The Role of Sipuleucel-T in Therapy for Castration-Resistant Prostate Cancer: A Critical Analysis of the Literature

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1 EUROPEAN UROLOGY 61 (2012) available at journal homepage: Platinum Priority Collaborative Review Prostate Cancer Editorial by Bertrand Tombal on pp of this issue The Role of Sipuleucel-T in Therapy for Castration-Resistant Prostate Cancer: A Critical Analysis of the Literature Guru Sonpavde a,b, *, Giuseppe Di Lorenzo c, Celestia S. Higano d, Philip W. Kantoff e, Ravi Madan f, Neal D. Shore g a Texas Oncology, Houston, TX, USA; b Veterans Affairs Medical Center and the Baylor College of Medicine, Houston, TX, USA; c University Federico II, Naples, Italy; d University of Washington, Seattle, WA, USA; e Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; f National Cancer Institute, Bethesda, MD, USA; g Grand Strand Urology, Myrtle Beach, SC, USA Article info Article history: Accepted October 14, 2011 Published online ahead of print on October 23, 2011 Keywords: Immunotherapy Prostate cancer Sipuleucel-T CTLA-4 PD-1 Prostvac VF Tricom Ipilimumab Abstract Context: Sipuleucel-T, an autologous antigen-presenting cell vaccine loaded with prostate acid phosphatase conjugated with granulocyte-macrophage colony-stimulating factor (GM-CSF), yielded a survival advantage in men with metastatic castrationresistant prostate cancer (mcrpc). Objective: Critically analyze the role of sipuleucel-t in therapy for mcrpc. Evidence acquisition: A systematic review of the literature was performed in June 2011 using Medline and an abstract search of major cancer conferences. The search strategy included the terms sipuleucel-t, APC-8015, castration-resistant, prostate cancer, and immunotherapy. Evidence synthesis: The era of targeted immunotherapy was initiated with the regulatory approval in 2010 of sipuleucel-t for asymptomatic and minimally symptomatic mcrpc. The median survival was prolonged by 4.1 mo (25.8 vs 21.7 mo; hazard ratio: 0.78; 95% confidence interval, ; p = 0.03), coupled with an improvement in 3-yr survival (31.7% vs 23.0%). Outcomes were characterized by the lack of tumor regression or delay in progression. Further development is proceeding in earlier stages of prostate cancer and in the context of a host of emerging agents. Conclusions: The addition of sipuleucel-t, an immunotherapeutic agent, to the armamentarium represents a paradigm shift in therapy for mcrpc. The rational combination and proper sequencing of sipuleucel-t with other newly approved agents (abiraterone acetate, cabazitaxel) and emerging agents (MDV3100, TAK-700, ipilimumab) will be important to evaluate. # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. 501 Medical Center Blvd, Webster, TX 77598, USA. Tel ; Fax: address: guru.sonpavde@usoncology.com (G. Sonpavde). 1. Introduction Metastatic castration-resistant prostate cancer (mcrpc) is still a fatal disease, given the availability of treatment options that modestly extend survival by a median of 2 4 mo. Docetaxel-based regimens have been acknowledged as the standard first-line chemotherapy. In 2010, health care authorities approved the combination of cabazitaxel and prednisone following docetaxel [1,2]. In 2011, abiraterone acetate, a CYP-17 targeting noncytotoxic androgensynthesis inhibitor, was approved in the United States and Europe for patients after treatment with docetaxel, and it will likely be approved around the world. Still, the survival gains with these agents are modest, and chemotherapy is often delayed until symptomatic disease appears. Sipuleucel- T is an autologous cellular immunotherapy that extends /$ see back matter # 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 640 EUROPEAN UROLOGY 61 (2012) [(Fig._1)TD$FIG] survival and is characterized by manageable acute toxicities [3]. This article will review data supporting sipuleucel-t. 2. Evidence acquisition A systematic review of the literature was performed in June 2011 using the Medline database and an abstract search of the major cancer conferences conducted by the American Society of Clinical Oncology and the European Society of Medical Oncology. The Medline search strategy included the following terms: sipuleucel-t, APC-8015, castrationresistant, prostate cancer, and immunotherapy. The search results were restricted to the English language, with