Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials

Prevalence of metastatic castration-resistant prostate cancer (mCRPC) is likely to increase over time as a growing number of patients survive long enough that their prostate cancer progresses to mCRPC because of both treatment advances and improvements in lifestyle behaviors (1). The primary goal of cancer treatment is to reduce mortality, given mCRPC exhibits an all-cause mortality rate of approximately 55% annually (2). Management of prostate cancer evolves as both treatment and detection options expand and improve. Treatment paradigms also evolve with an increasing interest in assessing agent sequencing and concurrent use, a possible source of risk given potential interactions among the different mechanisms of action.

Until 2010, when sipuleucel-T, the first cancer immunotherapy, was approved for use in individuals with asymptomatic or minimally symptomatic mCRPC, the only available treatment in this setting at the time was docetaxel. Sipuleucel-T is an autologous immunotherapy that has been shown to induce long-term, antigen-specific immune memory, resulting in persistent changes to B-cell repertoire (2, 3). Sipuleucel-T treatment induces the patient's immune system to recognize the prostate cancer antigen, prostatic acid phosphatase (PAP), through an ex vivo process of leukapheresis and cell culture, ending with a subsequent reinfusion back into the same patient [refs. 2–5, and see Provenge Prescribing Information; (cited August 25, 2022); http://www.provengehcp.com/Portals/5/Provenge-PI.pdf]. Three infusions are performed; the interval between them typically ranges between 7 and 14 days but is dependent on the type of access and patient factors. The cell culturing results in antigen-presenting cell (APC) activation, which is assessed before reinfusion by measuring CD54 upregulation (4). CD54, also known as ICAM-1, is a cell surface molecule that is pivotal in establishing the immune synapse between APC and T cells and is also a costimulatory molecule in its own right (4). This measure of potency correlates with overall survival (OS; refs. 5, 6).

Observed median OS in patients who received sipuleucel-T for mCRPC was prolonged in patients who received treatment more recently compared with those who were treated in the pivotal trial. Patients who received sipuleucel-T in the pivotal trial for sipuleucel-T (IMPACT; NCT00065442; 2003–2009) had a median OS of 25.8 months (7, 8). In a subsequent trial, Provenge Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED; NCT01306890), which was conducted between 2011 and 2017, patients who received sipuleucel-T had a median OS of 30.7 months (9). Two claims analyses using the Medicare Fee-for-Service 100% research identifiable dataset observed a median OS of between 30 and 35 months in male beneficiaries who had ever received sipuleucel-T and started treatment for mCRPC in 2014 or 2015 (10, 11).

Soon after the approval of sipuleucel-T, 2 additional treatments for prostate cancer became available for patients with mCRPC in the United States, the oral androgen receptor–targeting agents (ARTA) abiraterone acetate + prednisone (12, 13) and enzalutamide (14). Abiraterone acetate interferes with the production of extragonadal and intratumoral testosterone through its actions as a CYP17 inhibitor and is administered with prednisone. Enzalutamide has multiple cellular mechanisms, including preventing testosterone from binding to the androgen receptor (AR), thus inhibiting the androgen signaling pathway and also potentially inhibiting T-cell–mediated immune responses.

Initially, there was concern that the ARTAs might impact immune function through inhibiting testosterone activity (15–22). To examine whether their use interfered with sipuleucel-T promoting antitumor responses against prostate cancer, 2 studies assessed how immune activation and OS were affected by administration of sipuleucel-T and an ARTA administered sequentially (ARTA then sipuleucel-T) or concomitantly (ARTA + sipuleucel-T) in patients with mCRPC. The STAMP trial (NCT01487863) examined abiraterone acetate plus prednisone use, and the STRIDE trial (NCT01981122) examined enzalutamide use. Results of the primary analyses from both STAMP (23) and STRIDE have been described in part previously. For further information on study conduct and analysis, see the protocol and statistical analysis plan posted on ClinicalTrials.gov.

These studies, however, also offer insights to inform contemporary questions about treatment sequencing, especially as OS was included as a secondary objective in each trial. Herein, we performed post hoc analyses of the survival data by querying the National Death Index (NDI) to update the status of patients who were censored in the original analyses. We also summarize other outcomes across the 2 studies to provide information pertinent to contemporary questions about combination treatment protocols. Last, we provide data for STRIDE to complement the data previously published for STAMP (23).

