Despite warranted concerns regarding the overdiagnosis and overtreatment of many cases of biologically indolent prostate cancer, prostate cancer remains the second leading cause of cancer-related death in the United States behind only lung cancer.1 With current treatment paradigms, nearly all patients who die of prostate cancer first receive androgen-deprivation therapy and then progress to castrate-resistant prostate cancer.
In patients with metastatic castrate-resistant prostate cancer (mCRPC) treatment options depend, in general terms, on three factors: whether the patient is symptomatic from their disease, the patient’s performance status, and previous therapies which the patient may have received. In the guidelines of many urologic and oncologic societies, these factors, when taken together, are important in guiding treatment recommendations.
There are a growing number of treatment options for patients with metastatic castrate-resistant prostate cancer including those targeting the androgen axis (abiraterone acetate plus prednisone and enzalutamide), cytotoxic chemotherapy (docetaxel and cabazitaxel), radiopharmaceuticals (radium-223), and immunotherapeutic approaches (sipuleucel-T).2 The greatest number of treatment options exist for patients who are asymptomatic or minimally symptomatic, have good performance status, and have not yet received docetaxel chemotherapy, there are numerous treatment options. These include docetaxel, abiraterone plus prednisone, enzalutamide, and sipuleucel-T.2
Among these options, sipuleucel-T is perhaps the most poorly adopted. In this article, we will explore the data behind sipuleucel-T including both randomized controlled trials and prospectively collected real-world observational data. As previously mentioned, sipuleucel-T is indicated for patients who are asymptomatic or minimally symptomatic, have good performance status, and have not yet received docetaxel chemotherapy. The AUA guideline is clear that patients who are symptomatic regardless of performance status should not be offered sipuleucel-T.2
Sipuleucel-T is an autologous active cellular immunotherapy, a subtype of therapeutic cancer vaccine.3 Functionally, sipuleucel-T consists of autologous peripheral blood mononuclear cells (including antigen-presenting cells) which are activated ex vivo with a recombinant fusion protein to target prostate cancer. The recombinant protein, named PA2024, consists of prostatic acid phosphatase (a prostatic antigen) fused to granulocyte-macrophage colony-stimulating factor (an immune-cell activator).4
Published in 2010, the IMPACT study was the pivotal Phase III randomized controlled trial (RCT) which led to the approval of sipuleucel-T.4 Men were enrolled if they had metastatic castrate-resistant prostate cancer and expected survival of at least six months. Initially, patients were required to have a Gleason score of 7 or less although this was eventually amended to allow patients with any grade of disease. Similarly, initially only asymptomatic patients were enrolled but this was expanded to include minimally symptomatic disease. Patients with serum prostate-specific antigen (PSA) less than 5 or greater than 50 ng/mL, those with ECOG performance score greater than 2, visceral metastases, pathologic fractures, spinal cord compression, and use of systemic steroids within 28 days prior to enrollment were excluded. Patients were randomized in a 2:1 ratio to sipuleucel-T or placebo. Disease progression was monitored with scheduled computed tomography and bone scan as well as biochemical analysis (including PSA testing).
The IMPACT study demonstrated that treatment with sipuleucel-T was associated with approximately 20% improved overall survival (hazard ratio 0.78, 95% confidence interval 0.61 to 0.98)4. Despite this proven survival benefit, sipuleucel-T has not been widely adopted, perhaps in part because it doesn’t demonstrate improvements in observable intermediate endpoints such as PSA response and time to objective disease progression (hazard ratio 0.95, 95% confidence interval 0.75 to 1.12).
In the IMPACT trial, as well as three other randomized controlled trials (D9901, D9902A, and PROTECT), cerebrovascular events occurred in somewhat higher rates among patients receiving sipuleucel-T (3.5%) than those receiving placebo (2.6%), though this was not a statistically significant difference.
To further assess this in a stage IV trial, the PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data was undertaken to evaluate real-world safety and efficacy outcomes for patients receiving sipuleucel-T.
Recently, Higano and colleagues published the results of PROCEED, a prospective registry of men with metastatic castrate-resistant prostate cancer receiving sipuleucel-T therapy.5 PROCEED is a multi-center, open-label observational registry collecting data in both academic and private practice urology and medical oncology clinics, registered with clinicaltrials.gov (NCT01306890). On an a priori basis, the primary objective was to quantify the cerebrovascular event risk while the secondary objective was to assess overall survival. Cerebrovascular events were defined as any stroke (ischemic or hemorrhagic), intracranial hemorrhage, and transient ischemic attacks (TIAs; focal neurologic deficits with complete resolution within 24 hours), all adjudicated by an independent neurologist and included regardless of causality, severity, or outcome. Serious adverse events were also collected as was the initiation of other prostate cancer treatments.
As this was an observational registry, no randomization, blinding or treatment masking was performed. Per the standard sipuleucel-T procedure, patients underwent 1.5 to 2.0x blood volume leukapheresis for antigen-presenting cell isolation followed by sipuleucel-T infusion three to four days later. This protocol was repeated at 2-week intervals for a total of three infusions.
In keeping with the registry methodology, safety and survival outcomes were assessed during the course of regular clinical interactions and reported every three months following the last sipuleucel-T infusion. Further prostate cancer treatments were given at the discretion of the treating physician. Patients were followed by at least three years, or until death or study withdrawal.
Primary analyses were descriptive with Kaplan-Meier survival analysis used to assess overall survival. Multivariable Cox proportional hazards models were assembled using a stepwise variable selection methodology.
