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.

[1]  C. Redfern,et al.  A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer , 2015, Clinical Cancer Research.

[2]  P. Kantoff,et al.  Humoral Immune Response against Nontargeted Tumor Antigens after Treatment with Sipuleucel-T and Its Association with Improved Clinical Outcome , 2015, Clinical Cancer Research.

[3]  P. Carroll,et al.  Activated Lymphocyte Recruitment Into the Tumor Microenvironment Following Preoperative Sipuleucel-T for Localized Prostate Cancer , 2014, Journal of the National Cancer Institute.

[4]  P. Kantoff,et al.  Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. , 2013, Urology.

[5]  J. Lang,et al.  Current controversies in the management of biochemical failure in prostate cancer. , 2012, Clinical advances in hematology & oncology : H&O.

[6]  P. Kantoff,et al.  Sipuleucel-T immune parameters correlate with survival: an analysis of the randomized phase 3 clinical trials in men with castration-resistant prostate cancer , 2012, Cancer Immunology, Immunotherapy.

[7]  C. Drake,et al.  Combining immunological and androgen-directed approaches: an emerging concept in prostate cancer immunotherapy , 2012, Current opinion in oncology.

[8]  B. Trock,et al.  The natural history of metastatic progression in men with prostate‐specific antigen recurrence after radical prostatectomy: long‐term follow‐up , 2012, BJU international.

[9]  D. Brizel,et al.  National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology , 2012 .

[10]  C. Drake,et al.  Immunotherapy for Prostate Cancer: Recent Advances, Lessons Learned, and Areas for Further Research , 2011, Clinical Cancer Research.

[11]  P. Schellhammer,et al.  Randomized Trial of Autologous Cellular Immunotherapy with Sipuleucel-T in Androgen-Dependent Prostate Cancer , 2011, Clinical Cancer Research.

[12]  C. Mcmahan,et al.  Prostatic acid phosphatase expression in human tissues. , 2010, International journal of clinical and experimental pathology.

[13]  C. Drake.  Prostate cancer as a model for tumour immunotherapy , 2010, Nature Reviews Immunology.

[14]  P. Kantoff,et al.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. , 2010, The New England journal of medicine.

[15]  D. McNeel,et al.  Prostate cancer patients on androgen deprivation therapy develop persistent changes in adaptive immune responses. , 2010, Human immunology.

[16]  A. Mes-Masson,et al.  Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients. , 2009, Journal of immunological methods.

[17]  B. Trock,et al.  The natural history of metastatic progression in men with PSA-recurrent prostate cancer after radical prostatectomy: 25-year follow-up. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Andrew N. Gray,et al.  Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization , 2009, The Prostate.

[19]  S. Steinberg,et al.  Analysis of Overall Survival in Patients with Nonmetastatic Castration-Resistant Prostate Cancer Treated with Vaccine, Nilutamide, and Combination Therapy , 2008, Clinical Cancer Research.

[20]  J. Aragon-Ching,et al.  Impact of androgen-deprivation therapy on the immune system: implications for combination therapy of prostate cancer. , 2007, Frontiers in bioscience : a journal and virtual library.

[21]  Robert D. Schreiber,et al.  Interferons, immunity and cancer immunoediting , 2006, Nature Reviews Immunology.

[22]  Paul Schellhammer,et al.  Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. , 2006, International journal of radiation oncology, biology, physics.

[23]  T. Heng,et al.  Activation of Thymic Regeneration in Mice and Humans following Androgen Blockade , 2005, The Journal of Immunology.

[24]  Alan W Partin,et al.  Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. , 2005, JAMA.

[25]  C. Drake,et al.  Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. , 2005, Cancer cell.

[26]  B. Leibovich,et al.  Augmentation of T Cell Levels and Responses Induced by Androgen Deprivation1 , 2004, The Journal of Immunology.

[27]  M. T. Moser,et al.  T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  B. Freidlin,et al.  Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.