Both phase II, multicenter, randomized, open-label studies included in this post hoc analysis were conducted in accordance with applicable regulations of the U.S. FDA and the Good Clinical Practice guidelines of the International Conference on Harmonization. Each was approved by the Institutional Review Board at each study center.

Patient information remained deidentified when the NDI was queried.

Patients ≥ 18 years with mCRPC that was histologically confirmed on the basis of prostate biopsy or radical prostatectomy were included in the studies whether they met the following criteria: metastatic status (imaging done up to 56 days before enrollment) confirmed on the basis of bone and/or lymph node metastasis; CRPC with castrate levels of testosterone of <50 ng/dL; serum PSA 2.0 ng/mL or higher; and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1. Patients in each study provided informed written consent before participation.

Patients were excluded from each study whether they had known lung, liver, or brain metastases, malignant pleural effusions, or malignant ascites; previous pathologic fractures or spinal cord compression; prior treatment with sipuleucel-T, abiraterone acetate plus prednisone, ipilimumab, denosumab, opioid analgesics, or any prior chemotherapy.

The STAMP study was a randomized, open-label, phase II trial of sipuleucel-T with concurrent versus sequential administration of abiraterone acetate plus prednisone in patients with mCRPC. The study schema presented in Fig. 1A describes scheduled dosing for STAMP. Blinding was not considered relevant to the original study design. For further information on study conduct and analysis, see the description on ClinicalTrials.gov.

Planned enrollment for this study was 60 patients (randomized 1:1 to each arm). This study enrolled 69 patients: 35 patients were randomized to the concurrent arm and 34 patients were randomized to the sequential arm. Patients received 1,000 mg of abiraterone acetate every day and 5 mg of prednisone twice daily for 26 weeks. The first subject was registered on January 16, 2012, and the last subject visit occurred on February 12, 2016. Supplementary Table S1 shows the representativeness of study participants.

The STRIDE study was a randomized, open-label, phase II study of sipuleucel-T with concurrent versus sequential administration of enzalutamide in patients with mCRPC with tumors that were at least 50% adenocarcinoma. The study schema presented in Fig. 1B describes enzalutamide dosing for STRIDE. Treatment of patients in STRIDE is broadly similar to that described previously for STAMP, including production of sipuleucel-T, except that patients received enzalutamide (160 mg every day) for up to 52 weeks. Further enzalutamide drug supply was not provided by the sponsor. Blinding was not considered relevant to the original study design. For further information on study conduct and analysis, see the protocol and statistical analysis plan posted on ClinicalTrials.govClinicalTrials.gov.

The planned enrollment for this study was 100 patients (randomized 1:1 to each arm). Because of a corporate reorganization, enrollment was halted after 52 patients were enrolled: 25 patients were randomized to the concurrent arm and 27 patients were randomized to the sequential arm. The first subject was registered on October 11, 2013, and the last subject visit occurred on July 17, 2017.

To update the OS information for these studies, additional data about deaths were acquired through querying the NDI database. The NDI contains data regarding the deaths of U.S. citizens, including causes of death when available. Compilation of data for the NDI experiences official reporting lags, and as a result, at the time of this extraction, data were considered complete only through the end of 2018 [NDI: NCHS Fact Sheet (cited 2022 Aug 25) https://www.cdc.gov/nchs/data/factsheets/factsheet_ndi.htm].

Querying was performed by applying to the U.S. Centers for Disease Control and Prevention for the data and providing known patient identifiers to determine whether there was an associated date of death. The most accurate matching is achieved using a patient's name and social security number, which together increase the likelihood of identifying a unique individual; however, given these were trial patients, Dendreon did not have the social security numbers and provided first and last names along with month and year of birth. Consequently, there is a small possibility of mismatches because it is possible that multiple individuals with the same first and last name as well as the same month and year of birth and could have been matched under these criteria.

For this analysis, the datasets for the 2 studies were updated with death information about any study subject who could be identified in the NDI dataset, with the data extraction being performed in 2020. This extraction included available death data through early 2020.

Patients in either study who were either alive or lost to follow-up were matched with individuals in the NDI dataset based on patient characteristics. When a subject could not be matched with a person in the NDI, the last known outcome was used for these analyses. The resultant dataset had an increase in the known outcomes (death) and a reciprocal decrease in the amount of censoring (Supplementary Tables S2 and S3).