preference given to articles published within the last 5 yr. 3. Evidence synthesis 3.1. Autologous antigen-presenting cell-based immunotherapy as a therapeutic modality for prostate cancer Prostate cancer (PCa) expresses several relatively organspecific tumor-associated antigens (TAAs), such as prostatespecific antigen (PSA), prostatic acid phosphatase (PAP), and prostate-specific membrane antigen (PSMA), which provides an opportunity to use targeted immunotherapy. Endogenous antigens are cleaved to peptides, which bind the major histocompatibility complex (MHC) class I antigen and are presented by antigen-presenting cells (APCs), including dendritic cells (DCs), to cytotoxic CD8 + T cells. Peptides can also be presented by MHC class II molecules to helper CD4 + T lymphocytes, which augments the immune response. Autologous DC based immunotherapy may overcome defective antigen presentation mediated by downregulation of MHC class I and elevation of transforming growth factor b and interleukin-10, although the precise mechanism of action of DC immunotherapy, including sipuleucel-t, warrants further study [4] Sipuleucel-T Manufacture of sipuleucel-t Patients undergo leukapheresis, and the collection is processed to generate CD54 + APCs by exposing hematopoietic progenitor cells to a cocktail of cytokines (Fig. 1). CD54, or intercellular adhesion molecule-1, is a member of the immunoglobulin superfamily that induces transmigration of leukocytes from the bloodstream into the tissue and facilitates T cell receptor interaction with the APC by binding to its ligand, lymphocyte function associated molecule-1, and was considered a reasonable surrogate marker for activated APCs based on preliminary evidence [5]. Thereafter, APCs are cultured for h with PA2024, a fusion protein consisting of PAP and granulocyte macrophage colony-stimulating factor (GM-CSF) [5 7]. The final product also contains T cells, B cells, and natural killer cells [8]. The product, sipuleucel-t (Provenge, APC8015, Dendreon Corp., WA, USA), is then infused every 2 wk for a total of three times; each infusion comprises the maximum number of cells that can be manufactured from a Fig. 1 Logistics of the manufacture and administration of sipuleucel-t. PAP-GM-CSF = prostatic acid phosphatase granulocyte macrophage colony-stimulating factor. single leukapheresis, which is 50 million CD54 + cells (the minimum expected yield from one leukapheresis). Patients undergo leukapheresis before each of the three infusions and must comply with scheduled appointments, because the infusion bag cannot remain at room temperature >3 h after removal from the insulated container. If the patient is unable to receive an infusion, an additional leukapheresis is required if the treatment is continued Early evidence for the clinical activity of sipuleucel-t In a randomized double-blind trial (D9901), 127 previously untreated men with relatively asymptomatic mcrpc were assigned in a 2:1 ratio to receive sipuleucel-t (APC8015) or control APCs (not cultured with PA2024) as three intravenous infusions over 30 min every 2 wk [9,10]. Eligible patients were not on steroids, had not received prior radiopharmaceuticals within 1 yr, had no visceral metastasis, and were required to have PAP expression in >25% of tumor cells. Treatment with chemotherapy or other anticancer therapy was prohibited until the primary end point of time to progression (TTP) by radiographic or clinical events (not PSA progression) was met. Fewer than 10% of patients had received prior chemotherapy. The median TTP, 11.7 wk (95% CI, ) vs 10 wk (95% CI, ), was not significantly different ( p = 0.052; hazard ratio [HR]: 1.45; 95% CI, ), while overall survival was prolonged from 21.4 mo with placebo (95% CI, ) to 25.9 mo with sipuleucel-t (95% CI, ) ( p = 0.01; HR: 1.70; 95% CI, ). In a subsequent combined analysis of 225 patients from the D9901 trial and the identical D9902A trial, which was stopped at 98 patients based on initial negative disease progression results in D9901, patients randomized to sipuleucel-t demonstrated a 33% reduction in the risk of death (median survival: 23.2 mo [95% CI, ] vs 18.9 mo [95% CI, ]; HR: 1.50; 95% CI, ; p = 0.011) [10]. T-cell proliferation in response to PA2024 at

