Nancy N. Chang

A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer

Purpose: This phase II open-label study evaluated the effect of concurrent or sequential administration of abiraterone acetate plus prednisone (AA + P) on sipuleucel-T manufacture and immune responses in metastatic castration-resistant prostate cancer (mCRPC) patients. Experimental Design: mCRPC patients received sipuleucel-T followed by AA + P 1 day (concurrent) or 10 weeks (sequential) after the first sipuleucel-T infusion. AA + P treatment continued for 26 weeks. The primary endpoint was cumulative antigen presenting cell (APC) activation, and secondary endpoints included cumulative APC number and total nucleated cell counts. Additional endpoints included in vivo peripheral immune responses to sipuleucel-T (T-cell responses, T-cell proliferation, humoral responses, and antigen spread) as well as safety. Results: Sixty-nine mCRPC patients were enrolled, with 35 and 34 patients randomized to the concurrent and sequential arms, respectively. Ex vivo APC activation was significantly greater at the second and third infusions compared with baseline in both arms (P < 0.05), indicative of an immunologic prime-boost effect. In both arms, sipuleucel-T product parameter profiles and peripheral immune responses were consistent with previously conducted sipuleucel-T phase III trials. Antigen spread was similarly observed in both arms and consistent with the other immunologic endpoints. Conclusions: These data suggest that sipuleucel-T can be successfully manufactured during concurrent administration of AA + P without blunting immunologic effects or altering immune parameters that correlate with sipuleucel-Ts clinical benefit. Combination of these agents was well tolerated, with no new safety signals emerging. Clin Cancer Res; 21(17); 3862–9. ©2015 AACR.

Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men with Hormone-Sensitive Biochemically Recurrent Prostate Cancer: A Phase II Randomized Trial

Purpose: STAND, a randomized, phase II, open-label trial (NCT01431391), assessed sequencing of sipuleucel-T (an autologous cellular immunotherapy) with androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC) patients at high risk for metastasis. Experimental Design: Men with BRPC following prostatectomy and/or radiotherapy, a PSA doubling time ≤12 months, and no metastasis were enrolled. Patients were randomized (34/arm) to sipuleucel-T followed by ADT (started 2 weeks after sipuleucel-T completion), or ADT followed by sipuleucel-T (started 12 weeks after ADT initiation); ADT continued for 12 months in both arms. The primary endpoint was PA2024-specific T-cell response [enzyme-linked immunospot (ELISPOT)] over time. Results: PA2024-specific ELISPOT responses over time were similar between groups, except at week 6, where responses were higher with sipuleucel-T→ADT versus ADT→sipuleucel-T (P = 0.013). PA2024-specific T-cell proliferation responses, averaged across time points, were approximately 2-fold higher with sipuleucel-T→ADT versus ADT→sipuleucel-T (P = 0.001). PA2024-specific cellular and humoral responses and prostatic acid phosphatase–specific humoral responses increased significantly versus baseline (P < 0.001) and were maintained for 24 months (both arms). Median time-to-PSA recurrence was similar between arms (21.8 vs. 22.6 months, P = 0.357). Development of a PA2024-specific humoral response correlated with prolonged time-to-PSA progression (HR, 0.22; 95% CI, 0.08–0.67; P = 0.007). Sipuleucel-T with ADT was generally well tolerated. Conclusions: Sipuleucel-T→ADT appears to induce greater antitumor immune responses than the reverse sequence. These results warrant further investigation to determine whether this sequence leads to improved clinical outcomes, as well as the independent contribution of ADT alone in terms of immune activation. Clin Cancer Res; 23(10); 2451–9. ©2016 AACR.

Immune response from STRIDE, a randomized, Phase II, open-label study of sipuleucel-T (sip-T) with concurrent vs sequential enzalutamide (enz) administration in metastatic castration-resistant prostate cancer (mCRPC)

Meeting abstracts P12-2 (STRIDE; [NCT01981122][1]) is an ongoing, randomized, Phase II, open-label study evaluating concurrent vs sequential administration of the androgen receptor inhibitor, enz, with the autologous cellular immunotherapy, sip-T. The primary aim of this study is to determine if

Antigen-Specific CD8 Lytic Phenotype Induced by Sipuleucel-T in Hormone-Sensitive or Castration-Resistant Prostate Cancer and Association with Overall Survival