Immunologic endpoints including APC activation and in vivo measures of PA2024 (a recombinant fusion protein composed of PAP linked to granulocyte-macrophage colony-stimulating factor) and PAP-specific peripheral immune responses (e.g., T-cell responses, T-cell proliferation, and humoral responses) were collected in both studies. The data from STAMP were reported previously (23). The same methodologies were applied to STRIDE, and the results are published here for the first time.

APC activation is one of the ex vivo immunologic product parameters that is measured for every sipuleucel-T lot produced to determine whether it is released for patient infusion. It is considered a measure of potency given that the levels of APC activation are correlated with OS (5). APC activation is defined as the increase in surface CD54 expression on APCs, measured as the upregulation ratio of the average number of molecules on postculture versus preculture cells (4).

All randomized patients who had at least one leukapheresis were included in the safety analyses for each trial. Safety assessments were performed every 2 weeks. Adverse events (AEs) were summarized and listed on the basis of the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and system organ class. These included AEs that occurred within 1 day of an infusion.

OS was analyzed using Kaplan–Meier methodology. Median OS with 95% CIs was calculated for the study outcomes alone as well as for the outcomes updated with the updated NDI data. Median OS, original study versus NDI update, was 34.0 (95% CI, 24.4 to not estimable) versus 33.3 (24.1–40.7) for STAMP and 32.5 (26.0 to not estimable) versus 32.5 (26.0–45.1) months for STRIDE. The NDI-updated median OS remained consistent with that of the original studies [HR, 0.727; (0.458–1.155); P = 0.177, with STRIDE as the reference arm]. Median OS did not differ between concurrent and sequential arms in either study, regardless of combination agent [NDI update: HR, 0.963 (0.639–1.453); P = 0.845, with the concurrent arm as the reference arm].

OS was calculated both for the study time period alone as well as for the study period plus NDI updates. These post hoc survival analyses were performed by treatment group and study, by each study overall, and by treatment group across the 2 studies.

Given that previous analyses have indicated that certain variables are significant predictors of OS (8, 24), these data were analyzed accordingly and are presented in the supplemental materials. Significant variables included median baseline PSA level above/below median (Supplementary Table S4; Supplementary Fig. S1), baseline PSA level by quartiles (Supplementary Table S4; Supplementary Fig. S2), and baseline alkaline phosphatase level (Supplementary Table S5; Supplementary Fig. S3).

Kaplan–Meier survival curves were generated for OS assessment based on unadjusted analyses; statistical significance of the relationship was tested using log-rank tests. Adjusted OS was assessed using Cox proportional hazards regression models as implemented in SAS 9.4 and SAS/STAT 15.1 procedures. Summary statistics were used to describe patient characteristics as appropriate by type of variable.

The integrated dataset for these analyses comes from 2 clinical studies and a public domain resource (NDI). The data that support the findings of this study are available upon reasonable request. Please contact either the corresponding author (E.S. Antonarakis) or the sponsor (Dendreon). The latter can be reached via its Medical Information group ([email protected]).

Table 1 presents baseline patient characteristics across the 2 studies. The populations were broadly similar, but some differences were noted: 67% of STRIDE patients and 55% of STAMP patients had a Gleason sum of 8 or higher; and median PSA levels at baseline were numerically higher in STAMP than in STRIDE (25.44 vs. 10.8 ng/mL). Prior treatments are summarized in Supplementary Table S2.

In STAMP, the duration of protocol-directed abiraterone exposure was a median (min–max) of 182 (1–189) days in the concurrent arm (n = 35) and 179.5 (31–187) days in the sequential arm (n = 34). Forty-2 patients received abiraterone beyond the protocol-specified duration, with a median duration of exposure of 269 days in the concurrent arm (n = 23) and 700 days in the sequential arm (n = 19).

In STRIDE, the duration of protocol-directed enzalutamide exposure was a median (min–max) of 362 (78–392) days in the concurrent arm (n = 25) and 285 (78–406) days in the sequential arm (n = 27). Twenty-four patients received enzalutamide beyond the protocol-specified duration, with a median duration of exposure of 732 days in the concurrent arm (n = 10) and 281 days in the sequential arm (n = 14).

