Technology Evaluation
Center (TEC)

Special Report: Treatments for Metastatic Castration-Resistant

EXECUTIVE SUMMARY

Background:  Prostate cancer is the most common malignancy in men and a common cause of cancer mortality.  Initial treatment strategies for localized prostate cancer include active surveillance, radiation therapy, brachytherapy, and surgery.  If cancer recurs, as evidenced by a rising PSA and/or imaging that indicates the presence or high suspicion of metastasis, androgen-deprivation therapy (ADT) is the standard therapy. Effective ADT will cause serum PSA levels to fall, and if present will provide pain relief and regression of soft tissue metastases.  However, ADT does not permanently suppress the progression of cancer.  Some patients will eventually experience a rise in PSA levels, followed by development and/or progression of metastases.  Such a state of advanced cancer is called castration-resistant prostate cancer (CRPC). Even with treatment, the prognosis of castration-resistant prostate cancer is not very good, with median survival generally less than two years. At present docetaxel is the standard of care because it provides a modest survival improvement among patients with metastatic CRPC.

Recently several new drugs have gained FDA approval for the treatment of CRPC.  One of these, sipuleucel-T, is manufactured from the patient’s own white cells. Cells are collected during a procedure called leukapheresis, which filters out the cells of interest. The collected cells are cultured with a protein called PA2024 and then infused back into the patient. Antigen-presenting cells in the preparation take in antigens and then “present” them to T-cells throughout the body, which then react to cells with PAP sensing these prostate cancer cells as foreign substances.

Another drug, cabazitaxel is a tubulin-binding taxane drug in the same class as docetaxel.  Disruption of tubule function inhibits cell division and growth of cancer. In addition to inhibiting cell division, the taxanes promote apoptosis, or cell death.  In cell models which were resistant to paclitaxel and docetaxel, the drug showed antitumor activity.

Abiraterone acetate is an inhibitor of androgen biosynthesis which blocks an enzyme involved in testosterone synthesis. Abiraterone acetate is able to suppress androgen production from nongonadal sources such as the adrenal glands and the prostate cancer itself.

Enzalutamide is an androgen receptor signaling inhibitor that inhibits several aspects of androgen-receptor signaling. In castration-resistant prostate cancer, androgen receptors are overexpressed and the tumors are resistant to conventional antiandrogen agents.  Disruption of the androgen receptor signaling pathways prevents cell proliferation and tumor survival.

Objective:  The objective of this Special Report is to review the evidence on the effects of four drugs for metastatic castration-resistant prostate cancer (CRPC): sipuleucel-T, cabazitaxel, abiraterone acetate and enzalutamide. Two patient indications are considered: patients undergoing first-line systemic therapy and patients undergoing post-docetaxel second-line therapy. This review seeks evidence on health outcomes such as overall survival, symptoms, quality of life and adverse events. Intermediate outcomes include prostate-specific antigen (PSA) response, objective tumor response, progression-free survival and time to PSA progression. This review addresses the relative effects of these four drugs with head-to-head comparators from randomized controlled trials (RCTs). The review also attempts indirect comparisons between these drugs. Finally, the review explores whether there are differences in the effectiveness of these drugs based on patient or treatment characteristics.

Search strategy: A search strategy was entered on PubMed on September 13 and November 12, 2012. It used terms for trade names, generic names and substance names, cross-references with a MeSH term for prostatic neoplasms and limited to English language sources.

Selection criteria:  This Special Report sought any comparative or single-arm studies that entailed use of one of the four drugs and reported any health outcome or intermediate outcome. Published articles and FDA reports are both sought.

Main results:  Evidence for first-line therapy in patients with metastatic CRPC is available for three of the four drugs: sipuleucel-T, abiraterone acetate and enzalutamide. Only sipuleucel-T is represented by comparative studies (see table below). Three small single-arm studies that collectively enrolled 65 patients included mixed populations and do not contribute materially to RCT evidence.

PSA: prostate-specific antigen; PFS: progression-free survival

*Relates to objective radiographic tumor progression except in D9901 and D9902A (radiographic or clinical event progression).