3 EUROPEAN UROLOGY 61 (2012) wk, which was performed for 49 patients, was eight-fold higher after sipuleucel-t. A correlation was observed between CD54 upregulation in the product and survival, suggesting an association with the immunogenic potency of the product. There was an increase in grade 1 2 adverse events (AEs) with sipuleucel-t, including chills, pyrexia, headache, asthenia, dyspnea, vomiting, and tremor. A possible increase in cerebrovascular events was observed in the sipuleucel-t arm 7.5% (11 of 147 patients) compared with 2.6% (2 of 76 patients) the majority of which were not fatal and occurred over a wide period (median time: 167 d; range: d). However, another trial in androgen-dependent disease demonstrated an opposite trend, with more cerebrovascular events occurring in the placebo arm [11] Confirmatory IMPACT trial Subsequently, the double-blind IMPACT trial randomized 512 men with relatively asymptomatic mcrpc in a 2:1 ratio to sipuleucel-t or control nonantigen pulsed APCs (placebo) with a primary end point of survival [3]. The placebo control was considered appropriate in relatively asymptomatic patients, and therapy according to investigator discretion was allowed upon clinical progression after trial therapy. Radiographic or PSA progression was required for entry into the study, with a minimum PSA 5 ng/ml. Patients were stratified for Gleason score, bisphosphonate use, and number of bone metastases and were required to have Eastern Cooperative Oncology Group performance status 0 1, be >3 mo beyond chemotherapy, and harbor no visceral metastasis. Tumor PAP expression was not required based on the observation that PAP expression may be frequent enough in mcrpc to not require the demonstration of PAP expression in metastatic tumor tissue, which is not easily accessible, and moreover, initial biopsy is frequently performed many years earlier and may not be as relevant. Approximately 85% of enrolled patients were chemotherapy naive, and approximately 25% of the patients had a Gleason score 8. The median age was 71 yr, and 90% of the patients were Caucasian. Eighty-two percent of patients had a performance status of 0, and the median PSA was approximately 50 ng/ml. Forty-four percent had bone and soft tissue disease, 48% had bone-only disease, and 7% had soft tissue only disease. Patients underwent three leukapheresis procedures 2 wk apart, with each procedure followed approximately 3 d later by an infusion of sipuleucel-t or control. Owing to the logistics of administration, while the median time from the first to the third infusion was 28 d, the range was d, and the dosing interval between infusions was 1 15 wk. Each dose of sipuleucel-t or placebo contained 40 million large cells expressing CD54 suspended in 250 ml lactated Ringer solution. Intravenous infusion over 60 min (without using cell filter) occurred after premedication with acetaminophen and an antihistamine, followed by observation for at least 30 min. With a 36.5-mo median follow-up, survival was significantly improved in the sipuleucel-t group (HR: 0.78; 95% CI, ; p = 0.03), with a median survival of 25.8 mo for sipuleucel-t compared with 21.7 mo for placebo an improvement of 4.1 mo, which recapitulates the data from prior studies. Moreover, 3-yr survival (31.7% vs 23.0%) also improved (Fig. 2). The initial separation of survival curves was observed approximately 6 mo after therapy. The benefit was observed consistently across subgroups based on age, PSA, lactate dehydrogenase, alkaline phosphatase, number of bone metastases, Gleason score, performance status, and pain. Approximately 55% of men in both groups received subsequent docetaxel after a median of mo, but sensitivity analyses did not suggest that the differences in the frequency or time to docetaxel could account for differences in outcomes. Moreover, the survival effect was observed despite crossover of the control group to the cryopreserved product, APC8015F. Notably, the median TTP was again similar (HR: 0.95; 95% CI, ; p = 0.63; 14.6 vs 14.4 wk) and has been attributed to delayed biologic activity and lack of recording of subsequent progression events following initial progression, although an overly sensitive composite TTP end point may be partly responsible. Confirmed PSA [(Fig._2)TD$FIG] Fig. 2 Survival for sipuleucel-t compared with controls in the IMPACT trial (A) overall and (B) without later docetaxel. Reproduced with permission from the New England Journal of Medicine [3].