At the end of study, 45% of STAMP and 42% of STRIDE patients were censored as of the final analyses (Supplementary Table S3). Querying the NDI dataset in 2020 and updating patient status reduced the amount of censoring in the survival analyses of these studies to 14.3% in STAMP and 29% in STRIDE, respectively (Supplementary Table S3).

Figure 2 presents the post hoc Kaplan–Meier estimates of OS by study, by treatment arm, and overall incorporating the NDI updates. Table 2 presents the median OS with 95% CIs as well as the HRs; median follow-up for the on-study portion is also provided. No notable differences were observed between sequential and concurrent treatment both within studies and across the 2 studies combined (Table 2; Fig. 2).

Furthermore, this updated dataset was analyzed to examine the impact of baseline PSA and alkaline phosphatase (Supplementary Table S5; Supplementary Fig. S1). Analyses by treatment group across studies indicated a survival benefit when treatment was started in patients with lower PSA levels, regardless of whether examined by median baseline PSA or by PSA quartiles. There was also an improved survival benefit in patients with lower baseline alkaline phosphatase levels (Supplementary Table S5; Supplementary Fig. S2).

In both studies, levels of APC activation, a measure of sipuleucel-T potency, were higher for the second and third infusion lots compared with the first infusion lot, suggesting an immunologic prime-boost effect subsequent to initial sipuleucel-T exposure (Fig. 3).

Both STAMP and STRIDE also measured cellular and humoral responses. The data for STAMP were presented previously (Fig. 2 in ref. 23). The respective data for STRIDE are presented in Supplementary Fig. S3. Humoral responses (IgG + IgM antibody titers) to PA2024 and PAP were significantly higher at all timepoints from week 4 versus baseline. Furthermore, the responses in STRIDE were similar between concurrent and sequential arms, suggesting that adding enzalutamide did not impact the mechanism of action of sipuleucel-T (25).

The subject incidence AEs were similar regardless of whether patients received concurrent or sequential dosing and between studies, after accounting for the respective uses of abiraterone acetate plus prednisone and enzalutamide (Table 3). Nearly all patients in each study reported AEs. Sixty-five percent of patients in STAMP and 50% of those in STRIDE reported AEs within 1 day after sipuleucel-T infusion that were consistent with an infusion reaction. In STAMP, these included chills, back pain, fatigue, pyrexia, influenza-like illness, pain, muscle spasms, and nausea. In STRIDE, these included chills, myalgia, dizziness, fatigue, headache, hypotension, nausea, and tachycardia. In general, the safety data reported in the 2 studies are consistent with the prescribing information.

The increasing availability of novel agents to treat cancer raises questions about whether and how they can be combined to increase the possibility of achieving the best outcome for patients, including patients with prostate cancer. This question arose when the ARTAs abiraterone acetate and enzalutamide were approved for use in mCRPC after the approval of sipuleucel-T. Two studies (STAMP and STRIDE) analyzed the impact of combining these agents, administered either concurrently or sequentially, with sipuleucel-T on the immune response and OS in patients with mCRPC. Use of either ARTA did not appear to compromise sipuleucel-T outcomes, either at the cellular level or with respect to OS. Furthermore, no new adverse safety signals emerged.

Approximately 45% of patients in each study, however, had to be censored from the original OS analyses, and thus the upper bounds of the 95% CIs could not be estimated. To help inform physicians seeking data about the ability to combine these agents to treat prostate cancer, we sought to update the survival outcomes by getting the current (as of early 2020) status of patients who had been enrolled in the trials by querying the NDI. This updated analysis improved the precision of median OS estimates for the patients treated in these studies, although median OS itself remained relatively consistent regardless of whether the comparison was between treatment arms or between the 2 studies. As observed previously, regardless of agent, OS was better in patients with lower baseline PSA and lower alkaline phosphatase levels, suggesting that superior antitumor activity might be seen with lower disease burden. In addition, given that only STAMP had been published previously (23), data from STRIDE are included here to provide context for the survival results and are broadly similar to those observed in STAMP. These includes measure of APC activation, which has been demonstrated to be correlated with OS (4, 5) and safety data. In summary, the analyses from both STAMP and STRIDE suggest that concurrent or sequential administration of either ARTA results in a robust immune response and a similar median OS response (Figs. 2 and 3; Table 2).

