Description:
Sipuleucel-T (Provenge^®; Dendreon Corp.) is a new class of therapeutic agent used in the treatment of asymptomatic or minimally symptomatic, androgen-independent (castration-resistant), metastatic prostate cancer. The agent comprises specially treated dendritic cells obtained from the patient through leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic-stimulating factors and are then reinfused back into the patient. The proposed mechanism of action is that treatment stimulates the patient’s own immune system to resist cancer spread. 

For patients with metastatic, androgen-independent prostate cancer, 3 randomized controlled trials (RCTs) of sipuleucel-T reported an improvement in median survival of approximately 4 months. The 2 early studies of sipuleucel-T were not specifically designed to demonstrate a difference in overall mortality but did show a survival difference. The third study, which was designed to demonstrate a mortality difference, showed a similar improvement in overall survival. All 3 studies also were consistent in demonstrating that sipuleucel-T does not delay time to measurable progression of disease. In all studies, many patients had further chemotherapy treatment at the discretion of the treating physician; thus, the survival benefit accrues in the context of additional treatment as needed for symptomatic recurrence. This evidence is sufficient to conclude that sipuleucel-T improves net health outcome for patients with androgen-independent, asymptomatic or minimally symptomatic, metastatic prostate cancer.

For patients who do not meet the previously described criteria, evidence does not demonstrate an improvement in net health outcome. 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 prostate-specific antigen (PSA) doubling time. This evidence does not support the use of sipuleucel-T for patients with hormone-responsive prostate cancer, moderate-to-severe symptomatic metastatic prostate cancer, or visceral (liver, lung, brain) metastases..

Background
Prostate Cancer
Prostate cancer is the second leading cause of cancer-related deaths among American men, with an estimated incidence of 164,690 cases and an estimated number of 29,430 deaths in 2018.¹ In most cases, prostate cancer is diagnosed at a localized stage and is treated with prostatectomy or radiotherapy. However, some patients are diagnosed with metastatic or recurrent disease after treatment of localized disease.

Treatment
Androgen ablation is the standard treatment for metastatic or recurrent disease. Most patients who survive long enough eventually develop androgen-independent (castration-resistant) prostate cancer. At this stage of metastatic disease, docetaxel, a chemotherapeutic agent, has demonstrated a survival benefit of 1.9 to 2.4 months in randomized clinical trials.^2,3 Chemotherapy with docetaxel causes adverse events in large proportions of patients, including alopecia, fatigue, neutropenia, neuropathy, and other symptoms. Trials evaluating docetaxel included both asymptomatic and symptomatic patients, and results have suggested a survival benefit for both groups. Because of the burden of treatment and its adverse events, most patients defer docetaxel treatment until cancer recurrence is symptomatic.

Cancer immunotherapy has been investigated as a treatment that could 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 patient during this time is thought to be relatively low, and it is thought that an effective immune response to the cancer during this interval could effectively delay or prevent progression. Such a delay could allow a course of effective chemotherapy, such as docetaxel, to be deferred or delayed until necessary, thus providing an overall survival benefit.

Regulatory Status
In 2010, the U.S. Food and Drug Administration approved Provenge^® (sipuleucel-T; Dendreon Corp, now Sanpower) under a biologics licensing application for “the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.”⁴ Approval was contingent on the manufacturer conducting a postmarketing study, based on a registry design, to assess the risk of cerebrovascular events in 1,500 men with prostate cancer who receive sipuleucel-T.

Policy:
Sipuleucel-T therapy may be considered MEDICALLY NECESSARY in the treatment of asymptomatic or minimally symptomatic, no liver metastases, life expectancy >6 mo, and ECOG performance status 0 – 1. 

Sipuleucel-T therapy is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY: 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, treatment of small cell/NEPC and those with visceral (liver, lung or brain) metastases.  

Policy Guidelines
Coding
Please see the Codes table for details.