4 642 EUROPEAN UROLOGY 61 (2012) [(Fig._3)TD$FIG] declines 50% were observed in only 8 of 311 patients (2.6%) with sipuleucel-t and in 2 of 153 patients (1.3%) with placebo. One patient in the sipuleucel-t group displayed an objective partial response. Based on these data, sipuleucel-t was approved by the US Food and Drug Administration on April 29, Integrated results of D9901, D9902A, and IMPACT evaluated the time to disease-related pain (TDRP), which favored sipuleucel-t (HR: 0.84 [95% CI, ]; p =0.24) [12]. Separation in the TDRP curves was seen at approximately 6 mo, and 39.3% of sipuleucel-t patients, compared with 18.9% of controls, were pain-free at 12 mo, which suggests delayed antitumor efficacy. Among controls, 165 of 249 patients (66.3%) received APC8015F after a median time from randomization of 5.2 mo (range: mo), and the time from objective disease progression to first infusion was 2.2 mo (range: mo) [13]. Crossover subjects exhibited improved postprogression survival relative to untreated controls (HR: 0.52 [95% CI, ]; p = ), with median survivals of 20.0 and 9.8 mo, respectively. The poor outcomes in untreated controls who did not cross over might be secondary to rapidly progressive disease that rendered these patients unsuitable for APC8015F. An analysis of postprogression survival revealed a positive impact of both docetaxel (HR: 0.86 [95% CI, ]; p= 0.40) and APC8015F (HR: 0.78 [95% CI, ]; p = 0.17). In placebo subjects who crossed over, CD54 upregulation and total nucleated cell counts were associated with survival ( p = 0.03 and p = 0.04, respectively). These data suggest that postprogression therapy may have extended survival in the control arm, possibly resulting in an underestimation of the survival benefit for sipuleucel-t. An increase in antibody titer >400 against PA2024 was observed in 66.2% of patients in the sipuleucel-t group and in 2.9% of patients in the placebo group and was associated with survival benefit ( p < 0.001) [3,14]. Antibody responses against PAP (28.5% vs1.4%) and T cell proliferation responses to both PA2024 (73% vs 12.1%) and PAP (27.3% vs 8%) were observed more commonly with sipuleucel-t compared with controls but did not attain statistical significance for association with survival. The caveat is that the trial was not formally powered for these retrospective associations, which remain hypothesis generating. Sipuleucel-T products exhibited increased APC and T cell activation associated cytokines [14]. The antigen-specific immune response may be hypothesized to result in a delayed survival benefit, although the precise mechanism of action requires validation (Fig. 3). An association of survival with larger doses of CD54- expressing APCs has not been demonstrated. Importantly, no clinical evidence of nonspecific immune stimulation (eg, enterocolitis, hepatitis, or dermatitis) was observed, although extensive evaluation of immune responses against antigens other than PAP or PA2024 has not been reported, and some nonspecific immune stimulation cannot be completely excluded Safety profile of sipuleucel-t Sipuleucel-T was associated with generally mild and manageable grade 1 and 2 infusional AEs in the IMPACT trial (Table 1). Common toxicities of all grades in the Fig. 3 Hypothesized mechanism of action of sipuleucel-t. PAP = prostatic acid phosphatase; PAP-GM-CSF = prostatic acid phosphatase granulocyte macrophage colony-stimulating factor. IMPACT trial included fever (29.3%), chills (54.1%), fatigue (39.1%), nausea (28.1%), and headache (16%). AEs of grade 3 or more within 1 d after infusion were reported in 6.8% of patients in the sipuleucel-t group and 1.8% of patients in the placebo group. Grade 3 events with sipuleucel-t were chills, fatigue, back pain, hypertension, hypokalemia, and muscular weakness, and the only grade 4 event was catheterassociated bacteremia. Only 3 of 338 patients (0.9%) in the sipuleucel-t group were unable to receive all three infusions because of AEs. Cerebrovascular events were reported for 8 of 338 patients (2.4%) in the sipuleucel-t group and 3 of 168 patients (1.8%) in the placebo group ( p = 1.00). A phase 4 registry study (PROCEED) with a target accrual of 1500 patients will better quantify the incidence of cerebrovascular events (NCT , Table 2) Optimal patient selection for sipuleucel-t and the development of tailored immunotherapy At this time, validated molecular biomarkers are unavailable to optimally select patients for sipuleucel-t. In the absence of such predictive markers, appropriate patient selection should reflect eligibility criteria for the IMPACT trial; specifically, men with minimally symptomatic or

