- Email: [email protected]
Durable Complete Remission From Castration-Resistant Prostate Cancer With Sipuleucel-T After Estrogen Withdrawal
Case Report
Durable Complete Remission From Castration-Resistant Prostate Cancer With Sipuleucel-T After Estrogen Withdrawal Tanya B. Dorff,1,2 Cy Wilkins,1 Mehmet Hepgur,1 David I. Quinn1,2 Clinical Practice Points Sipuleucel-T has been shown to prolong overall sur-
Withdrawal of hormonal therapies has been associ-
vival, without commonly affecting prostate-specific antigen (PSA) or inducing objective disease regression; however, objective responses do occur. The need to continue androgen deprivation after complete response to sipuleucel-T is uncertain.
ated with PSA and objective responses in men with prostate cancer; the optimal sequence for introduction and withdrawal of androgen-targeted agents and sipuleucel-T should be explored.
Clinical Genitourinary Cancer, Vol. 12, No. 2, e55-8 ª 2014 Elsevier Inc. All rights reserved. Keywords: Anti-androgen withdrawal response, Bone metastases, Estrogen withdrawal, Prostate cancer immunotherapy, Testosterone recovery
Introduction Prostate cancer is the leading cause of cancer for men in the United States, with an estimated 241,740 new diagnoses and 28,170 deaths in 2012.1 Metastatic prostate cancer is initially treated with androgen deprivation therapy (ADT), which initially controls disease in most patients. However all patients eventually develop progressive disease despite ADT, a condition called castration-resistant prostate cancer (CRPC).2 Until 2010, the primary treatment for CRPC was docetaxel chemotherapy, which had demonstrated a survival advantage in phase III clinical trials.3 Immunotherapy for prostate cancer emerged as a treatment option after preclinical studies demonstrated that tumor vaccines were able to induce antitumor immune responses.4 Phase I/II studies with sipuleucel-T supported further development of immunotherapy for prostate cancer.5 Sipuleucel-T was approved by the Food and Drug Administration in April 2010 for the treatment of asymptomatic or minimally symptomatic metastatic CRPC after randomized phase III clinical trials identified a significant improvement in overall survival for men treated with sipuleucel-T compared with placebo.6 However, progression-free survival at 12 weeks was similar in men treated with 1
Department of Medicine, USC Keck School of Medicine, Los Angeles, CA USC Norris Comprehensive Cancer Center, Los Angeles, CA
2
Submitted: Jul 20, 2013; Accepted: Nov 8, 2013; Epub: Nov 14, 2013 Address for correspondence: Tanya B. Dorff, MD, USC Keck School of Medicine, Department of Medicine, USC Norris Comprehensive Cancer Center, 1441 Eastlake Ave. #3440, Los Angeles, CA 90033 Fax: 323-865-0061; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.11.006
sipuleucel-T or placebo, and PSA responses were uncommon, with only a single objective partial response noted. Complete response to sipuleucel-T is extremely rare and limited to anecdotal reports.7,8 With multiple new agents demonstrating survival benefit in CRPC, it is becoming increasingly important to identify factors that might contribute to the achievement of an objective response after sipuleucel-T treatment. In this setting, we present a rare case of a complete PSA response after treatment with sipuleucel-T, accompanied by radiographic disease regression that persisted for more than 2 years, with a review of the literature to understand clinical factors that might have contributed to his excellent outcome.
Case Report A 55-year-old man was diagnosed with prostate cancer in 2006, with a baseline PSA of 19 ng/mL. Imaging revealed no evidence of metastatic disease. He underwent radical prostatectomy in September of 2006 and pathologic examination showed a Gleason 3þ4 adenocarcinoma, stage T3aN0. After a 9-month period of undetectable PSA, his PSA levels began to increase, reaching 2.38 ng/dL at 1 year after surgery. Combined ADT and radiation were recommended but the patient chose only ADT. In August of 2008 his PSA level began to increase despite castrate levels of testosterone. He received salvage radiation from September to December 2008 with PSA response to undetectable levels. Over the next 3 months, despite castrate levels of testosterone, his PSA again increased, and reached 7.46 ng/mL by March 2009. At that time, asymptomatic metastatic bone lesions were found in the sternum and ribs. Treatment was resumed with bicalutamide until September 2009
Clinical Genitourinary Cancer April 2014
- e55
Estrogen Withdrawal, Sipuleucel-T, and CR in CRPC when his PSA began to increase again; at that time bicalutamide was withdrawn and leuprolide injections were continued. After a 1-month washout period failed to reveal an antiandrogen withdrawal response, he was still asymptomatic, so treatment with estrogen transdermal patches was prescribed in October 2009 with a baseline PSA of 1.79 ng/mL. During estrogen therapy the patient’s PSA continued to increase slowly, reaching 2.92 ng/mL by July 2010. Estrogen was stopped, and after a 2-week washout period, sipuleucel-T was administered. There were no adverse events during his leukapheresis or infusion procedures, and his only reported complaint was minor fatigue, not interfering with his ability to work full time. His product parameters were: CD54þ upregulation ¼ 29.69, total nucleated cell (TNC) count ¼ 0.79 109, and CD54þ cell count ¼ 5.2 109. He had no detectable circulating tumor cells (CTCs) before or after treatment. Immediately after completing sipuleucel-T treatment, his PSA level decreased to 2.52 ng/mL with a testosterone level of 27 ng/dL. One month later his PSA level decreased to undetectable. He continued to have an undetectable PSA level, so in December 2010 leuprolide was stopped. A restaging bone scan in May 2011 showed regression of his bony metastatic disease. Despite normalization of his testosterone levels in August 2011, his PSA level remained undetectable
until August 2012. Repeat restaging scans in October 2012 showed continued regression of the bony metastases (Fig. 1).