Between January 27, 2011, and January 17, 2017, a total of 1976 were enrolled across 192 clinical sites. Of these, 1902 patients received at least one sipuleucel-T infusion and formed the analytic cohort. The median patient age was 72 years. The vast majority (87%) were white while 12% were African American. The vast majority were ECOG performance status 0 or 1, in keeping with sipuleucel-T’s indications for asymptomatic or minimally symptomatic men with good performance status. The median baseline PSA was 15.0 ng/mL (interquartile range 5.2 to 46.1 ng/mL). Gleason score was 8 or greater in 963 men (50.6%). Most men had bone-only disease (64.3%) with 1117 (70.0%) having 1-10 bone metastasis, 274 (17.2%) having more than 10 bone metastases and 204 (12.8%) having an unknown volume of bone metastasis. Most men had received some form of local therapy (radical prostatectomy, radiotherapy, or radical prostatectomy and radiotherapy; 87.4%). A minority of men had received other advanced anti-cancer therapies including abiraterone acetate (8.3%), enzalutamide (2.8%), docetaxel (11.3%), cabazitaxel (1.7%), and radium-223 (0.1%).
The majority (65.6%) were treated in medical oncology practices with the remainder treated in urology practices. Similarly, the majority (79.1%) were treated in community-based practices. The vast majority of patients (1813, 95.3%) received three sipuleucel-T infusions while 57 (3%) received two infusions, and 32 (1.7%) received one infusion. Reasons for failing to complete the planned three infusions included serious adverse events, disease progression, patient refusal, venous access issues, and other reasons.
Independently adjudicated cerebrovascular events (excluding TIAs) were identified in 54 patients (2.8%). The corresponding rate per 100 person-years was 1.2 (95% confidence interval 0.9 to 1.6). A corresponding analysis utilizing the SEER-Medicare data and examining men with prostate cancer who presented with metastatic castrate-resistant disease demonstrated an incidence of cerebrovascular events (excluding TIAs) of 2.8% with a corresponding rate of 1.5 events per 100 person-years (95% confidence interval 1.4 to 1.7). Cerebrovascular events were more common in older men, African American men, those with more advanced disease, and those with underlying risk factors for cerebrovascular disease. The median time to cerebrovascular events was 321 days (79 to 689 days).
After a median follow-up of 46.6 months, the median overall survival was 30.7 months (95% confidence interval 28.6 to 32.2 months). One thousand two hundred and fifty-five (66.0%) patients died during follow-up, the majority of which was due to prostate cancer progression (964 of 1255, 76.8%). Only 17 patients died of cerebrovascular events (1.4%). In post-hoc analyses, the investigators determined that baseline PSA was an important predictor of median overall survival: for patients with PSA ≤5.27 ng/mL (the lowest quartile), survival was 47.7 months (95% confidence interval 43.5 to 50.7 months) compared to 33.2 months (95% confidence interval 30.9 to 35.5 months) in the second quartile (PSA 5.27 – 15.08 ng/mL), 27.2 months (95% confidence interval 24.1 to 29.8 months) in the third quartile (PSA 15.08 – 46 ng/mL) and 18.4 months (95% confidence interval 15.9 to 21.2 months) in the fourth quartile (PSA > 46 ng/mL). Age, ethnicity, ECOG performance status, time since diagnosis, alkaline phosphatase level, hemoglobin, lymph node only metastasis, prior androgen axis inhibitor (abiraterone acetate or enzalutamide) and prior cytotoxic chemotherapy (docetaxel or cabazitaxel) were significantly associated with overall survival.
Two hundred and sixty patients (13.7%) reported any grade serious adverse events. The most common serious events were disease progression (28 patients), cerebrovascular accidents (16 patients), chills (13 patients), syncope (12 patients) and device-related infections (10 patients). Of the 260 patients with serious adverse events, 74 had one or more serious adverse events that were deemed possibly or probably related to sipuleucel-T. Of these, nine were cerebrovascular accidents. Grade 4 adverse events occurred in 21 patients (1.1%). Grade 5 adverse events occurred in 52 patients (2.7%), including 22 deaths due to disease progression.
In an exploratory analysis assessing subsequent anticancer interventions, the authors identified 338 patients (17.8%) who received an agent with proven survival benefit prior to receiving sipuleucel-T. At one year following sipuleucel-T, approximately 32.5% of patients had not received additional overall survival prolonging therapy. This dropped to 17.4% at two years. During the course of PROCEED follow-up, 1483 patients (78.0%) received one or more lines of survival-prolonging therapy and 48.3% received two or more lines of therapy. Most commonly, abiraterone acetate, enzalutamide, and docetaxel were utilized.
Compared to the IMPACT trial, the PROCEED registry shows that sipuleucel-T is currently being used in patients with lower PSA levels (15.0 vs 51.7 ng/mL), in keeping with previous analyses showing that overall survival results were substantially greater among patients with low PSA levels.
Taken together with the data from randomized controlled trials, the results of PROCEED indicate that sipuleucel-T is a safe and well-tolerated treatment for patients with metastatic castrate-resistant prostate cancer. The registry results also corroborated previous analyses demonstrating that patients with lower PSA levels receiving sipuleucel-T had significantly better overall survival. The utilization of sipuleucel-T is limited by the lack of benefit in objective intermediate endpoints which can be monitored (such as PSA progression). Another significant barrier is the cost (exceeding $90,000 USD)6 though novel anti-androgens (e.g. abiraterone acetate and enzalutamide) are similarly expensive.
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia
Published Date: April 2020