5 EUROPEAN UROLOGY 61 (2012) Table 1 Adverse events reported for I10% of patients in either treatment arm of the IMPACT trial or for I5% of patients in either treatment arm if there was at least a twofold difference between arms. Reproduced with permission from the New England Journal of Medicine [3] Adverse Event a Sipuleucel-T N = 338 Placebo N = 168 n (%) n (%) Chills 183 (54.1) 21 (12.5) Fatigue 132 (39.1) 64 (38.1) Back Pain 116 (34.3) 61 (36.3) Pyrexia 99 (29.3) 23 (13.7) Nausea 95 (28.1) 35 (20.8) Arthralgia 70 (20.7) 40 (23.8) Citrate Toxicity b 68 (20.1) 34 (20.2) Vomiting 60 (17.8) 20 (11.9) Headache 54 (16.0) 8 (4.8) Anaemia 50 (14.8) 21 (12.5) Pain in Extremity 49 (14.5) 25 (14.9) Dizziness 49 (14.5) 16 (9.5) Paraesthesia b 45 (13.3) 26 (15.5) Constipation 45 (13.3) 24 (14.3) Musculoskeletal Pain 44 (13.0) 20 (11.9) Pain 44 (13.0) 12 (7.1) Paraesthesia Oral b 41 (12.1) 21 (12.5) Asthenia 37 (10.9) 13 (7.7) Diarrhoea 36 (10.7) 17 (10.1) Musculoskeletal Chest Pain 33 (9.8) 19 (11.3) Myalgia 33 (9.8) 8 (4.8) Influenza-like Illness 33 (9.8) 6 (3.6) Bone Pain 32 (9.5) 18 (10.7) Hypertension 25 (7.4) 5 (3.0) Anorexia 24 (7.1) 27 (16.1) Weight Decreased 20 (5.9) 18 (10.7) Hyperhidrosis 18 (5.3) 1 (0.6) Groin Pain 17 (5.0) 4 (2.4) Anxiety 13 (3.8) 14 (8.3) Contusion 9 (2.7) 9 (5.4) Flank pain 9 (2.7) 10 (6.0) Depression 8 (2.4) 11 (6.5) a Adverse events are listed by Medical Dictionary for Regulatory Activities (MedDRA) Version 11.0 preferred terms. The incidence of adverse events presented in bold font was 2-fold larger in the sipuleucel-t arm than in the placebo arm. Safety population was defined as all subjects undergoing at least one leukapheresis. b Citrate toxicity results from the leukapheresis procedure; paraesthesia and paraesthesia oral are likely symptoms of citrate toxicity. asymptomatic disease and no visceral metastases may be key. Sipuleucel-T does not yield early clinical benefits and should not be considered an alternative to chemotherapy or irradiation for patients with symptomatic disease. Rather, sipuleucel-t should be considered in minimally symptomatic or asymptomatic patients, probably before extensive use of corticosteroids and/or chemotherapy that could blunt the immunomodulatory effects of sipuleucel-t. Following sipuleucel-t, a rising PSA without symptomatic or radiographic objective progression is not necessarily an indication for institution of chemotherapy [15,16]. In the IMPACT trial, patients treated with chemotherapy at least 3 mo earlier were also eligible, and corticosteroids must have been stopped for at least 1 mo. Subsequent to the approval of sipuleucel-t, denosumab, a receptor activator of nuclear factor k (RANK) ligand antagonist, was added to the therapeutic arsenal after demonstrating a modest decline in skeletal events compared with zoledronic acid [17]. Preclinical evidence has demonstrated that activated T cells produce RANK ligand and that monocytes/macrophages and DCs express RANK, the receptor for RANK ligand. This raises the question of whether concomitant use of a RANK ligand inhibitor with sipuleucel-t could impair the immune response [18,19]. This issue will be studied in a prospective trial. Many patients with nonmetastatic disease who are treated eventually develop castration resistance. Recent data have shown that many of these men actually have asymptomatic metastatic disease that was undetected until a screening bone scan was performed for entry into a clinical trial. As sipuleucel-t is now an option for this population of patients, periodic imaging in men with apparent nonmetastatic castration-resistant PCa (CRPC) appears