Benefit Application
BlueCard^®/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Metastatic, Castration-Resistant Prostate Cancer
Clinical Context and Therapy Purpose
The purpose of cellular immunotherapy with sipuleucel-T (Provenge) in patients who have metastatic castration-resistant prostate cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does cellular immunotherapy improve the net health outcome in men with asymptomatic or minimally symptomatic metastatic, castration-resistant prostate cancer?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who have asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer.

Interventions
The therapy being considered is cellular immunotherapy, specifically, sipuleucel-T (Provenge) is a newer class of therapeutic agent used to treat asymptomatic or minimally symptomatic, androgen-independent (castration-resistant), metastatic prostate cancer. The agent comprises specially treated dendritic cells obtained from the patient through leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic-stimulating factors and reinfused into the patient. The cells are administered as 3 intravenous infusions given approximately 2 weeks apart. The proposed mechanism of action is that the treatment stimulates the patient's own immune system to resist cancer spread.

Comparators
The following therapy is currently being used to make decisions about asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer: standard treatment includes docetaxel, a chemotherapeutic agent. Chemotherapy with docetaxel causes adverse events in large proportions of patients, including alopecia, fatigue, neutropenia, neuropathy, and other symptoms.

Outcomes
The general outcomes of interest are the time to progression, mortality, and toxicity from treatment. Median survival for metastatic castration-resistant prostate cancer is less than 2 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
Yi et al. (2016) reported on a meta-analysis that identified 3 RCTs on sipuleucel-T for treating castration-resistant prostate cancer (see details below).⁵ 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.

Randomized Controlled Trials
Sipuleucel-T has been studied in 3 double-blind, placebo-controlled randomized trials.⁶ These trials were published by Small et al. (2006),⁷ Higano et al. (2009),⁸ and Kantoff et al. (2010),⁹ and were reviewed by the U.S. Food and Drug Administration (FDA).¹⁰ Patients enrolled in these trials all had castration-resistant metastatic prostate cancer, were asymptomatic or mildly symptomatic, in good physical health characterized by the Eastern Cooperative Oncology Group Performance Status at 0 or 1, and had tumors with positive staining for prostatic acid phosphatase.

Table 1 describes the 2 early identically designed studies.^6,7,8,10 Patients with asymptomatic metastatic prostate cancer were randomized to sipuleucel-T or to a control infusion of untreated dendritic cells. The principal outcome 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, e.g., pathologic fracture), or pain progression (based on onset of pain corresponding to the anatomic location of the disease).

Studies were not designed to establish efficacy based on OS. On the progression of cancer, patients were allowed 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 antigen (recombinant fusion protein comprising human prostatic acid phosphatase linked to granulocyte-macrophage-colony-stimulating factor) but prepared from frozen dendritic cells harvested from their initial leukapheresis procedures.

Table 1. Characteristics of Randomized Phase 3 Trials of Sipuleucel-T

Study	Design	Eligibility	Treatment	Outcomes
9901A,7 9902A8	Randomized double-blind, placebo-controlled	Metastatic prostate cancer by imaging, asymptomatic and progressing by imaging or rising PSA	Exp: 3 infusions of vaccine Ctl: 3 infusions of placebo dendritic cells	Primary: disease progression (radiologic, clinical, pain) Secondary: time to pain, time to progression
IMPACT9	Randomized double-blind, placebo-controlled	Metastatic prostate cancer by imaging, asymptomatic or minimally symptomatic and progressing by imaging or rising PSA	Exp: 3 infusions of vaccine Ctl: 3 infusions of placebo dendritic cells	Primary: overall survival Secondary: time to objective disease progression

Ctl: control arm; Exp: experimental arm; PSA: prostate-specific antigen; IMPACT: A Randomized, Double Blind, Placebo Controlled Phase 3 Trial of Immunotherapy With Autologous Antigen Presenting Cells Loading With PA2024 (Provenge[R], APC8015) in Men With Metastatic Androgen Independent Prostatic Adenocarcinoma
As shown in Table 2, results of study 9901A for the principal outcome of time to progression did not show a significant difference between the vaccine and infusion control. Median time to progression was 11.7 weeks for the vaccine group and 10.0 weeks for the control group.