Purpose: Sipuleucel-T is FDA approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) based on the IMPACT trial showing a 4.1-month benefit in median overall survival (OS) for patients receiving sipuleucel-T versus control. Although efficacy of sipuleucel-T is well established, its mechanism remains incompletely understood. Patients and Methods: Patient samples from three sipuleucel-T trials were assessed for peripheral cellular immune responses to the immunogen PA2024 and the target antigen prostatic acid phosphatase (PAP). PAP- and PA2024-specific proliferative and cytolytic responses were characterized to delineate sipuleucel-T–induced immune responses. To quantify potential cytotoxic T lymphocyte (CTL) activity, cell-surface CD107a expression on PAP- or PA2024-specific CD8+ T cells was measured in sipuleucel-T–treated patient and healthy volunteer samples. Results: Increased PA2024-specific CD4+ (P = 0.030) and CD8+ (P = 0.052) T-cell proliferation from baseline to week 6 was observed (N = 14) post–sipuleucel-T, with greater magnitude of PA2024-specific responses compared with PAP. PAP- and PA2024-CTL activity (CD107a positivity) significantly increased at weeks 6 and 26 after sipuleucel-T treatment (P < 0.0001; N = 22). At 26 weeks post–sipuleucel-T, OS correlated with the magnitude of PAP (Pearson R, 0.52; P = 0.013) or PA2024 (Pearson R, 0.67; P = 0.0006) CTL activity. Higher PA2024-CTL activity at week 26 was significantly associated with longer OS using tertile analysis (P = 0.0005; N = 22), with PA2024 responses correlating with PAP responses at week 26 (R = 0.90; P = 1.53E−08). Conclusions: This study is the first to report PAP-specific CD8+ T-cell responses elicited by sipuleucel-T treatment. Increased and persistent potential PA2024-specific CTL activity correlated with PAP-specific CTL activity and associated with improved OS following sipuleucel-T treatment. Clin Cancer Res; 24(19); 4662–71. ©2018 AACR.

PD24-12 OVERALL SURVIVAL ANALYSIS OF AFRICAN AMERICAN AND CAUCASIAN PATIENTS RECEIVING SIPULEUCEL-T: PRELIMINARY DATA FROM THE PROCEED REGISTRY

INTRODUCTION AND OBJECTIVES: The paradigm of first testing systemic treatments in advanced disease followed by development in earlier disease states and finally large-scale trials evaluating whether the approach, in combination with local therapy, can prevent or delay the time-to-event measures of disease progression or death in patients with 00high-risk00 tumors is no longer practical now that 6 lifeprolonging systemic therapies in metastatic castration-resistant prostate cancer are available. Our objective was to evaluate a multimodal treatment platform and a short term endpoint of treatment efficacy as a new strategy to rapidly evaluate and prioritize regimens for large-scale phase 3 testing. METHODS: We conducted a pilot study of twenty men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis. All sites of disease were treated using a multimodal approach that included androgen deprivation (ADT), radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease and/or the primary site. ADT was discontinued in responding patients. Outcomes of each treatment were assessed sequentially. The primary endpoint of 00no evidence of disease00 (NED) was defined by an undetectable PSA (<0.05 ng/mL) with noncastrate levels of testosterone at 20 months (>150 ng/dL). RESULTS: Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after ADT alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval 3-38%) achieved the primary endpoint, which persisted for 5, 6, 27+, and 46+ months. All patients meeting the primary endpoint had been classified with M1b disease at presentation. CONCLUSIONS: Treatment directed at all sites can eliminate detectable disease in selected patients with newly diagnosed metastatic prostate cancer. A multimodal treatment strategy inclusive of the NED endpoint for patients who present with disease that is beyond the limits of curability by any single modality should be considered to enable the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease.

Changing characteristics of patients treated with sipuleucel-T (sip-T) over time: Real-world experience from the PROCEED registry.

320 Background: Sip-T is an autologous cellular immunotherapy approved by the FDA for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. PROCEED (NCT01306890) is a phase 4 registry evaluating men receiving sip-T therapy in the US. Patient characteristics and treatment trends were assessed from 2011 to 2013, when several agents with an overall survival benefit became commercially available. Methods: For patients enrolled from 2011 to 2013, baseline patient and disease characteristics at the first sip-T infusion, trends in prior therapy, and pre–sip-T baseline prostate-specific antigen (PSA) levels were examined year over year. Results: From 2011 to 2013, 1902 patients were enrolled and received ≥ 1 sip-T infusion: 2011, n = 145; 2012, n = 967; 2013, n = 790. During this time period, enrollment of African American men nearly doubled from 6.9% to 13.4%, and central venous catheter use to facilitate sip-T infusion decreased (from 53.8% to 44.1%). Median bas...