warranted to detect early clinical metastases [20] Development of sipuleucel-t in earlier settings of prostate cancer and in novel combinations and sequences It is intriguing that androgen-deprivation therapy (ADT) has been demonstrated to induce T cell infiltration of the prostate, although its clinical impact is unclear [21 24]. The Table 2 Ongoing or planned trials evaluating sipuleucel-t for prostate cancer Trial ID Setting Institution Phase Target accrual Primary end point NCT (PROCEED) Castration resistant, metastatic International Cerebrovascular events P-10 4 Castration sensitive, metastatic International Overall survival NCT Castration resistant, metastatic United States, multicenter NCT Not available Castration resistant, metastatic, previously treated with sipuleucel-t on NCT Castration resistant, metastatic, concurrent or sequential therapy with abiraterone acetate plus prednisone United States, multicenter United States, multicenter NCT (NeoACT) Neoadjuvant, preceding prostatectomy United States, multicenter CD54 upregulation in vaccine when manufactured with different concentrations of PA Immune response 2 Not available Not available 2 40 Immune response

6 644 EUROPEAN UROLOGY 61 (2012) sequence of immunotherapy preceding ADT appeared preliminarily optimal [25 27]. Interestingly, irradiation can upregulate some TAAs, MHC class I, Fas, and TLR4 agonists, while chemotherapy may deplete regulatory T cells and may enhance the activity of subsequent vaccination. Conversely, an immune response to initial vaccination may be associated with an augmented response to subsequent chemotherapy [28] Biochemically recurrent castration-sensitive disease PROTECT (Provenge Treatment and Early Cancer Treatment, NCT ), a randomized double-blind phase 3 trial (n = 176), investigated the efficacy of sipuleucel-t (after a brief 3- to 4-mo course of ADT) in biochemically recurrent nonmetastatic castration-sensitive disease [11]. The median time to biochemical failure was 18 mo for sipuleucel-t and 15.4 mo for control (HR: 0.936; p = 0.737). Sipuleucel-T patients displayed a 48% increase in PSA-doubling time following testosterone recovery (155 d compared with 105 d; p = 0.038). With only 16% of patients having developed distant metastasis, clinical outcomes were not statistically different (HR: 0.728; p = 0.421), and quality of life was comparable to controls [29]. T-cell proliferative and ELI- SPOT responses to PA2024 were sustained at a median of 22.6 mo and 67.3 mo in a subset. In another trial, sipuleucel-t favorably modulated PSA and induced immune responses when combined with bevacizumab (without ADT) in biochemically recurrent hormone-naive PCa [30] Ongoing, planned, or potential trials A phase 3 international trial is planned to evaluate the value of combining ADT with sipuleucel-t in metastatic castrationsensitive PCa (Table 2). An ongoing trial is evaluating sipuleucel-t as neoadjuvant therapy before radical prostatectomy for localized disease to assess the immune response in prostate tissue. Activity demonstrated in this extremely early setting may spawn larger controlled trials to consolidate the efficacy of local therapy. In this context, it may be relevant that an autologous tumor cell bacillus Calmette-Guérin based immunotherapeutic agent, OncoVAX, is approved in Europe after demonstrating improved outcomes as adjuvant therapy for resected stage II colon cancer. Combination or sequencing with the androgen-synthesis inhibitor abiraterone acetate is being developed, and the impact of corticosteroids on efficacy warrants study (Table 2) [31]. Additionally, evaluation in the biochemically progressive nonmetastatic CRPC setting may be warranted, given the frequent detection of metastatic disease on radiographic evaluation and median time to metastatic disease of approximately 2 yr in selected populations [20,32,33]. Combinations with concurrent chemotherapy may warrant caution given the decrement in outcomes with GVAX in combination with docetaxel, although different sequences of sipuleucel-t and chemotherapy may warrant evaluation [34] Sipuleucel-T in the context of need for