What is the role of sipuleucel-T in the treatment of patients with advanced prostate cancer? An update on the evidence

Abstract

Prostate cancer is the most common cancer in men and the second most deadly. About one-third of patients with prostate cancer will develop metastatic disease. We discuss the six United States Food and Drug Administration (FDA) approved treatments for metastatic castrate-resistant prostate cancer (mCRPC) with a strong focus on sipuleucel-T. Sipuleucel-T is the first immunotherapy shown to improve survival in asymptomatic or minimally-symptomatic mCRPC. Herein, we discuss the proposed mechanism of sipuleucel-T and its synthesis. We describe in detail the three randomized controlled trials (RTCs) that led to its approval. We also compiled the newest research regarding use of sipuleucel-T with other agents and in different patient populations. Finally, we discuss the current ongoing trials.

Introduction

Prostate cancer is the most common cancer and second most deadly cancer in men. An estimated 222,800 new cases of prostate cancer were diagnosed in the United States during 2015, and an estimated 27,540 men died from prostate cancer [Siegel et al. 2015]. Nearly one-third of patients with prostate cancer develop metastatic disease. About 80–90% of patients will have a good initial response rate to treatment; however, most will go on to develop progressive disease [Zhang et al. 2013].

Standard treatments

The initial treatment of castration-sensitive prostate cancer (CSPC) relies heavily on androgen deprivation therapy (ADT). Treatment includes medical therapy or surgical castration. Prostate cancer that no longer responds to ADT is called castration-resistant prostate cancer (CRPC). Unfortunately once the cancer has become castration resistant, it is also often metastatic. Currently, the treatments approved by the United States Food and Drug Administration (FDA) for metastatic castration-resistant prostate cancer (mCRPC) include abiraterone, enzalutamide, docetaxel, cabazitaxel, radium-223, and sipuleucel-T [Zhang et al. 2013; Graff and Chamberlain, 2015].

Abiraterone acetate and enzalutamide are two oral therapies targeting the androgen receptor (AR) axis. Abiraterone acetate selectively blocks cytochrome P450 C17, which is a critical enzyme in testosterone synthesis in the adrenal glands, testes, and within the prostate cancer itself. Two major phase III trials led to its approval. The COU-AA-301 trial randomized patients with mCRPC previously treated with docetaxel to receive either abiraterone with prednisone versus placebo with prednisone. The primary endpoint, overall survival (OS), was longer in the abiraterone group versus the placebo group (19.0 versus 14.8 months; p < 0.001) [De Bono et al. 2011]. The COU-AA-302 study randomized patients with mCRPC who were chemotherapy naïve to receive abiraterone plus prednisone or placebo plus prednisone. Median radiographic progression-free survival was longer in the abiraterone group versus placebo (16.5 versus 8.3 months;p < 0.001) [Ryan et al. 2013]. OS was also improved in the treatment group versus placebo (34.7 versus 30.3 months; p < 0.0027) with median follow up of 49.4 months [Ryan et al. 2014]. With these data, the FDA approved abiraterone acetate for the treatment of mCRPC both in the chemotherapy naïve as well as post-chemotherapy settings.

Enzalutamide (formerly MDV3100) is an AR inhibitor, binding at the ligand-binding domain of AR, thus blocking nuclear translocation, deoxyribonucleic acid (DNA) binding, and coactivator recruitment. Two important phase III trials showed the clinical benefit of enzalutamide. AFFIRM (a study evaluating the efficacy and safety of the investigational drug MDV3100) randomized patients with mCRPC who had received prior chemotherapy to either enzalutamide or placebo. Enzalutamide showed an improved median OS when compared to placebo (18.4 versus 13.6 months; p < 0.001) [Scher et al. 2012]. Subsequently, the PREVAIL study evaluated patients with mCRPC who had not yet received chemotherapy. Patients were randomized to receive either enzalutamide or placebo, and the enzalutamide group had an increased OS versus the placebo group (32.4 versus 30.2 months;p < 0.001) [Beer et al. 2014].