These median OS outcomes were consistent across treatment arms and agent received, both within studies and between studies, with a median OS for all patients of 32.5 months. This estimate is consistent with estimates of median OS reported in other trials with sipuleucel-T. PROCEED, a large registry of patients with mCRPC who received sipuleucel-T after FDA approval between 2011 and 2017 and who also received a variety of subsequent agents (9), reported an estimated median OS of 30.7 months. Furthermore, it is consistent with median OS estimates of 30.4 and 35.2 months reported by previous Medicare claims analyses based on patients who started treatment with sipuleucel-T and an ARTA in similar time frames (2014 in both, or 2015 in Hafron alone; refs. 10, 11). The consistency in the duration of median OS across these different studies may arise from the broad similarity in mechanisms of action of the 2 ARTAs and that neither agent appears to interfere with the activity of sipuleucel-T nor result in any additive toxicity.

These data show that sipuleucel-T can be appropriately combined with either abiraterone acetate plus prednisone or enzalutamide without compromising product parameters or efficacy. In the era of early augmented hormonal therapy for metastatic hormone-sensitive prostate cancer [e.g., androgen-deprivation therapy (ADT) + abiraterone acetate + prednisone or enzalutamide upfront, or ADT + enzalutamide upfront], these data from STAMP/STRIDE suggest that adding sipuleucel-T at the time of early CRPC onset could be safe and effective. In other words, the addition of sipuleucel-T in such patients and continuation of ADT + abiraterone acetate plus prednisone or enzalutamide despite biochemical evidence of CRPC would be a reasonable strategy.

These analyses, however, should be considered in context. Using the NDI provides additional information about the long-term outcomes of patients enrolled in these studies. However, there is some possibility for error identifying and matching patients, as this process was based on a limited set of patient-identifying parameters and demographic characteristics. Furthermore, data about treatments received after the close of each study are unavailable. As part of these analyses, data from the 2 studies were pooled. Although the studies share similar design structures, sequencing patterns, follow-up periods, and population characteristics, there may be heterogeneity within the treatment groups that requires exercising care in interpreting any of these findings. Given the small sample size in both studies, caution should be used in interpreting the results. These trials were not powered to evaluate the clinical or PSA-modulating effects of concurrent or sequential sipuleucel-T, either within studies or across studies. These studies included only those patients who met the labeled indication for sipuleucel-T, asymptomatic, or minimally symptomatic mCRPC. In addition, the patient sample included in the STAMP and STRIDE studies was not diverse; however, in the PROCEED registry, sipuleucel-T was shown to be associated with approximately a 9.5-month OS benefit in African American men compared with white men (26). The STAMP and STRIDE studies focused on how administration of abiraterone acetate plus prednisone and enzalutamide could impact the ability to mount an immunologic response to sipuleucel-T treatment. Therefore, comparisons in this study were focused on the relative timing of the treatments and did not include abiraterone acetate plus prednisone or enzalutamide as a comparator arm.

Despite these potential limitations, the study findings provide insight into treatment approaches for prostate cancer, and particularly advanced prostate cancer in the modern era with multiple available choices for mCRPC management. Newer trials have examined the impact of administering sipuleucel-T along with other agents. For example, one recently published randomized, open-label, phase II multicenter trial showed longer median progression-free survival (39 vs. 12 weeks; HR, 0.32; 95% CI, 0.14–0.76) and OS (not reached vs. 2.6 years; HR, 0.32; 95% CI, 0.08–1.23) in men receiving sipuleucel-T and radium-223 compared with those receiving only sipuleucel-T (27). Additional research to study sipuleucel-T use in combination with newer-generation agents is warranted.

In summary, updating survival information from 2 clinical trials with data from the NDI demonstrated that the median OS outcomes were robust. The 2 studies support the concept that combining treatments for mCRPC is feasible and that administering ARTAs with sipuleucel-T yielded a median OS of approximately 33 months, regardless of whether administered sequentially or concurrently. No new safety signals were seen.