cost-effective agents In June 2010, the US Centers for Medicare and Medicaid Services (CMS) launched a national coverage analysis [35,36]. Although by law, the CMS cannot make decisions based on price, the cost of a course of sipuleucel-t of approximately $93,000 for all three infusions was likely a factor. On June 30, 2011, the CMS decided that sipuleucel-t improves health outcomes for Medicare beneficiaries and was therefore reasonable and necessary for their treatment. Whether such a view will be taken by the European health authorities is unclear. Future drug development should prospectively incorporate formal cost-efficacy analyses. The generally high cost of most new cancer drugs, in conjunction with their modest benefits, warrants a close examination, especially in the current economic climate [37]. Concurrently, a more reasonable balance between incentivizing pharmaceutical companies to engage in expensive drug development and sustainable affordability of the product is also required. Clearly, an ongoing discourse is necessary at different levels to enable such a balance Emerging immunotherapeutic agents Novel immunotherapeutic agents continue to be studied in early trials, with promising preliminary results [38,39]. A double-blind randomized phase 2 trial of 122 patients with chemotherapy-naive, minimally symptomatic mcrpc, Gleason score 7, and no visceral metastasis compared an offthe-shelf poxvirus-based vaccine, PROSTVAC-VF TRICOM, to placebo [27,40]. Progression-free survival was similar in the two groups ( p = 0.56), but survival was superior (HR: 0.57; p = 0.006), with median survival of 25.1 and 16.6 mo, and 3-yr survival rates of 30% and 17% [41]. A DNA-based vaccine comprising plasmid DNA encoding PAP in combination with GM-CSF demonstrated antigen-specific T cell stimulation and slowing of PSA doubling [42]. The cytotoxic T lymphocyte associated antigen 4 (T-cell checkpoint) inhibiting fully human monoclonal antibody, ipilimumab, has extended survival in advanced melanoma and demonstrated clinical and PSA responses in mcrpc [43,44]. Based on these encouraging results, separate phase 3 clinical trials have been launched in chemotherapy-naive or postdocetaxel men with mcrpc. In these placebo-controlled trials, a metastatic site is irradiated before ipilimumab or placebo based on data supporting a role for irradiation to enhance the immune response [45,46]. However, the immune phenomena induced by ipilimumab (colitis, hypophysitis, hepatitis) warrant careful monitoring and patient selection. Programmed cell death-1 (PD-1) and its ligand PD-L1 constitute another T cell checkpoint axis whose inhibition may be associated with fewer toxicities [27]. While the naked anti-psma antibody has marginal antitumor activity, immunoconjugates of anti- PSMA monoclonal antibodies and radiopharmaceuticals or toxins appear safe and active [47]. Currently, separate phase 2 trials are evaluating the lutetium 177 labeled PSMA monoclonal antibody for metastatic or nonmetastatic CRPC Immune response criteria as end points for evaluating immunotherapy Given the difficulty of measuring clinical responses owing to delayed activity of immunotherapy, new immune-related

7 EUROPEAN UROLOGY 61 (2012) response criteria were defined to better capture the antitumor activity. Four distinct response patterns were identified to be associated with favorable survival: immediate response, durable stable disease, response after tumor burden increase, and response in the presence of new lesions [15]. The recommendations allow the assessment of tumor burden as a continuous variable considering index lesions and new lesions. Statistical models describing HRs as a function of time were recommended to account for the delayed separation of survival curves. The issue is compounded in the setting of metastatic PCa by the difficulty in measuring responses in, and the lack of validation of, PSA declines in the setting of biologic agents [16,48]. PSA doubling time and circulating tumor cell alterations may warrant study as intermediate end points [49,50] Emerging nonimmunotherapeutic agents for castrationresistant prostate cancer