Table 2. Results of the Randomized, Phase 3 Trials of Sipuleucel-T

Study	Vaccine Group	Control Group	p
Study 9901A7
n	82	45
Median time to progression, wk	11.7	10.0	.052
Median time to clinical progression, wk	10.7	9.1	.061
Median overall survival, mo	25.9	21.4	.01
Overall survival at 36 mo, %	34	11	.005 (multivariable adjusted, 0.002)
Study 9902A8
n	65	33
Median time to progression, wk	10.9	9.9	.719
Median overall survival, mo	19.0	15.7	.331
IMPACT study9
n	341	171
Overall median survival, mo	25.8	21.7	.032
Overall survival at 36 mo, %	31.7	23.0	.036
Time to progression	Not reported	Not reported	HR = 0.95, p = .628

HR: hazard ratio; IMPACT: A Randomized, Double Blind, Placebo Controlled Phase 3 Trial of Immunotherapy With Autologous Antigen Presenting Cells Loading With PA2024 (Provenge(R), APC8015) in Men With Metastatic Androgen Independent Prostatic Adenocarcinoma

A survival analysis of study 9901A was presented in the FDA briefing document, with 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. Median survival times were 25.9 months for vaccine-treated patients and 21.4 months for placebo-treated patients, a statistically significant difference (p = 0.011). At 36 months, the survival rate was 34% for vaccine-treated patients and 11% for placebo-treated patients.

The FDA briefing document also analyzed possible confounders in the survival analysis.10, After disease progression, patients in both groups received chemotherapy; however, the rate of chemotherapy was slightly higher in the placebo group (48% vs 36%, respectively). Examination of the causes of death did not reveal any obvious spurious elevation of noncancer deaths in the placebo group. The published version of study 9901A by Small et al. (2006) analyzed the survival data after adjusting for prognostic factors and found a significant association between sipuleucel-T treatment and survival (HR = 2.12; 95% CI, 1.31 to 3.44).⁷

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. As shown in Table 2, results for study 9902A showed a median time to progression of 10.9 weeks in the vaccine group vs 9.9 weeks in the placebo group, which was not statistically significant. A survival analysis of study 9902A showed that median survival was 19 months in vaccine-treated patients and 15.7 months in control, which also was not statistically significant.

Higano et al. (2009) pooled survival data from the 2 studies.⁸ Pooled analysis showed a 33% reduction in the risk of death (HR = 1.50; 95% CI, 1.10 to 2.05; p = 0.011). The association was robust to adjustments in imbalances in baseline prognostic factors and postprogression 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 3 trial of similar design, Immunotherapy for Prostate Adenocarcinoma Treatment, enrolling 512 patients, was designed with a principal endpoint of OS.⁹ Analyses used to support the FDA approval reported a 22% reduction in overall mortality in patients treated with sipuleucel-T. Treatment extended median survival by 4.1 months compared with placebo (25.8 months vs 21.7 months, respectively) and improved relative 3-year survival by a 38% compared with placebo (31.7% vs 23.0%, respectively). Results adjusted for subsequent docetaxel use and timing, as well as analyses examining prostate cancer-specific survival, showed a similar magnitude and statistical significance of the survival benefit. Of note, 14% of enrolled subjects in this trial had received prior docetaxel. In a retrospective, prespecified, multivariate subgroup analysis by Schellhammer et al. (2013), several baseline factors were associated with OS: prostate-specific antigen (PSA) levels, lactate dehydrogenase levels, hemoglobin levels, the Eastern Cooperative Oncology Group Performance Status scores, alkaline phosphatase levels, and Gleason scores.¹¹ Analysis of PSA levels by quartiles showed that men in the lowest quartile had the greatest survival benefit with sipuleucel-T: 49% reduced mortality rate, compared with 26% reduced mortality rate in the second quartile, 19% in the third quartile, and 16% in the highest quartile.