Docetaxel and cabazitaxel are two chemotherapy agents that have been approved for the treatment of mCRPC. The TAX-327 trial showed that patients with mCRPC had increased survival when treated with 10 cycles of docetaxel and prednisone versus mitoxantrone and prednisone (hazard ratio [HR] for death 0.76; 95% confidence interval [CI] 0.62–0.94; p = 0.009) [Tannock et al. 2004]. The TROPIC study evaluated the use of cabazitaxel plus prednisone versus mitoxantrone plus prednisone in patients with mCRPC that had disease progression on docetaxel. Median survival and median progression-free survival was improved in the cabazitaxel group with a HR for death of 0.70 (95% CI 0.59–0.83; p < 0.0001) [De Bono et al. 2010].

More recently, docetaxel has shown clinical benefit for patients with metastatic castration-sensitive prostate cancer (mCSPC) in the CHAARTED study. Patients were treated with either ADT alone or ADT and six cycles of docetaxel. The addition of docetaxel extended median OS from 44 to 57.6 months (HR, 0.61; 95% CI 0.47–0.80; p = 0.0003) [Sweeney et al. 2015]. This survival benefit has increased the use of docetaxel in the early mCSPC setting.

Radium-223 dichloride (radium-223) is a targeted radiopharmaceutical that selectively binds to areas of increased bone turnover in bone metastases and emits high-energy alpha particles. The alpha particles induce double-stranded DNA breaks, thus leading to a highly localized cytotoxic effect. In the ALSYMPCA phase III trial, patients with mCRPC and bone metastases were randomized to receive radium-223 versus placebo and best standard of care. Median OS was improved in the patients receiving radium-223 versus placebo (14.9 versus 11.3 months; p < 0.001) [Parker et al. 2013].

Sipuleucel-T is an autologous cellular immunotherapy that was approved by the FDA in 2010 for the treatment of asymptomatic or minimally-symptomatic mCRPC. It was the first immunotherapy approved for this group of patients [Mulders et al. 2015]. Sipuleucel-T is manufactured by first obtaining the patient’s peripheral blood mononuclear cells (PBMC), including antigen-presenting cells (APCs). These cells are then activated ex vivo with a recombination fusion protein (PA2024) that consists of prostatic acid phosphate (PAP) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The cells are then reinfused into the patient, and the activated APCs are thought to stimulate an immune response to PAP. Since PAP is only found on prostatic cells, this leads to a localized treatment. [Kantoff et al. 2010; Mulders et al. 2015].

The administration of sipuleucel-T is time consuming and requires careful coordination. Treatment consists of three sipuleucel-T infusion sessions, typically over a course of 4 weeks. Treatment must occur at an approved cell collection center. Three days prior to the infusion, patients undergo leukapheresis. Cells are sent to a central processing facility, where they are matured into the final product, as described above. Cells are then suspended in lactated ringer’s solution and returned for infusion into the patient. The entire process takes about 4 weeks to complete [Graff and Chamberlain, 2015].

Aim of this review

Several studies and reviews have shown that sipuleucel-T is a treatment option with clinical benefit for patients with early mCRPC; however, there are many unanswered questions regarding its optimal clinical use, especially in combination or sequencing with other agents [Small et al. 2006; Higano et al. 2009; Kantoff et al. 2010]. The aim of this paper is to review studies performed to evaluate the optimal role of sipuleucel-T in the treatment of mCRPC.

Sipuleucel-T in asymptomatic or minimally-symptomatic mCRPC – phase III trials completed prior to the approval of sipuleucel-T

D9901 study

In order to evaluate sipuleucel-T in men with asymptomatic mCRPC, Small and colleagues performed a randomized, double-blinded, placebo-controlled, phase III study with 127 patients [Small et al. 2006]. Patients were randomly assigned in a 2:1 ratio to receive three infusions of sipuleucel-T or placebo every 2 weeks. The primary endpoint was time to disease progression (TTP), which did not achieve statistical significance (11.7 weeks for men treated with sipuleucel-T versus 10.0 weeks for placebo, log-rank p = 0.52; HR, 1.45; 95% CI 0.99–2.11). However, sipuleucel-T yielded a longer median survival versus placebo (25.9 versus 21.4 months; log-rank p = 0.01; HR, 1.79; 95% CI 1.13–2.56). They found that the safety profile of sipuleucel-T was similar to that of placebo. Only a few side effects were more common in the sipuleucel-T group, including rigors (59.8% versus 8.9%), pyrexia (29.3% versus 2.2%), tremor (9.8% versus 0.0%), and feeling cold (8.5% versus 0.0%) [Small et al. 2006].