The role and further development of sipuleucel-t and other immunotherapeutic agents need to be considered in the context of new classes of emerging agents. Abiraterone acetate was recently approved in combination with prednisone in the setting of progressive disease following docetaxel [31]. Demonstration of a benefit in the chemotherapy-naive mcrpc setting might allow the earlier administration of abiraterone. However, given the current requirement for concurrent prednisone and the need to administer sipuleucel-t at least 4 wk after prednisone, the correct sequencing of sipuleucel-t and abiraterone acetate warrants study. Additionally, other androgen pathway targeting agents are being developed (eg, MDV3100) that do not necessarily require prednisone. Docetaxel prednisone is being used as the platform to develop combinations with biologic agents, for example, dasatinib, aflibercept, custirsen, and lenalidomide. Tasquinimod, an antiangiogenic and immune-modulating agent, is being developed as monotherapy in the chemotherapy-naive mcrpc population. 4. Conclusions The regulatory approval of sipuleucel-t for asymptomatic and minimally symptomatic mcrpc has ushered in the era of targeted immunotherapy for advanced malignancies. In addition to a panoply of other emerging immunotherapeutic agents, the autologous APC platform is being used to generate an immune response against relevant antigens in other malignancies, for example, human epidermal growth factor receptor 2 in breast and bladder cancer. Sipuleucel-T extends and provides an increment in survival in conjunction with a favorable toxicity profile. It is important to identify appropriate patients based on the populations studied in the clinical trials and to further investigate host and tumor variables to optimize patient selection. Additionally, the ongoing rational evaluation of sipuleucel-t in earlier stages of PCa might further expand its therapeutic indication. The combination and proper sequencing of sipuleucel-t with other newly approved agents (abiraterone acetate, cabazitaxel) and emerging agents (MDV3100, TAK-700, ipilimumab) must be explored to improve benefits. Author contributions: Guru Sonpavde had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Sonpavde. Acquisition of data: Sonpavde, Di Lorenzo, Higano, Kantoff, Madan, Shore. Analysis and interpretation of data: Sonpavde, Di Lorenzo, Higano, Kantoff, Madan, Shore. Drafting of the manuscript: Sonpavde. Critical revision of the manuscript for important intellectual content: Sonpavde, Di Lorenzo, Higano, Kantoff, Madan, Shore. Statistical analysis: Sonpavde, Di Lorenzo, Higano, Kantoff, Madan, Shore. Obtaining funding: None. Administrative, technical, or material support: Sonpavde, Di Lorenzo, Higano, Kantoff, Madan, Shore. Supervision: Sonpavde, Di Lorenzo, Higano, Kantoff, Madan, Shore. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Guru Sonpavde receives research support for his institution from Bellicum Pharmaceuticals and is on the speakers bureau or advisory boards for Dendreon, Centocor Biotech, Amgen, Novartis, and Sanofi-Aventis. Giuseppe Di Lorenzo receives research support from, and is on the advisory board for, Dendreon. Celestia S. Higano receives research support for her institution from Dendreon, Medivation, and Cougar Biotech and is on the advisory board for Dendreon, Medivation, and Amgen. Philip W. Kantoff is a consultant to Dendreon, Bellicum Pharmaceuticals, and BN- IT. Neal D. Shore receives research support from, and is on the advisory board for, Dendreon. Funding/Support and role of the sponsor: Dendreon Corporation sponsored the trials that are discussed in this review. Acknowledgment statement: Arjun Guru is acknowledged for assisting with the images. References [1] Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008;26: [2] de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised openlabel trial. Lancet 2010;376: [3] Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363: [4] Kusmartsev S, Vieweg J. Enhancing the efficacy of cancer vaccines in urologic oncology: new directions. 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