Medical Policy: 08.01.27 

Original Effective Date: December 2017 

Reviewed: December 2017 



Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.


This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.



Provenge (Sipuleucel-T) (also referred to as a vaccine) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC).  The agent comprises specially treated dendritic cells (antigen presenting cells, also known as accessory 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 proposed mechanism of action is that treatment stimulates the patient’s own immune system to resist cancer spread.


An estimated 161,360 new cases of prostate cancer will be diagnosed in 2017, accounting for 19% of new cancer cases in men. Researchers have estimated prostate cancer to account for 26,730 deaths in 2017, which represents 8% of male cancer deaths. In most cases of prostate cancer, 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.


Androgen deprivation therapy (ADT) is the standard treatment for metastatic prostate cancer or recurrent disease. Most patients who survive long enough eventually develop androgen-independent prostate cancer (hormone refractory 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. 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 suggested a survival benefit for both groups. Due to 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 (hormone refractory prostate cancer) before significant symptomatic manifestations have occurred. The quantity of prostate 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.


Provenge (Sipuleucel-T) is a new class of therapeutic agent used to treat asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer (i.e. androgen independent). Provenge (Sipuleucel-T) consists of autologous peripheral blood mononuclear cells, including antigen presenting cells (APCs) (dendritic cells) that have been activated during a defined culture period with a recombinant human protein, PAP-CM-CSF, consisting of prostatic acid phosphatase (PAP), an antigen expressed in prostate cancer tissue, linked to granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The patient’s peripheral blood mononuclear cells are obtained via a standard leukapheresis procedure approximately 3 days prior to the infusion date.


The active components of Provenge (Sipuleucel-T) are autologous APCs (dendritic cells) and PAP-GM-CSF. During culture, the recombinant antigen can bind to and be processed by APCs into smaller protein fragments. The recombinant antigen is designed to target APCs, and may help direct the immune response to PAP. Minimal residual levels of the intact PAP-GM-CSF are detectable in the final Provenge product.


The cellular composition of Provenge (Sipuleucel-T) is dependent on the composition of cells obtained from the patient’s leukaphersis. In addition to APCs (dendritic cells), the final product contains antigen presenting cells to include T-cells, B-cells, natural killer (NK) cells and other cells. The number of cells present and the cellular composition of each Provenge (Sipuleucel-T) dose will vary. Each does contains a minimum of 50 million autologous CD54+ cells activated with PAP-CM-CSF, suspended in 250 mL of Lactated Ringers injection.


The potency of Provenge (Sipuleucel-T) is in part determined by measuring the increased expression of the CD54 molecule, also known as ICAM-1, on the surface of APCs (dendritic cells) after culture with PAP-CM-CSF. CD54 is a cell surface molecule that plays a role in the immunologic interaction between APCs and T-cells, and is considered a marker of immune cell activation.


Provenge (Sipuleucel-T) is administered in 3 intravenous infusions given approximately 2 weeks apart. Each infusion takes about 60 minutes and following each infusion the patient will be monitored for at least 30 minutes. The most common side effects include chills, fatigue, fever, back pain, nausea, joint ache and headache. The proposed mechanism of action is that the treatment stimulates the patient’s own immune system to resist cancer spread.


