Medical Policy


Subject: Sipuleucel-T (Provenge®)
Document #: MED.00106 Publish Date:    08/29/2018
Status: Reviewed Last Review Date:    07/26/2018


This document addresses the use of autologous cellular immunotherapy with sipuleucel-T (Provenge) as a treatment method for prostate cancer. The only currently available product of this type is sipuleucel-T (Provenge, Valeant Pharmaceuticals, Laval, Quebec, Canada). Also referred to as a vaccine, autologous cellular immunotherapy is designed to activate an individual’s immune system to respond to prostate tumor antigens.

Note: Please see the following document for related information:

Position Statement

Medically Necessary:

Use of sipuleucel-T (Provenge) for the treatment of prostate cancer is considered medically necessary as a treatment for individuals with metastatic castrate-resistant prostate cancer (CRPC) or hormone refractory prostate cancer (HRPC) who meet all of the following criteria:

Investigational and Not Medically Necessary:

Use of sipuleucel-T (Provenge) for the treatment of prostate cancer is considered investigational and not medically necessary for all other conditions, including when the above criteria are not met.


In 2010, the U.S. Food and Drug Administration (FDA) approved sipuleucel-T as an autologous cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). CRPC (also known as androgen-independent prostate cancer [AIPC] or hormone-resistant [or recurrent or refractory] prostate cancer [HRPC]) is a form of prostate cancer that is resistant to standard hormone treatment, and is further defined as follows:

Disease progression evidenced by a progressively rising prostate specific antigen (PSA) (defined as a PSA rise by 2 ng/ml or more above the nadir PSA) or an increase in tumor mass on bone scan, X-ray, computerized tomography (CT) scan or magnetic resonance image (MRI) despite a castrate level of testosterone less than 20 ng/dl.

The precise mechanism of action for sipuleucel-T is unknown. The vaccine is designed to direct an immune response by targeting against prostatic acid phosphatase (PAP), an antigen expressed in most prostate cancers. Autologous peripheral blood mononuclear cells, including antigen presenting cells (APCs) collected by leukapheresis are activated during culture with PAP and granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune cell activator. The final product contains a minimum of 50 million autologous CD54+ cells activated with PAP-GM-CSF as well as T cells, B cells, natural killer (NK) cells and other cells. Sipuleucel-T is indicated for autologous use (Product Information Label, 2010).

The National Comprehensive Cancer Network® (NCCN, 2018) Clinical Practice Guidelines for prostate cancer V2.2018 include the use of sipuleucel-T vaccine as salvage treatment for CRPC. Additional clinical indicators for appropriate use include symptomatic or minimally symptomatic disease, ECOG performance level of 0-1, life expectancy of greater than 6 months, and the lack of visceral disease.

In their guideline for Castration-Resistant Prostate Cancer, the American Urological Association (2015) recommends the following in relation to sipuleucel-T:

The results of four randomized controlled trials (RCTs) 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. Two early studies of sipuleucel-T were not specifically designed to demonstrate a difference in overall mortality, but showed survival effects consistent with a third study which was designed to demonstrate a mortality difference (Rini, 2006; Small, 2002). Two other studies demonstrated a statistically significant survival benefit for individuals with castrate-resistant metastatic prostate cancer treated with sipuleucel-T compared with those treated with placebo (Higano, 2009; Kantoff, 2010).

The Kantoff study from 2010 reported the results of a large controlled trial of 512 subjects with metastatic prostate cancer randomized in a 2:1 ratio to receive either sipuleucel-T (n=341) or placebo (n=171). The study’s inclusion and exclusion criteria included that the individuals evaluated had: (i) no visceral metastasis, pathologic long bone fracture, or spinal cord compression; (ii) a serum prostate-specific antigen (PSA) level of 5 ng/ml or more; (iii) a serum testosterone level less than 50 ng/dl (17 nmol/l); (iv) progressive disease based on imaging studies or PSA measurements; (v) no treatment within the previous 28 days with systemic glucocorticoids, external-beam radiation (EBRT), surgery, or systemic therapy for prostate cancer (except medical or surgical castration); and (vi) no chemotherapy within the previous 3 months. Exclusions related to recent chemotherapy and systemic corticosteroids were specified to address the concern that treatments which impact the immune system could also interfere with the subject’s immununologic function and response to sipuleucel-T treatment. Accordingly, it is appropriate to discontinue these treatments prior to beginning a course of sipuleucel-T treatment. A significant finding from this study is that there was a relative risk reduction of death of 22% for subjects in the sipuleucel-T group. Additionally, there was a median survival benefit of 4.1 months in the sipuleucel-T group when compared to placebo. However, the authors note that the mean times to objective and clinical disease progression showed no significant difference between groups. This finding has been noted in the previously reported studies and the reasons behind this finding are currently unclear. Further research is warranted to understand this effect.