Three fair quality placebo-controlled RCTs with a total of 737 patients consistently show an overall survival advantage for active treatment groups with between-group differences in median survival of 4.1 months, 4.5 months and 3.3 months; the smallest was not statistically significant. While there are concerns about time-dependent confounding of survival results due to differences in treatments given for progression, particularly docetaxel, the survival advantage appears to be reliable. No significant differences between sipuleucel-T and placebo were seen on measures of progression-free survival. Adverse events do not appear to be a major concern and include pyrexia, chills, myalgia, headache and influenza-like symptoms. Evidence for abiraterone acetate comes from 3 single-arms studies of 108 patients which report no data on health outcome benefits. Similarly, evidence on enzalutamide was produced by one single-arm studies of 65 patients with no health outcome benefit data. It is difficult to judge whether patients benefit from abiraterone acetate or enzalutamide when there are no studies comparing them with active treatment or natural history of disease. Clear evidence of treatment effect interactions by patient and treatment subgroup factors is lacking.

Regarding second-line therapy (see table below), evidence from a fair quality open-label RCT of 755 patients comparing cabazitaxel plus prednisone and mitoxantrone plus prednisone found a statistically significant advantage for cabazitaxel in overall survival, with a between-group difference in median survival of 3.4 months. Pain response and pain progression favored cabazitaxel but were not statistically significant. Significant advantages for cabazitaxel were found for these intermediate outcomes: PSA response, objective tumor response, composite progression-free survival, objective progression-free survival and time to PSA progression. Adverse events were much more common and concerning for cabazitaxel over mitoxantrone, including neutropenia, febrile neutropenia, leukopenia, hematuria, pyrexia and various gastrointestinal events.

PSA: prostate-specific antigen; PFS: progression-free survival

*Relates to objective radiographic tumor progression except in and TROPIC (PSA progression, tumor progression, pain progression or death)

Abiraterone acetate is represented by one good quality placebo-controlled RCT of 1195 patients and three single arm studies with a collective 162 patients. The RCT found a statistically significant difference favoring abiraterone acetate, an advantage of 3.9 months in median survival. Pain palliation was significantly better in the group receiving abiraterone acetate. These intermediate outcomes also saw significantly superior results for abiraterone acetate: PSA response, objective progression-free survival and time to PSA progression. Adverse events include edema and hypokalemia.

One good quality placebo-controlled RCT with 1195 patients and one subgroup of 75 patients from a dose escalation study provided evidence on use of enzalutamide. In a planned interim statistical analysis, the RCT found significantly better overall survival for enzalutamide, leading to early unblinding of patients. The difference in median survival between groups was 4.8 months.  There was a significantly higher frequency of response on a disease-related quality-of-life scale. These intermediate outcomes also significantly favored enzalutamide: PSA response, objective soft-tissue response and objective progression-free survival. Adverse events included spinal cord compression, fractures, hot flushes, neutropenia and headache.

Comparing overall survival results for cabazitaxel, abiraterone acetate and enzalutamide, these drugs had a gain in median survival over comparators of between 3.4 and 4.8 months. At one year, overall survival was 64% for cabazitaxel, 60% for abiraterone acetate and 68% for enzalutamide. While such comparisons cannot take into account differences between trials in composition of patient samples, it suggests similar survival for these three drugs among patients with metastatic CRPC who have progressed after docetaxel. Adverse events may affect choice of treatment.

Clear evidence of treatment effect interactions by patient and treatment subgroup factors is lacking for all three drugs relevant to the second-line therapy indication.

Discussion:  Evidence reviewed here indicates a survival advantage for sipuleucel-T as first-line systemic therapy in patients with metastatic CRPC. Studies are insufficient to show a similarly beneficial impact from abiraterone acetate or enzalutamide because none compare these treatments with other active treatment or natural history of disease. In the setting of post-docetaxel second-line therapy, evidence demonstrates survival benefit for three drugs: cabazitaxel, abiraterone acetate and enzalutamide. The magnitude of gain in survival appears similar for these three drugs in terms of both difference from comparator in median survival and in 1 year survival rates. Indirect comparisons cannot take into account differences between trials in characteristics of patient samples, so conclusions must be made with caution. Adverse events seem more frequent with use of cabazitaxel and may affect choice of treatment.

Among the strengths of this review are inclusion of available comparative and single-arm studies, use of both published sources and FDA documents and appraisal of the quality of RCTs. The main limitation of the review relates to indirect comparisons; none of these drugs were compared head-to-head in the same study.

Patients undergoing treatment for metastatic CRPC face many challenges and deciding whether to pursue one of these four drugs must take these challenges into account. Median survival in this cohort is less than two years. The health consequences of metastases to bone and viscera, along with advancing age and comorbidities, raise worries for these men. Bisphosphonates and denosumab can be given to ameliorate skeletal-related events.  Knowledge of treatment-related adverse events may influence decisions to pursue supportive and palliative care rather than systemic anticancer therapies.

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NOTICE OF PURPOSE:  TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.