Randomized Controlled Trials for Metastatic Castration Resistant Prostate Cancer 

The analyses used to support the FDA approval for Provenge (Sipuleucel-T) was based on three similar randomized, double blinded, placebo controlled, multicenter phase III trials in asymptomatic or minimally symptomatic mCRPC (metastatic castrate resistant prostate cancer). In study 1 (IMPACT Trial) (Kantoff, et. al) 512 patients were randomly assigned in a 2:1 ratio to receive either Sipuleucel-T (341 patients) or placebo (171 patients) administered intravenously every 2 weeks, for a total of three infusions. The primary end point was overall survival, analyzed by means of a stratified Cox regression model adjusted for baseline levels of serum prostate-specific antigen (PSA) and lactate dehydrogenase. In the Sipuleucel-T group, there was a relative reduction of 22% in the risk of death compared with the placebo group (hazard ratio, 0.78; 95% confidence interval [CI], 0.61 to 0.98; P=0.03). This reduction represented a 4.1 month improvement in median survival (25.8 months in the Sipuleucel-T group vs. 21.7 months in the placebo group). The 36 month survival probably was 31.7% in the Sipuleucel-T group versus 23.0% in the placebo group. The treatment effect was also observed with the use of an unadjusted Cox model and a log-rank test (hazard ratio, 0.77; 95% CI, 0.61 to 0.97; P=0.02) and after adjustment for use of docetaxel after the study therapy (hazard ratio, 0.78; 95% CI, 0.62 to 0.98; P=0.03), The time to objective disease progression was similar in the two study groups. Immune response to the immunizing antigen were observed in patients who receive Sipuleucel-T. Adverse events that were more frequently reported in the Sipuleucel-T group than in the placebo group included chills, fever and headache. The authors concluded the use of Sipuleucel-T prolonged overall survival among men with metastatic castration-resistant prostate cancer. No effect on the time to disease progression was observed. In study 2, 127 patients were randomly assigned to receive Sipuleucel-T (82 patients) or placebo (45 patients). This study demonstrated a significant reduction in the risk of death (overall survival) with Sipuleucel-T (25.9 months) versus control (placebo 21.4 months). In study 3, 98 patients were randomly assigned to receive Sipuleucel-T (65 patients) and placebo (33 patients) a trend towards improved survival was observed despite early discontinuation of enrollment Sipuleucel-T 19.0 months and placebo 15.7 months.



For patients who have asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC) who receive Provenge (Sipuleucel-T), the evidence includes 3 randomized controlled trials (RCTs). The 3 RCTs are consistent in reporting an improvement in overall survival (OS) of approximately 4 months compared with placebo. All 3 studies were consistent in demonstrating that Provenge (Sipuleucel-T) does not delay time to measurable progression of disease. The most common adverse events in the Provenge (Sipuleucel-T) group at a rate ≥ 15% were chills, fatigue, fever, back pain, nausea, joint ache and headache. Serious adverse events were reported in 24% of the patients in Provenge (Sipuleucel-T) group which included acute infusion reactions and cerebrovascular events. Due to the increase risk of stroke, this risk is being evaluated in a post-marketing study. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.


Non-Metastatic Androgen-Dependent Prostate Cancer 

In 2011, Beer et. al. published a double blinded randomized controlled trial (RCT) (PROTECT – PROvenge Treatment and Early Cancer Treatment) evaluating patients with androgen-dependent prostate cancer. The trial was designed to examine time to biochemical failure (BF), the primary endpoint defined as serum PSA ≥ 3.0 ng/mL. PSA doubling time (PSADT), time to distant failure, immune response and safety were also evaluated. Patients with prostate cancer detectable by serum prostate specific antigen (PSA) following radical prostatectomy receiving 3 to 4 months of androgen suppression therapy, were randomized 2:1 to receive Sipuleucel-T (117 patients) or control (59 patients). Median time to BF 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 PSADT following testosterone recovery (155 vs 105 days, P = 0.038). With only 16% of patients having developed distant failure, the treatment effect favored Sipuleucel-T (HR = 0.728, P = 0.421). The most frequent adverse events in Sipuleucel-T patients were fatigue, chills and pyrexia. Immune response to the immunizing agent were greater in the Sipuleucel-T patients at weeks 4 and 13 (P = 0.0001, all) and were sustained prior to boosting as measured in a subset of patients a medial of 22.6 months (range 14.3-67.3 months) following randomization. The authors concluded that no significant different in time to biochemical failure (BF) could be shown. The finding of increased PSADT in the Sipuleucel-T arm is consistent with biologic activity in the ADPC. Long term follow-up will be necessary to determine if clinically important events, such as distant failure are affected by therapy. Additional studies in this patient population are needed.



Only one randomized controlled trial (RCT) has evaluated Provenge (Sipuleucel-T) in patients with non-metastatic androgen-dependent prostate cancer. This trial did not show a statistically significant benefit for Provenge (Sipuleucel-T) compared with control. Also, society guidelines at this time do not include within their recommendations use of Provenge (Sipuleucel-T) in patients with non-metastatic androgen-dependent prostate cancer. Therefore, the evidence on treatment using autologous cellular immunotherapy Provenge (Sipuleucel-T) for non-metastatic androgen-dependent prostate cancer is not sufficient to determine that health outcomes are improved. 