Small et al. (2014) pooled data for time to disease-related pain and time to the first use of opioid analgesics from all 3 RCTs.¹² Median time to disease-related pain was 5.6 months for sipuleucel-T and 5.3 months for control (HR = 0.82; 95% CI, 0.62 to 1.09). Median time to the first use of opioid analgesics was 12.6 months for sipuleucel-T and 9.7 months for control (HR = 0.76; 95% CI, 0.58 to 0.99).

Regarding the safety of sipuleucel-T, most adverse events were grade 1 and 2 and resolved within 48 hours. The rate of serious adverse events did not differ statistically between vaccine- and placebo-treated patients. However, a difficulty in assessing potential adverse events by comparing sipuleucel-T with placebo is that placebo comprised infusion of untreated dendritic cells, which may cause adverse events. The FDA reviewers expressed concern about a possible association of sipuleucel-T with cerebrovascular events; 8 (5%) of 147 vaccine-treated patients experienced cerebrovascular-related adverse events, compared with zero placebo-treated patients in the 2 early trials.10, In the FDA review summarizing cerebrovascular event rates from studies 9901A, 9902A, and interim Immunotherapy for Prostrate Adenocarcinoma Treatment data, the incidence of stroke was 4.9% (17/345) in sipuleucel-T-treated patients and 1.7% (3/172) in placebo-treated patients (p = 0.092). The FDA review called the cerebrovascular event rate a "potential safety signal" and included as part of its approval a postmarketing study, based on a registry design, to assess the risk of cerebrovascular events in 1500 patients with prostate cancer who receive sipuleucel-T.

Section Summary: Metastatic, Castration-Resistant Prostate Cancer
For patients with metastatic, castration-resistant prostate cancer, 3 RCTs of sipuleucel-T have been published. The 3 RCTs are consistent in reporting an improvement in OS of approximately four months compared with placebo. Additionally, 2 trials also reported that 36-month survival was significantly improved for patients receiving sipuleucel-T, with absolute improvements in survival of 9% and 23%. Time to progression was slightly longer in the sipuleucel-T groups but this difference was not statistically significant. A meta-analysis of the 3 RCTs found significantly improved OS, but not the time to progression, with sipuleucel-T compared with placebo. Serious adverse events were not increased in the sipuleucel-T groups. However, given data reported to the FDA, there was a concern about a possible increase in stroke risk and this is being studied in an ongoing postmarketing study.

Nonmetastatic, Androgen-dependent Prostate Cancer
Clinical Context and Therapy Purpose
The purpose of cellular immunotherapy with sipuleucel-T (Provenge) in patients who have nonmetastatic, androgen-dependent prostate cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does cellular immunotherapy improve the net health outcome in men with nonmetastatic, androgen-dependent prostate cancer?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who have nonmetastatic, androgen-dependent prostate cancer.

Interventions
The therapy being considered is cellular immunotherapy, specifically sipuleucel-T (Provenge), is a newer class of therapeutic agent used to treat asymptomatic or minimally symptomatic, androgen-independent (castration-resistant), metastatic prostate cancer. The agent comprises specially treated dendritic cells obtained from the patient through leukapheresis. The cells are then exposed in vitro to proteins that contain prostate antigens and immunologic-stimulating factors and reinfused into the patient. The cells are administered as 3 intravenous infusions given approximately 2 weeks apart. The proposed mechanism of action is that the treatment stimulates the patient's own immune system to resist cancer spread.

Comparators
The following therapy is currently being used to make decisions about cellular immunotherapy: Androgen deprivation therapy is the standard treatment for metastatic or recurrent disease.