D9902A study

The D9902A study was identical in design to the D9901 study. A total of 98 patients with asymptomatic metastatic hormone refractory prostate cancer and an expected survival of at least 3 months were enrolled in this double-blinded, placebo-controlled study. As in D9901, the primary endpoint was TTP. The primary endpoint favored sipuleucel-T but did not achieve statistical significance (HR, 1.09; 95% CI 0.69–1.70;p = 0.72). There was a 21% reduction in risk of death for sipuleucel-T relative to placebo but this was not statically significant (HR, 1.27; 95% CI 0.78–2.07; p = 0.33). A Cox multiple regression model was used to adjust for potential imbalances in baseline prognostic factors such as lactate dehydrogenase (LDH), prostate-specific antigen (PSA), localization of disease, and number of bone metastasis. This increased the magnitude of survival effect for patients treated with sipuleucel-T (adjusted HR, 1.92; 95% CI 1.09–3.35;p = 0.23). Additionally, when data from both the D9901 and D9902A studies were integrated, there was a statistically significant increase in median OS for the sipuleucel-T group versus placebo with a benefit of 4.3 months (HR, 1.50; 95% CI 1.10–2.05; log rank p = 0.01) [Higano et al. 2009].

IMPACT study

The Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) study was a larger phase III, double-blinded, placebo-controlled, multicenter trial involving 512 men with mCRPC [Kantoff et al. 2010]. Patients received an infusion of either sipuleucel-T or placebo every 2 weeks for 6 weeks (three total infusions). There was a 22% relative reduction in risk of death in the sipuleucel-T group compared to placebo (HR, 0.78; 95% CI 0.71–0.98; p = 0.03). Sipuleucel-T was associated with a longer median OS by 4.1 months (25.8 versus 21.7 months, p = 0.03). However, the median TTP was similar (14.6 versus 14.3 weeks; p = 0.63). Overall, sipuleucel-T was tolerated well and had a similar side effect profile to placebo. Adverse events more common in the treatment group included chills (54% versus 13%), fever (29% versus 14%), headache (16% versus 5%), influenza-like illness (10% versus 4%), myalgia (10% versus 5%), hypertension (7% versus 3%), hyperhidrosis (5% versus 1%), and groin pain (5% versus 2.4%). All of these, except groin pain, were thought to be related to the infusion and occurred within 1 day of infusion [Kantoff et al. 2010]. Based on these data, sipuleucel-T was approved by the US FDA on 29 April 2010.

Meta-analysis

In order to aggregate the data from the three phase III trials discussed above, Kawalec and colleagues performed a meta-analysis and included a total of 737 participants [Kawalec et al. 2012]. The OS of patients who received sipuleucel-T versus placebo was significantly longer with a HR of 0.73 (95% CI 0.61–0.88; p = 0.001). There was no significant difference between groups for TTP or risk of adverse events. They concluded that the use of sipuleucel-T prolonged OS in men with asymptomatic or minimally symptomatic mCRPC without affecting TTP or posing a significant safety risk [Kawalec et al. 2012].

Sipuleucel-T in androgen-dependent prostate cancer (PROTECT)

To determine the biological activity of sipuleucel-T in CSPC, Beer and colleagues performed a randomized controlled, double-blind, multicenter trial named PROTECT (PROvenge Treatment and Early Cancer Treatment) [Beer et al. 2011]. A total of 176 patients with prostate cancer, detectable by serum PSA following radical prostatectomy, received 3–4 months of androgen suppression therapy and then were randomized to receive sipuleucel-T or control PBMCs without antigen exposure. The primary endpoint was biochemical failure (BF), defined as a serum PSA greater than or equal to 3.0 ng/ml. The median time to BF was 18 months in the sipuleucel-T group and 15.4 months for the placebo group, a difference which was not statistically significant (HR, 0.936;p = 0.737). The PSA doubling time (PSADT) was also evaluated; this difference was statistically significant between groups. Patients who received sipuleucel-T had a 48% increase in PSADT after testosterone recovery (155 versus 105 days;p = 0.038). While PSADT is not often used as an endpoint in clinical trials, and PSADT has not been validated as a surrogate endpoint of OS, this study argues that further studies should be pursued with sipuleucel-T in CSPC [Beer et al. 2011].