Practice Guideline and Position Statements 

National Comprehensive Cancer Network (NCCN) 

NCCN guideline prostate cancer version 2.2017 has the following guideline for principles of immunotherapy and chemotherapy:


Men with asymptomatic or minimally symptomatic mCRPC (metastatic castrate resistant prostate cancer) may consider immunotherapy:

  • Sipuleucel-T has been shown in phase 3 clinical trial to extend mean survival from 21.7 months in the control arm to 25.8 months in the treatment arm, which constitutes a 22% reduction in mortality risk.
  • Sipuleucel-T is well tolerated; common complications include chills, pyrexia and headache
  • Sipuleucel-T may be considered for men with mCRPC who meet the following (category 1):
    • Good performance status (ECOG 0-1)
    • Estimated life expectancy > 6 months
    • No hepatic metastases
    • No or minimal symptoms


American Urological Association (AUA) 

In 2015, the American Urological Association amended their 2013 guideline on castration resistant prostate cancer. The guideline includes the following statements on Sipuleucel-T:

  • Clinicians should not offer systemic chemotherapy or immunotherapy to patients with non-metastatic CRPC outside the context of a clinical trial. (Recommendation; Evidence Level Grade C)
  • Clinicians should offer abiraterone + prednisone, enzalutamide, docetaxel, or sipuleucel-T to patients with asymptomatic or minimally symptomatic mCRPC with good performance status and no prior docetaxel chemotherapy. (Standard; Evidence Level Grade A – abiraterone + 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; Evidence Level Grade C)
  • Clinicians should not offer sipuleucel-T to patients with symptomatic mCRPC with poor performance status and no prior docetaxel chemotherapy. (Recommendation; Evidence Level Grade C)
  • Clinicians should not offer systemic chemotherapy or immunotherapy to patients with mCRPC with poor performance status who received prior docetaxel chemotherapy. (Expert Opinion)  


American Society of Clinical Oncology (ASCO) 

In 2014, the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario issued a joint evidence-based guidelines on systemic therapy in men with metastatic castration-resistant prostate cancer. The guideline includes the following recommendations regarding sipuleucel-T:

 Therapies with demonstrated survival benefit and unclear quality-of-life benefit:

  •  Sipuleucel-T may be offered to men who are asymptomatic or minimally symptomatic (Benefit: moderate; harm: low; evidence strength: moderate; recommendation strength: weak)


Regulatory Status 

In April 2010, the U.S. Food and Drug Administration (FDA) approved Provenge (Sipuleucel-T) (Dendreon Corp) via a biologics licensing application for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Approval was contingent on the manufacturer conducting a post-marketing study based on a registry design to assess the risk of cerebrovascular events in 1500 men with prostate cancer who receive Provenge (Sipuleucel-T).


Prior Approval:


Not applicable



See also Medical Policy 08.01.26 CAR-T Cell Therapy and Adoptive Immunotherapy*


Provenge (Sipuleucel-T) autologous cellular immunotherapy may be considered medically necessary for the treatment of individuals with metastatic castrate-resistant prostate cancer (mCRPC) or hormone refractory prostate cancer (HRPC) who meet the following criteria:

  • Serum testosterone level < 50 ng/dl; and
  • PSA (prostate specific antigen) ≥ 5.0 ng/dl; and
  • Asymptomatic or minimally symptomatic (see Policy Guidelines below); and
  • Good performance status ECOG (Eastern Cooperative Oncology Group) 0-1; and
  • No visceral (liver, lung, brain) metastasis; and
  • No long bone fractures or spinal cord compression; and
  • No treatment within the previous 28 days with systemic glucocorticoids, external beam radiation therapy (EBRT) or systemic therapy for prostate cancer (except the individual may be kept on ablative hormonal treatment to maintain castrate level in accordance to National Comprehensive Cancer Network (NCCN) guidelines which is defined as serum testosterone level <50 ng/dl); and
  • No chemotherapy within the previous 3 months; and
  • Life expectancy > 6 months


Provenge (Sipuleucel-T) autologous cellular immunotherapy is considered investigational for all other indications, including when the above criteria is not met as the scientific evidence is insufficient as the safety and efficacy has not been established for any other indications.