The Agency for Healthcare Research and Quality (AHRQ) published a technology assessment titled, Outcomes of Sipuleucel-T Therapy on February 10, 2011. This report addressed the use of sipuleucel-T for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer. The conclusions of the report support the use of sipuleucel-T for the FDA-approved indications. However, concern was noted that the methodology used in the available studies hinders full understanding of the impact of sipuleucel-T on health outcomes. Specifically, significant variation in post-progression treatment approaches within and between studies imparts significant bias into the methodology, clouding the studies’ ability to assess the impact of sipuleucel-T on overall survival. The report also comments that it is not clear what impact sipuleucel-T has in the absence of chemotherapy. Future studies should be designed with these issues in mind to avoid confounding variables and allow for assessment.

Beer and colleagues published the results of a study on the effect of sipuleucel-T therapy on PSA kinetics (2011). This double-blind RCT involved 176 subjects with metastatic prostate cancer randomized in a 2:1 ratio to treatment with either sipuleucel-T (n=117) or control (n=59), treatment with peripheral blood monoclonal cells. The authors reported no significant difference between groups in terms of time to biochemical failure (18 months for the experimental group vs. 15.4 months for controls, p=0.737). PSA doubling time (PSADT) was reported to be 34.4% greater in the sipuleucel-T group for values collected greater than 90 days post-randomization (p=0.046). PSADT was 47.6% greater in the sipuleucel-T group in an analysis controlling for testosterone recovery (p=0.038). The sipuleucel-T group had statistically better results with regard to antigen presenting cell activation (p<0.001) and T cell proliferation (p<0.001) when compared to controls. While this study does not demonstrate any benefits in terms of time to biochemical failure, and PSADT is not widely recognized as a clinically meaningful endpoint, it does demonstrate that sipuleucel-T therapy does have significant impact on PSA kinetics and stimulates a significant and prolonged immune response. How these findings relate to improved survival or disease progression is unclear.

In 2013, Schellhammer and colleagues published the results of an exploratory analysis using data from the Kantoff (2010) study described above. Using data from 512 subjects, the authors investigated the prognostic and predictive value of baseline variables in subjects receiving treatment with sipuleucel-T. They discovered that the most powerful prognostic factor was baseline prostate-specific antigen (PSA) (p<0.0001). When PSA data were subdivided into quartiles to evaluate treatment effect patterns, they found that the sipuleucel-T treatment effect appeared greater with decreasing baseline PSA. The overall survival (OS) hazard ratio for subjects in the lowest baseline PSA quartile (≤ 22.1 ng/mL) was 0.51 (95% confidence interval (CI), 0.31-0.85) compared with 0.84 (95% CI, 0.55-1.29) for subjects in the highest PSA quartile (> 134 ng/mL). The estimated improvement in median survival ranged from 13.0 months in the lowest baseline PSA quartile to 2.8 months in the highest quartile. Furthermore, the estimated 3 year survival in the lowest PSA quartile was 62.6% for the sipuleucel-T group and 41.6% for the control group, representing a 50% relative increase. The authors concluded that their findings suggest that individuals with less advanced disease may benefit the most from sipuleucel-T treatment. They postulate that this may provide a rationale for immunotherapy as an early treatment strategy for the treatment of metastatic castration-resistant prostate cancer.

In 2017, Bilen published the results of a retrospective study of 56 subjects treated with sipuleucel-T to evaluate the patterns of progression and determine clinical predictors of survival.  They concluded that individuals with age > 70 years, increased tumor burden in bone (> 20 metastases and/or elevated ALP level), and/or prior systemic treatment are more likely to experience rapid deterioration after sipuleucel-T. 

In a similar study, Wei (2017) retrospectively reviewed 94 subjects treated with sipuleucel-T.  This study concluded that, “A poorer baseline performance status, faster disease pace measured by the PSA doubling time, and previous novel androgen signaling inhibitor exposure could be important prognostic considerations.”


According to the American Cancer Society (ACS), prostate cancer is the most common form of cancer, other than skin cancer, among men in the United States. It is second only to lung cancer as a cause of cancer-related death among men. The American Cancer Society estimated that in 2015, about 220,800 new cases of prostate cancer would be diagnosed and 27,540 men would die of the disease. About 70% of all diagnosed prostate cancers are found in men aged 65 years or older.

According to the National Cancer Institute (NCI, 2012), cancer vaccines are biological response modifiers. The biological response modifiers stimulate or restore the ability of the individual’s immune system to fight infections and disease. The broad categories for cancer vaccines are:

Therapeutic cancer vaccines presumably work by refreshing the immune system’s memory in recognizing cancer cells as foreign for removal by the body. The cancer vaccine may contain inactivated cancer cells, viruses that express tumor antigens (unique proteins or protein bits that sit on the surface of cancer cells and can trigger some immune response), or any antigens that are overexpressed by cancer cells. The intent of cancer vaccine therapy is to delay or stop cancer cell growth; cause tumor shrinkage; prevent cancer from coming back; or eliminate cancer cells that are not killed by other forms of treatment, such as surgery, radiation therapy, or chemotherapy (NCI, 2012).

The recommended course of therapy for sipuleucel-T vaccine is 3 complete doses given at 2-week intervals. If the individual is not able to receive the scheduled intravenous vaccine infusion, an additional leukapheresis procedure may be required to complete the course of treatment (Product Information Label, 2017).


