-T and control in time to biochemical failure or PSA doubling time. This evidence does not support the use of sipuleucel-T for these patients, and therefore sipuleucil-T is considered investigational for all other indications, including but not limited to hormone-responsive prostate cancer, treatment of moderate to severe symptomatic metastatic prostate cancer, and treatment of visceral (liver, lung, or brain) metastases.
 
Current NCCN Guidelines for prostate cancer (version 2.2014) sipuleucel-T as a category 1 treatment for patients with metastatic castration-recurrent prostate cancer.(10) A note states that sipuleucel-T is appropriate for asymptomatic or minimally symptomatic patients with ECOG performance status 0-1; and it is not recommended for indicated in patients with liver metastasis, or life expectancy less than 6 months. Sipuleucel-T also is recommended for second-line treatment of symptomatic patients with metastatic castration recurrent prostate cancer who fail chemotherapy and otherwise meet criteria for treatment with sipuleucel-T (category 2A recommendation). This recommendation was based on further analysis of the previously reviewed clinical trials, which showed similar benefit in both those who had and had not received prior chemotherapy (Mohler, 2012).
 
European Consensus Panel
On September 7, 2013, 21 experts in the field of prostate cancer met in France to “evaluate current opinion regarding the most appropriate sequencing of available therapies for metastatic castration resistant prostate cancer,” among other objectives (Fitzpatrick, 2014). The panel used a modified Delphi method to obtain consensus, based on the biannual St. Gallen Early Breast Cancer Consensus Conference. The panel agreed (≥70% consensus) that sipuleucel-T is a reasonable option for patients with asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer and should be considered before docetaxel, abiraterone, and enzalutamide. The panel considered sipuleucel-T a new treatment option “during the time period between development of hormone-refractory disease and becoming a candidate for chemotherapy.”
 
2016 Update
A literature search was conducted using the MEDLINE database through December 2015. There was no new literature identified that would prompt a change in the coverage statement. Two new publications were identified and summarized below.
 
In 2014, Small et al pooled data for time to disease-related pain and time to first use of opioid analgesics from all 3 RCTs discussed above (Small, 2014). Median time to disease-related pain was 5.6 months for sipuleucel-T versus 5.3 months for control (HR=0.82; 95% CI, 0.62 to 1.09). Median time to first use of opioid analgesics was 12.6 months for sipuleucel-T versus 9.7 months for control (HR=0.76; 95% CI, 0.58 to 0.99).
 
American Society of Clinical Oncology-Cancer Care Ontario
In 2014, the American Society of Clinical Oncology and Cancer Care Ontario issued a joint, evidence-based clinical practice guideline on systemic therapy in men with metastatic castration-resistant prostate cancer (Basch, 2014). The guideline includes a weak recommendation that “sipuleucel-T may be offered to men who are asymptomatic or minimally symptomatic (benefit: moderate; harm: low; evidence strength: moderate).”  
 
2018 Update
A literature search conducted using the MEDLINE database did not identify any new literature that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
In 2016, Yi et al reported on a meta-analysis that identified 3 randomized controlled trials (RCTs) on sipuleucel-T for treating castration-resistant prostate cancer (Yi, 2016). A pooled analysis of the 3 RCTs found significantly improved overall survival (OS) with sipuleucel-T compared with placebo (hazard ratio [HR], 0.73, 95% confidence interval [CI], 0.61 to 0.88; I2=0%). There was no significant difference between sipuleucel-T and placebo in time to progression of prostate cancer (HR=0.88; 95% CI, 0.74 to 1.06; I2=4%). Rates of individual adverse events were pooled, and there were no significant differences between sipuleucel-T and placebo in any of the adverse events, which consisted of fatigue, back pain, headache, arthralgia, and constipation. Stroke rates were not reported.
 
In 2016, the European Association of Urology, the European Society for Radiotherapy & Oncology, and the International Society of Geriatric Oncology published joint guidelines on the treatment of relapsing, metastatic, castration-resistant prostate cancer (Cornford, 2017). The guidelines stated that the choice of first-line treatment should be based on factors including performance status, symptoms, comorbidities, and the extent of disease, and that recommended treatment options are in “(alphabetic order: abiraterone, cabazitaxel docetaxel, enzalutamide, Ra 223 and sipuleucel-T).”
 