Discussion Sipuleucel-T (Provenge, or APC8015) is a novel cancer vaccine developed from autologous dendritic cells incubated with an engineered fusion protein of prostatic acid phosphatase and granulocytemacrophage colony-stimulating factor. The treatment, consisting of 3 infusions of activated cells from 3 leukapheresis procedures, was found to prolong overall survival by 4.5 months compared with placebo among men with asymptomatic/minimally symptomatic metastatic CRPC.6 In general, sipuleucel-T is well tolerated, with minor side effects predominantly involving infusion reactions and complications of pheresis catheter placement (in men for whom peripheral access is not feasible).9 Although early studies noted occasional PSA declines, the phase III trials failed to identify prolonged progression-free survival.10,11 We report a case of objective response after sipuleucel-T treatment followed by remission lasting more than 26 months, despite testosterone recovery. PSA level declines > 50% are not common after sipuleucel-T treatment, as delineated in the Immunotherapy Prostate Adenocarcinoma Treatment (IMPACT) trial in which only 8 of 311 subjects (2.6%) treated with
Figure 1 Bone Scintigraphy. (A) Bone Scintigraphy on May 29, 2010. (B) Bone Scintigraphy on October 30, 2012
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Abbreviations: LAO ¼ left anterior oblique; RAO ¼ right anterior oblique; RPO ¼ right posterior oblique.
Clinical Genitourinary Cancer April 2014
Tanya B. Dorff et al sipuleucel-T had a PSA level decline 50%, compared with 2 of 153 subjects (1.3%) taking placebo.6 Complete response is extremely rare and was reported in a single patient from the phase II sipuleucelT trials.7 Our patient’s PSA level decreased from 2.92 ng/mL to undetectable levels within 2 months of vaccine administration and continued to be undetectable after testosterone recovery. This patient’s baseline PSA of 2.92 ng/mL would have placed him in the lowest quartile of patients in the phase III IMPACT trial. A subgroup analysis of IMPACT data demonstrated that greater benefit from sipuleucel-T was observed in the patients with lowest baseline PSA levels.12 Current paradigms favor incorporating sipuleucel-T treatment early in metastatic CRPC, when the disease burden is lowest and before extensive use of corticosteroids or chemotherapy could potentially attenuate the ability to induce an immune response.13 Treatment in the setting of low PSA might have contributed to his positive response, although a previously reported complete response occurred in a patient with a baseline PSA level of 224 ng/mL.7 The ability of ADT to evoke immune responses is well known. Clinical studies suggest that ADT enhances immune responses to vaccines by partially reversing age-related thymic involution and augmenting B-cell development.14 Exposure to ADT has been associated with generation of new antibodies against prostate cancer antigens.15,16 However, whether this occurs on withdrawal of hormonal therapies has not been well studied. Withdrawal of androgen-targeted therapies has been associated with clinical responses, making it plausible that immune activation could occur.17,18 Recently, Graff et al reported a complete PSA response in a patient who was treated with sipuleucel-T concurrent with enzalutamide, after the patient had responded to and then begun to experience progression while taking enzalutamide.8 The optimal sequence of application or withdrawal of hormonal therapies in relationship to immunotherapy is not known.19 In both of the previously published cases of complete response to sipuleucel-T, castration therapy was maintained. Recovery of testosterone might have affected the duration of our patient’s remission. As described in the Case Report section, our patient with CRPC with metastases to bone was refractory to several lines of ADT. He then received 10 months of transdermal estrogen therapy with modest effect. Estrogen was withdrawn before sipuleucel-T treatment because of an increasing level of PSA and concern for hypercoagulability interfering with leukapheresis. We recognize this as a possible confounding variable to explain the patient’s dramatic response. Although the phenomenon of antiandrogen withdrawal response has been well documented,17,18 few publications have reported the effect of estrogen withdrawal on PSA kinetics or prostate cancer. In 1995, Bissada and Kaczmarek reported a case of a patient with advanced adenocarcinoma of the prostate who had progression of disease while taking diethylstilbestrol but durable complete remission lasting 3 years after its withdrawal.20 For antiandrogens, withdrawal responses occur in approximately 20% of patients, with a median duration of less than 14.5 months.17 In our case, it is possible that estrogen withdrawal contributed to our patient’s response; however, the timing makes response to sipuleucel-T a more plausible explanation, or raises the possibility of a synergistic effect. Markers of response to sipuleucel-T treatment are needed, because disease progression is not visibly affected before patients go on to subsequent lines of therapy. Eosinophilia, CD54