Policy Guidelines 

  • In clinical trial with Sipuleucel-T “minimally symptomatic” was defined as not requiring opioid analgesics for cancer pain and an average weekly pain score of less than 4 on a 10-point visual analog scale.
  • In clinical trial with Sipuleucel-T patients were without signs of prognostically poor disease (i.e. without visceral metastases, long bone fractures or spinal cord progression); reasonably distant time from prior chemotherapy and had a normal immunologic function
  • ECOG (Eastern Cooperative Oncology Group) performance status criteria assess disease progression and its effect on daily living. The grading criteria are summarized below:
    • Performance Status 0: Fully active; no performance restrictions
    • Performance Status 1: Strenuous physical actively restricted; fully ambulatory and able to carry out light work
    • Performance Status 2: Capable of all self-care but unable to carry out any work activities. Up and about > 50% of waking hours
    • Performance Status 3: Capable of only limited self-care; confined to bed or chair > 50% of waking hours
    • Performance Status 4: Completely disabled; cannot carry out any self-care; totally confined to bed or chair
  • For autologous use only – from the individuals own body
  • Administer 3 doses approximately 2 weeks apart, infused over approximately 60 minutes
  • To minimize potential acute infusion reaction such as chills and/or fever, it is recommended that patients be pre-medicated orally with acetaminophen and an antihistamine such as diphenhydramine approximately 30 minutes prior to administration
  • The use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or Provenge (Sipuleucel-T) has not been studied. Provenge (Sipuleucel-T) is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy  and/or safety of Provenge (Sipuleucel-T). Patients should carefully be evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with Provenge (Sipuleucel-T).


Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • Q2043 Sipuleucel-T, minimum of 50 million autologous cd54+ cells activated with PAP-CM-CSF, including leukapheresis and all other preparatory procedures, per infusion (Use this code for Provenge)


Selected References:

  • National Cancer Institute (NCI) Cancer Vaccine.
  • Southwest Oncology G, Berry DL, Moinpour CM, 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):2828-2835. PMID 16782921
  • 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):1502-1512. PMID 15470213
  • Food and Drug Administration (FDA). April 29, 2010 Approval Letter - Provenge. 2010
  • 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
  • Provenge.
  • 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):3089-3094. PMID 16809734
  • 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):3670-3679. PMID 19536890
  • 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):411-422. PMID 20818862
  • 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):1297-1302. PMID 23582482
  • 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):259-264. PMID 24957547
  • 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):4558-4567. PMID 21558406
  • Cornford P, Bellmunt J, Bolla M, et al. 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
  • Cookson M, Roth B, Dahm P, et al. Castration-resistant prostate cancer: AUA Guideline Amendment 2015. J Urol. May 2016;195(5):1444-1452. PMID 26498056
  • Basch E, Loblaw DA, Oliver TK, et al. 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
  • Center for Medicare and Medicaid Services. National Coverage Determination (NCD) for Autologous Cellular Immunotherapy Treatment (110.22)
  • National Comprehensive Cancer Network (NCCN) Prostate Cancer Version 2.2017.
  • UpToDate. Investigational Approaches for the Treatment of Advanced Prostate Cancer. Janet R. Walczak MSN, R.N., CRNP, Roberto Pili M.D., Michael A. Carducci M.D., Emmanuel S. Antonarakis M.D.. Topic last updated October 19, 2017.
  • UpToDate. Overview of the Treatment of Castration-Resistant Prostate Cancer (CRPC). Nancy C. Dawson M.D. Topic last updated July 19, 2017.
  • UpToDate. Principles of Cancer Immunotherapy. Alexander N. Shoushtari M.D., Jedd Wolchok M.D., PhD, Michael E. Ross M.D. Topic last updated July 5, 2017.
  • UpToDate. Sipuleucel-T Drug Information (Lexicomp).
  • Agency for Healthcare Research and Quality (AHRQ) Technology Assessment – Outcomes of Sipuleucel-T Therapy. February 2011.
  • ECRI. Therapeutic Vaccines for Prostate Cancer. Published 3/21/2008 and Updated 6/10/2015.


Policy History:

December 2017 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.


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