Autologous: From the individual’s own body.

Biological therapy: Treatment to boost or restore the ability of the immune system to fight cancer; including monoclonal antibodies, growth factors, and vaccines; also referred to as biological response modifier therapy, biotherapy, BRM therapy, and immunotherapy.

ECOG (Eastern Cooperative Oncology Group) performance status: A scale used to assess how an individual’s disease is progressing, determine how the disease affects the daily living abilities of the individual, and determine appropriate treatment and prognosis (Oken, 1982):

0= Fully active, able to carry on all pre-disease performance without restriction
1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3= Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4= Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5= Dead

Hormonal therapy: Treatment that adds, blocks, or removes hormones to slow or stop the growth of certain cancers, synthetic hormones or other drugs may be given to block the body’s natural hormones.                                     

Immune system: The complex group of organs and cells that defends the body against infections and other diseases.

Metastatic: The spread of cancer from one part of the body to another; a metastatic tumor contains cells that are like those in the original (primary) tumor and have spread.

Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. A vaccine can help the body recognize and destroy cancer cells or microorganisms.


The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:




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 Diagnosis




Malignant neoplasm of prostate



Elevated prostate specific antigen [PSA]



Rising PSA following treatment for malignant neoplasm of prostate



Hormone resistant malignancy status



Encounter for antineoplastic immunotherapy


When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.


Peer Reviewed Publications:

  1. 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. 2011; 17(13):4558-4567.
  2. Bilen MA, Hess KR , Subudhi SK, et al. Clinical predictors of survival in patients with castration-resistant prostate cancer receiving sipuleucel-T cellular immunotherapy. Cancer Chemother Pharmacol. 2017; 80(3):583-589.
  3. 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. 2009; 115(16):3670-3679.
  4. Kantoff PW, Higano CS, Shore ND, et al.; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010; 363(5):411-422.
  5. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982; 5(6):649-655.
  6. Rini BI, Weinberg V, Fong L, et al. Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy. Cancer. 2006; 107(1):67-74.
  7. 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. 2013; 81(6):1297-1302.
  8. Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006; 24(19):3089-3094.
  9. Wei XX, Perry J, Chang E, et al. Clinical variables associated with overall survival in metastatic castration-resistant prostate cancer patients treated with sipuleucel-T immunotherapy. Clin Genitourin Cancer. 2018. 16(3):184-190.e2.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Agency for Healthcare Research and Quality. Mark D, Samson DJ, Bonnell CJ, et al. Outcomes of Sipuleucel-T Therapy. Technology Assessment Report. Prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center. February 10, 2011. Available at: Accessed on May 11, 2018.
  2. Cookson MS, Roth BJ, Dahm P, et al. Castration-Resistant Prostate Cancer: AUA Guideline. 2015 Available at Accessed on May 11, 2018.
  3. National Cancer Institute (NCI). Cancer Vaccines. Reviewed April 26, 2018. Available at: Accessed on May 11, 2018.
  4. National Comprehensive Cancer Network® (NCCN). NCCN Clinical Guidelines in Oncology™. 2018. Prostate Cancer (V.2.2018). March 8, 2018. For additional information visit the NCCN website: Accessed on May 11, 2018.
  5. National Comprehensive Cancer Network®. NCCN Drugs & Biologic Compendium™ (electronic version). For additional information visit the NCCN website: Accessed on May 11, 2018.
  6. Provenge [Product Information], Seattle, WA. Dendreon Corporation. July, 2017. Available at:  Accessed on June 6, 2018.
  7. Sipuleucel–T. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated (8/12/2016). Available at: Accessed on May 11, 2018.
Websites for Additional Information
  1.  American Cancer Society. Prostate cancer. Revised February 26, 2016. Available at: . Accessed on May 11, 2018.


The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History






Medical Policy & Technology Assessment Committee (MPTAC) review.



Hematology/Oncology Subcommittee review. Updated Rationale and References sections.



MPTAC review.



Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Revised title and position statement to be more specific to sipuleucel-T. Updated References and Websites sections.



MPTAC review.



Hematology/Oncology Subcommittee review. Updated formatting in the Position Statement section. Updated References and Websites sections.



Updated Coding section with 10/01/2016 ICD-10-CM diagnosis code changes.



MPTAC review.



Hematology/Oncology Subcommittee review. Removed ICD-9 codes from Coding section.



MPTAC review.



Hematology/Oncology Subcommittee review.



MPTAC review.



Hematology/Oncology Subcommittee review. Revised medically necessary criteria regarding PSA levels. Updated Rationale and Reference sections.



MPTAC review.



Hematology/Oncology Subcommittee review. Updated Rationale and Reference sections.



MPTAC review.



Hematology/Oncology Subcommittee review. Updated Rationale and Reference sections.



MPTAC review.



Hematology/Oncology Subcommittee review. Updated Rationale and Reference sections. Updated Coding section with 07/01/2011 HCPCS changes; removed C9273 deleted 06/30/2011.



MPTAC review.



Hematology/Oncology Subcommittee review. Added additional criteria to medically necessary section. Updated Rationale section.



MPTAC review. Initial document development.