Outcomes
The general outcomes of interest are the time to progression, mortality, and toxicity from treatment. The time frame for outcome measures varies from short-term management of toxicity and symptoms of cancer progression or recurrence and OS.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Randomized Controlled Trials
Beer et al. (2011) published an RCT evaluating sipuleucel-T in the setting of nonmetastatic, androgen-dependent prostate cancer.¹³ Patients with prostate cancer detectable by PSA levels after radical prostatectomy received 3 to 4 months of androgen suppression therapy and were then randomized (2:1) to sipuleucel-T (n = 117) or to control (n = 59). The primary endpoint was time to biochemical failure. The median time to biochemical failure was 18.0 months for sipuleucel-T and 15.4 months for control. The difference between groups was not statistically significant (HR = 0.936, p = 0.737). The PSA doubling time after testosterone recovery was 155 days in the sipuleucel-T group and 105 days in the placebo group (p = 0.038). At the data cutoff point, 16% developed distant failure. The risk of distant failure did not significantly favor the sipuleucel-T group (p = 0.021); however, the authors noted that this analysis had limited power.

Section Summary: Nonmetastatic, Androgen-Dependent Prostate Cancer
Only 1 RCT has evaluated sipuleucel-T in patients with nonmetastatic, androgen-dependent prostate cancer. This trial did not show a statistically significant benefit for sipuleucel-T compared with control. Therefore, evidence on the treatment of nonmetastatic prostate cancer is not sufficiently robust to determine that health outcomes are improved.

Summary of Evidence
For individuals who have asymptomatic or minimally symptomatic, metastatic, castration-resistant prostate cancer who receive sipuleucel-T (Provenge), the evidence includes 3 randomized controlled trials (RCTs) and a systematic review of these RCTs. Relevant outcomes are overall survival (OS), disease-specific survival, change in disease status, and treatment-related morbidity. The 2 earlier RCTs of sipuleucel-T were not specifically designed to demonstrate a difference in overall mortality but did show a survival difference. The third RCT, which was designed to demonstrate a mortality difference, showed a similar improvement in OS. All 3 studies were consistent in demonstrating that sipuleucel-T does not delay time to a measurable progression of the disease. A meta-analysis of the 3 RCTs found significantly improved OS but not the time to progression, with sipuleucel-T compared with placebo. Serious adverse events did not increase in the sipuleucel-T group. However, the available data suggested, but did not confirm, an increase in stroke risk; this risk is being evaluated in a postmarketing study. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have nonmetastatic, androgen-dependent prostate cancer who receive sipuleucel-T (Provenge), the evidence includes an RCT. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The RCT did not find a statistically significant difference between sipuleucel-T and control in time to biochemical failure. The RCT was not designed to evaluate the impact of sipuleucel-T on mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Urological Association
The American Urological Association (2018) amended their 2013 guidelines on castration-resistant prostate cancer.¹⁴ Table 3 provides the guideline statements on sipuleucel-T.

Table 3. Guidelines on Treatment of Castration-Resistant Prostate Cancer

Guideline	SOE	LOE
"Clinicians should offer abiraterone plus prednisone, enzalutamide, docetaxel, or sipuleucel-T to patients with asymptomatic or minimally symptomatic mCRPC with good performance status and no prior docetaxel chemotherapy."	Standard	A (abiraterone plus prednisone and enzalutamide) B (docetaxel and sipuleucel-T)
"Clinicians should not offer treatment with either estramustine or sipuleucel-T to patients with symptomatic, mCRPC with good performance status and no prior docetaxel chemotherapy."	Recommendation	C
"Clinicians should not offer sipuleucel-T to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy."	Recommendation	C

LOE: level of evidence; mCRPC: metastatic castration-resistant prostate cancer; SOE: strength of evidence.

National Comprehensive Cancer Network
Current National Comprehensive Cancer Network (v.2.2021 ) guidelines for prostate cancer recommend sipuleucel-T as a category 1 treatment only for patients with metastatic castration-recurrent prostate cancer, asymptomatic or minimally symptomatic; Eastern Cooperative Oncology Group Performance Status 0 or 1; no liver metastasis; and life expectancy greater than 6 months.¹⁵

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this policy are listed in Table 4.