Sipuleucel-T with concurrent versus sequential abiraterone acetate plus prednisone in mCRPC

A phase II open-label study was performed to evaluate the effect of concurrent or sequential administration of abiraterone acetate plus prednisone on sipuleucel-T manufacturing and immune response. Previously, sipuleucel-T had been given as a monotherapy due to concern that concurrent or sequential addition of other agents may blunt the immune response to sipuleucel-T, thus decreasing its effectiveness. This phase II study randomized 69 patients with asymptomatic or minimally symptomatic mCRPC to receive sipuleucel-T followed by abiraterone plus prednisone on day 1 (concurrent) or 10 weeks after the first sipuleucel-T infusion (sequential). The primary endpoint was cumulative APC activation. This was an ex vivo endpoint that was assessed by evaluating second and third manufactured sipuleucel-T products. APC activation was significantly greater at the second and third infusion compared with the baseline in both the concurrent and sequential arms (p < 0.05). Thus, the authors of this study concluded that co-administration of sipuleucel-T and abiraterone plus prednisone does not impair the manufactured product of sipuleucel-T. Additionally the side effect profile in both groups was similar the side effects observed in the IMPACT trial [Small et al. 2015].

NEOadjuvant Active Cellular Immunotherapy (NeoACT) study

In order to evaluate the use of neoadjuvant sipuleucel-T therapy, Fong and colleagues conducted a single-arm, open-label, phase II study [Fong et al. 2014]. A total of 37 patients with untreated localized prostate cancer were treated with sipuleucel-T prior to radical prostatectomy. Immune infiltrates of the prostate specimen were assessed by immunohistochemistry and compared to pretreatment biopsies. There was increased infiltration of CD3-positive T cells at the tumor interface in the prostatectomy samples compared to pretreatment biopsies (p < 0.001). There was a greater than threefold increase of CD3+ T cells detected in 57% (95% CI 39–79%) of patients treated with sipuleucel-T. This study suggested that sipuleucel-T may lead to a localized immune response. How this correlates with a clinical response remains unknown. Additionally, since sipuleucel-T is approved in the mCRPC setting, it is unclear if the T-cell response seen in this study is also seen at areas of metastatic disease [Fong et al. 2014].

A randomized phase II study evaluating optimal sequencing of sipuleucel-T and ADT in biochemically recurrent prostate cancer (STAND) study

To evaluate the sequencing of sipuleucel-T and ADT in biochemically-recurrent prostate cancer, a phase II randomized trial was performed by Antonarakis and colleagues [Antonarakis et al. 2015]. Importantly, this was performed in patients with CSPC. A total of 68 patients were enrolled. Inclusion criteria were biochemically-recurrent prostate cancer, serum testosterone level of 200 mg/ml or higher, PSADT of 12 months or less, and no radiographic evidence of metastases. Patients were randomized to receiving sipuleucel-T with ADT starting 2 weeks after sipuleucel-T was completed versus starting ADT 3 months prior to initiation of sipuleucel-T. The main objective was to compare immune responses between arms. Results showed similar immune activation in both groups; however, there appeared to be a greater cellular immune response in those who received sipuleucel-T prior to ADT. PSA response on treatment was a secondary endpoint, and both groups achieved PSA levels that were 5% or less of PSA levels measured at baseline. Combination therapy was well tolerated from a side effect perspective. The authors concluded that the combination of ADT after immunotherapy may enhance T-cell immune responses in patients with biochemically recurrent prostate cancer [George, 2014; Antonarakis et al. 2015].

Ongoing studies

Phase IV analysis – PROCEED registry

PROCEED is a phase IV registry established by the manufacturers of sipuleucel-T to evaluate patient characteristics and product parameters for patients treated with sipuleucel-T [Graff et al. 2015].

In order to understand the efficacy of sipuleucel-T in African American patients, the PROCEED study by Tutrone and colleagues enrolled 11.7% African American patients (compared to just 5.8% African American enrollment in the three RCTs described above, despite the twofold greater incidence of prostate cancer in African Americans versus White patients) [Tutrone et al. 2015]. This is similar to the African American population of 13.7% in the United States. Data such as OS are currently not available.