2019 Update
A literature search conducted through December 2018 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2020. No new literature was identified that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
36511Therapeutic apheresis; for white blood cells
96365Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
J3590Unclassified biologics
Q2043Sipuleucel t, minimum of 50 million autologous cd54+ cells activated with pap gm csf, including leukapheresis and all other preparatory procedures, per infusion
References: Basch E, Loblaw DA, Oliver TK, et al.(2014) Systemic therapy in men with metastatic castration-resistant prostate cancer:American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol. Oct 20 2014;32(30):3436-3448. PMID 25199761

Tannock IF, de Wit R, Berry WR et al.(2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351(15):1502-12.

Beer TM, Bernstein GT, Corman JM et al.(2011) Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer. Clin Cancer Res 2011; 17(13):4558-567.

Berry DL, Moinpour CM, Jiang CS et al.(2006) Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol 2006; 24(18):2828-35.

Cookson MS, Roth BJ, Dahm P, et al(2013) Castration-resistant prostate cancer: AUA Guideline J Urol. Aug 2013; 190(2): 429-38. PMID 23665272

Cookson MS, Roth BJ, Dahm P, et al.(2013) Castration-resistant prostate cancer: AUA Guideline. J Urol. Aug 2013;190(2):429-438. PMID 23665272

Cornford P, Bellmunt J, Bolla M, Briers E et al(2017) EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer Eur Urol. 2017 Apr;71(4):630-642. PMID: 27591931.

Cornford P, Bellmunt J, Bolla M, et al.(2017) EAU-ESTRO-SIOG guidelines on prostate cancer. part ii: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. Apr 2017;71(4):630-642. PMID 27591931

Dendreon Corporation.(2010) Provenge® (sipuleucel-T) prescribing information. Seattle, WA; April 2010. Available online at http://www.provenge.com/pdf/prescribing-information.pdf. Last accessed May 2010.

Dendreon Corporation.(2014) Provenge® (sipuleucel-T) suspension for intravenous infusion prescribing information, June 2011. Available online at: http://www.provenge.com/. Last accessed June 2014.

Fitzpatrick JM, Bellmunt J, Fizazi K et al.(2014) Optimal management of metastatic castration-resistant prostate cancer: Highlights from a European Expert Consensus Panel. Eur J Cancer 2014; 50(9):1617-27.

Higano CS, Schellhammer PF, Small EJ et al.(2009) Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115(16):3670-9.

Higano CS, Schellhammer PF, Small EJ et al.(2009) Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115(16):3670-9.

Hu R, George DJ, Zhang T(2016) What is the role of sipuleucel-T in the treatment of patients with advanced prostate cancer? An update on the evidence Ther Adv Urol. 2016;8(4):272-278.

Kantoff PW, Higano CS, Shore ND et al.(2010) Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med 2010; 363(5):411-22.

Mohler JL, Armstrong AJ, Bahnson RR et al.(2012) Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw 2012; 10(9):1081-7.

National Cancer Institute (NCI). Surveillance, Epidemiology, and End Results Program (SEER). SEER Stat Fact Sheets: Prostate Cancer. http://seer.cancer.gov/statfacts/html/prost.html. Accessed June 29, 2015.

National Comprehensive Cancer Network (NCCN)(2020) NCCN Clinical Practice Guidelines in Oncology: prostate cancer.Version 2.2021. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf.

NCCN Drugs & Biologics Compendium® for Sipuleucel-T (e.g., Provenge), National Comprehensive Cancer Network, Inc. 2023. All rights reserved. Accessed [December 27, 2023]. To view the most recent and complete version of the Compendium, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Schellhammer PF, Chodak G, Whitmore JB et al.(2013) Lower Baseline Prostate-specific Antigen Is Associated With a Greater Overall Survival Benefit From Sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) Trial. Urology 2013; 81(6):1297-302.

Small EJ, Higano CS, Kantoff PW, et al.(2014) Time to disease-related pain and first opioid use in patients with metastatic castration-resistant prostate cancer treated with sipuleucel-T. Prostate Cancer Prostatic Dis. Sep 2014;17(3):259-264. PMID 24957547

Small EJ, Schellhammer PF, Higano CS et al.(2006) 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(19):3089-94.

Small EJ, Schellhammer PF, Higano CS et al.(2006) 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(19):3089-94.

U.S. Food and Drug Administration. Cellular, Tissue and Gene Therapies Advisory Committee Meeting, March 29, 2007. Clinical Briefing Document: Provenge (Sipuleucel T). Available online at http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_2a.pdf. Last accessed May 2010.

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US Food & Drug Administration (FDA)(2017) PROVENGE® (sipuleucel-T). FDA Label. 07/2017 Initial approval 2010. Available from: https://www.accessdata.fda.gov/drugsatfda

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