Table 4. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT01807065	Randomized Phase II Trial of Sipuleucel T Immunotherapy Preceded by Sensitizing Radiation Therapy and Sipuleucel-T Alone in Patients With Castrate Resistant Metastatic Prostate Cancer	51	Dec. 2019 (completed, no results posted)
NCT01804465a	A Randomized Phase 2 Trial of Immediate vs. Delayed Anti-CTLA4 Blockade Following Sipuleucel-T Treatment for Prostate Cancer Immunotherapy	50	Oct. 2021
Unpublished
NCT01306890a	A Registry of Sipuleucel-T Therapy in Men With Advanced Prostate Cancer (PROCEED)	1976	Jan. 2017 (completed)

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.

References:

1. National Cancer Institute, Surveillance Epidemiology and End Results Program. Cancer Stat Fact: Prostate Cancer. n.d.; https://seer.cancer.gov/statfacts/html/prost.html. 
2. Berry DL, Moinpour CM, Jiang CS, et al. 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. Jun 20 2006; 24(18): 2828-35. PMID 16782921
3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. Oct 07 2004; 351(15): 1502-12. PMID 15470213
4. Food and Drug Administration (FDA). April 29, 2010 Approval Letter - Provenge. 2010; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/provenge-sipuleucel-t. 
5. Yi R, Chen B, Duan P, et al. Sipuleucel-T and Androgen Receptor-Directed Therapy for Castration-Resistant Prostate Cancer: A Meta-Analysis. J Immunol Res. 2016; 2016: 4543861. PMID 28058266
6. Dendreon Corporation. Provenge (sipuleucel-T) suspension for intravenous infusion prescribing information. n.d.; http://www.provenge.com/. .
7. 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. Jul 01 2006; 24(19): 3089-94. PMID 16809734
8. Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. Aug 15 2009; 115(16): 3670-9. PMID 19536890
9. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. Jul 29 2010; 363(5): 411-22. PMID 20818862
10. Food and Drug Administration (FDA). Summary Basis for Regulatory Action: Provenge (sipuleucel T). 2010; https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/provenge-sipuleucel-t. 
11. Schellhammer PF, Chodak G, Whitmore JB, et al. 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. Jun 2013; 81(6): 1297-302. PMID 23582482
12. Small EJ, Higano CS, Kantoff PW, et al. 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): 259-64. PMID 24957547
13. Beer TM, Bernstein GT, Corman JM, et al. Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer. Clin Cancer Res. Jul 01 2011; 17(13): 4558-67. PMID 21558406
14. Cookson MS, Roth BJ, Dahm P, et al. Castration-resistant prostate cancer: AUA Guideline. J Urol. Aug 2013; 190(2): 429-38. PMID 23665272
15. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: prostate cancer. Version 2.2021. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. 
16. Center for Medicare and Medicaid Services. National Coverage Determination (NCD) for Autologous Cellular Immunotherapy Treatment (110.22). 2011; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId = 344&ncdver = 1&bc = AAAAIAAAAAAA&. .

Coding Section    

Codes	Number	Description
CPT	36511	Therapeutic apheresis; for white cells
	96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
HCPCS	Q2043	Sipuleucel-T, minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF, including leukapheresis and all other preparatory procedures, per infusion
ICD-10-CM	C61	Malignant neoplasm of prostate
ICD-10-PCS		ICD-10-PCS codes are only used for inpatient services
	6A550Z1, 6A551Z1	Extracorporeal therapies, physiological systems, pheresis, circulatory, leukocytes, code by duration (single or multiple)
	30233Q0, 30243Q0	Administration, circulatory, transfusion, percutaneous, white cells, autologous, code by body part (peripheral vein or central vein)
Type of service	Surgery
Place of service	IInpatient/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2024 Forward     

06/27/2024 Annual review,  updating medical necessity criteria in policy section. 

01012024  NEW POLICY