E.S. Antonarakis reports grants and personal fees from Dendreon during the conduct of the study; grants and personal fees from Janssen, Sanofi, Bayer, Bristol Myers Squibb, Curium, Merck, Pfizer, AstraZeneca, Clovis, and Constellation, personal fees from Astellas, Amgen, Blue Earth, Exact Sciences, Invitae, and Eli Lilly, and grants from Novartis and Celgene outside the submitted work; and is the co-inventor of a patented biomarker technology licensed to Qiagen. S.K. Subudhi reports other support from Dendreon, Janssen, and Pfizer outside the submitted work. C. Pieczonka reports grants, personal fees, and nonfinancial support from Dendreon during the conduct of the study, as well as grants and personal fees from AstraZeneca, Bayer, Janssen, Pfizer, Merck, and Eli Lilly, grants from Veru, and personal fees from Blue Earth and Sankyo Daiichi outside the submitted work. L. Karsh reports personal fees and other support from Bayer, AstraZeneca, Pfizer, Janssen, Ferring, AbbVie, Myovant, Bristol Myers Squibb, and Dendreon outside the submitted work. D.I. Quinn reports personal fees from Astellas, Bayer, Merck, Pfizer, and AbbVie during the conduct of the study. J. Hafron reports grants and personal fees from Astellas Pharma Inc., Bayer, Dendreon Pharmaceuticals LLC, Merck & Co. Inc., Myriad Genetics, Myovant Sciences, Pfizer, and Tolmar Pharmaceuticals; personal fees from Amgen, Inc., Blue Earth Diagnostics, Eli Lilly and Company, Janssen Biotech Inc., Lantheus, and Procept-Biorobotic; and grants from Lipella Pharmaceuticals and miR Scientific Inc. outside the submitted work. H.M. Wilfehrt reports other support from Dendreon Pharmaceuticals during the conduct of the study and other support from Dendreon Pharmaceuticals outside the submitted work. N.A. Sheikh reports personal fees from Dendreon Pharmaceuticals during the conduct of the study. N.D. Shore reports nonfinancial support from Dendreon, Bayer, Astellas, AbbVie, Allessa, BMS, Ferring, Janssen, Merck, Myovant, Pfizer, AstraZeneca, Sanofi, and Tolmar during the conduct of the study. D.P. Petrylak reports grants from Ada Cap (Advanced Accelerator Applications), Agensys Inc., Arvinas, Astellas, AstraZeneca, Bayer, BioXcel Therapeutics, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo Company Limited, Eisai, Eli Lilly, Endocyte, Ferring, Genentech, Gilead Sciences, Innocrin, MedImmune, Medivation, Merck, Mirati, Novartis, Pfizer, Progenics, Replimune, Roche, Sanofi Aventis, and Seattle Genetics and personal fees from Ada Cap (Advanced Accelerator Applications), Amgen, Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Eli Lilly, Exelixis, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Ipsen, Janssen, Merck & Company Inc., Mirati, Monopteros, Pfizer, Pharmacyclics, Regeneron, Roche, Sanofi Aventis Pharmaceuticals, Seattle Genetics, and Urogen during the conduct of the study. No disclosures were reported by the other authors.

E.S. Antonarakis: Investigation, writing–original draft, project administration, writing–review and editing. S.K. Subudhi: Investigation, writing–review and editing. C.M. Pieczonka: Investigation, project administration, writing–review and editing. L.I. Karsh: Investigation, project administration, writing–review and editing. D.I. Quinn: Investigation, writing–review and editing. J.M. Hafron: Investigation, writing–review and editing. H.M. Wilfehrt: Visualization, writing–original draft, writing–review and editing. M. Harmon: Conceptualization, data curation, formal analysis, validation, visualization, methodology, writing–original draft, writing–review and editing. N.A. Sheikh: Resources, formal analysis, supervision, funding acquisition, investigation, methodology, project administration, writing–review and editing. N.D. Shore: Investigation, project administration, writing–review and editing. D.P. Petrylak: Investigation, project administration, writing–review and editing.

The authors thank the patients and investigators who participated in the original studies, STAMP and STRIDE. The authors also thank Ishveen Chopra, PhD, and Esther Tazartes, MS, of the Global Outcomes Group for providing assistance in developing the manuscript and finalizing it for submission. The authors also thank Tuyen Vu, M.S., Scott Flanders, PhD, and other former Dendreon staff for their contributions to the individual studies and to this current analysis. Dendreon Pharmaceuticals funded the original STAMP and STRIDE studies as well as the work performed to develop these post hoc analyses. Dendreon also paid for any fees related to the publication of this manuscript, including open access fees.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.