In order to assess the feasibility of sipuleucel-T outside of the clinical trial, Higano and colleagues performed a retrospective review. PROCEED patients who received at least one sipuleucel-T infusion were evaluated for number of infusions, time between infusions, reasons for delay, and baseline characteristics [Higano et al. 2015]. Over 95% of patients who were treated with one infusion of sipuleucel-T completed all three infusions, with the majority at the recommended 2-week intervals. Approximately 5% of patients did not complete the full course and their baseline characteristics suggested more advanced disease.

A randomized phase 2 study evaluating sipuleucel-T with concurrent or sequential enzalutamide in mCRPC (STRIDE)

A randomized open-label, phase II trial is currently underway to assess the effects of sipuleucel-T when administered concurrently or sequentially with enzalutamide. This study is expected to provide results in July 2017. Patients with asymptomatic or minimally-symptomatic mCRPC were randomized to start enzalutamide either 2 weeks prior to sipuleucel-T (concurrent) or 10 weeks after sipuleucel-T initiation. The primary endpoint is the peripheral T-cell immune response to the immunizing antigen, PA2024. Preliminary data presented at ASCO 2014 showed no differences in product potency, measured by assessing APC activation [Quinn et al. 2014; George, 2014].

Other ongoing trials

There is ongoing interest in the use and optimal efficacy of sipuleucel-T. Ongoing clinical trials combine sipuleucel-T with approved therapies such as radium-223 [ClinicalTrials.gov identifier: NCT02463799], novel agents such as indoximod [ClinicalTrials.gov identifier: NCT01560923] or tasquinimod [ClinicalTrials.gov identifier: NCT02159950], and immune therapies such as ipilimumab [ClinicalTrials.gov identifiers: NCT01832870, NCT01804465], CT-011 [ClinicalTrials.gov identifier: NCT01420965], or bevacizumab [ClinicalTrials.gov identifier: NCT00027599]. With the interest in the abscopal effect, several ongoing trials are also studying the effect of radiation combined with sipuleucel-T [ClinicalTrials.gov identifiers: NCT01807065, NCT01818986, NCT02232230, NCT01833208]. Additionally, given sipuleucel-T is a unique immunotherapy agent, there is a study looking at the effects of the addition of a DNA booster vaccine [ClinicalTrials.gov identifier: NCT01706458].

Discussion

It is known that sipuleucel-T is an effective treatment option for patients with early mCRPC. Ongoing research focuses on how to maximize its potential in the context of additional standard of care options, many of which were approved subsequent to the IMPACT study. A few studies have suggested that concurrent treatment with abiraterone and enzalutamide does not lead to a decrease in the ex vivo immunologic response and manufactured cellular product of sipuleucel-T. However, these are only phase II trials and thus further studies are needed to evaluate outcomes.

A proposed therapeutic algorithm in mCRPC is the addition of sipuleucel-T early on when patients have asymptomatic disease with low tumor burden and lower PSA levels. In certain patients with higher risk features, sipuleucel-T may be added to enzalutamide or abiraterone acetate at the time of PSA progression without radiographic progression. Patients who develop resistance to the novel hormonal agents may then be chemotherapy candidates for docetaxel and cabazitaxel. Patients who go on to develop symptomatic bone metastases should be candidates for radium-223.

Currently in our practice we will administer sipuleucel-T alone to informed patients who have asymptomatic, subjectively low tumor burden disease with typically a low PSA level (<20 ng/ml), and follow them for disease progression. However, in patients with rapidly rising PSA (DT < 3 months), PSA levels > 50 ng/ml, minimally-symptomatic disease, or subjectively higher tumor burden, we have increasingly administered sipuleucel-T in the context of additional hormonal therapy (either enzalutamide or abiraterone acetate) either concomitantly or immediately following. Given the very separate mechanisms of action of these treatments, the clinical data suggesting no detrimental effect on mechanism of action, and with the goal of improving OS with each, we feel concomitant use is reasonable. The major advantage is that patients are able to achieve disease control (with secondary hormonal therapy), while maximizing the survival benefit to sipuleucel-T by treating them early in their CRPC disease course.

Recent and ongoing studies also address the possibilities of expanding the patient populations for which sipuleucel-T is used. Phase II studies have shown that patients with localized prostate cancer and those with CSPC may benefit from sipuleucel-T. In summary, sipuleucel-T is an exciting immune therapy in the treatment of prostate cancer but its optimal sequencing with other approved therapies of mCRPC is yet to be determined.