upregulation, CD54þ cell count, and TNC count are emerging as potential biomarkers that correlate with benefit from sipuleucel-T treatment.21,22 This patient’s CD54þ upregulation result was 29.69, which is slightly greater than the median value reported by Sheikh at al from the IMPACT population.22 However, our patient’s TNC and CD54þ cell count were lower than the 25th percentile reported by Sheikh et al. Therefore, immunologic parameters did not delineate our patient’s marked response. Circulating tumor cells are a commercially available biomarker with strong prognostic significance, independent of PSA, in men with CRPC. Although CTC data were not reported as part of the IMPACT trial, we found declines in CTC counts after sipuleucel-T treatment in 7 of 18 patients who had detectable pretreatment CTCs.23 Further evaluation of CTC changes and other biomarkers of response are needed to assist physicians and patients in optimal use of sipuleucel-T and subsequent therapies.
Conclusion We present a case of a durable complete remission in a man with metastatic CRPC after withdrawal of estrogen and sipuleucel-T treatment. We believe that immune activation by sipuleucel-T was a significant contributor to the patient’s response and ability to remain in remission despite normalization of testosterone levels.
Acknowledgments Supported by the USC Norris Comprehensive Cancer Center Core Grant P30 CA014089.
Disclosure Doctors Dorff and Quinn have served as paid consultants to Dendreon. Doctors Hepgur and Wilkins have no disclosures to report.
References 1. Siegel R, Naishadham M, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62:10-29. 2. Perlmutter MA, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer. Rev Urol 2007; 9:S3-8. 3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502-12. 4. Laus R. Dendritic cells immunotherapy of prostate cancer: preclinical models and early clinical experience. Cancer Res Therapy Control 2001; 11:1-10. 5. Beinart G, Rini BI, Weinberg V. Antigen-presenting cells 8015 (Provenge) in patients with androgen dependent, biochemically relapsed prostate cancer. Clin Prostate Cancer 2005; 4:55-60. 6. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411-22. 7. Burch PA, Croghan GA, Gastineau DA, et al. Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a phase 2 trial. Prostate 2004; 60: 197-204. 8. Graff JN, Drake CG, Beer TM. Complete biochemical (prostate-specific antigen) response to sipuleucel-T with enzalutamide in castration-resistant prostate cancer: a case report with implications for future research. Urology 2013; 81:381-3. 9. Flanigan RC, Polcari AJ, Shore ND, et al. An analysis of leukapheresis and central venous catheter use in the randomized, placebo-controlled, phase 3 IMPACT trial of sipuleucel-T for metastatic castrate resistant prostate cancer. J Urol 2013; 189: 521-6. 10. Shore ND, Mantz CA, Dosoretz DE, et al. Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer. Cancer Control 2013; 20:7-16. 11. Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 clinical trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115:3670-9. 12. Schellhammer PF, Chodak G, Whitmore JB, et al. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the
Clinical Genitourinary Cancer April 2014
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Estrogen Withdrawal, Sipuleucel-T, and CR in CRPC 13. 14. 15. 16. 17.
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immunotherapy for prostate adenocarcinoma treatment (IMPACT) trial. Urol 2013; 81:1297-302. Crawford DE, Kibel A, Shore N. Optimal timing for treatment of metastatic castration-resistant prostate cancer (MCRPC): sequencing and identifying parameters of early progression with sipuleucel-T. J Urol 2013; 189:393-4. Aragon-Ching JB, Williams KM, Gulley JL. Impact of androgen deprivation therapy on the immune system: implications for combination therapy of prostate cancer. Front Biosci 2007; 12:4957-71. Morse MD, McNeel DG. Prostate cancer patients on androgen deprivation therapy develop persistent changes in adaptive immune response. Hum Immunol 2010; 71:496-504. Nesslinger NJ, Sahota RA, Stone B, et al. Standard treatments induce antigenspecific immune responses in prostate cancer. Clin Cancer Res 2007; 13: 1493-502. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castraterefractory prostate cancer: a Southwest Oncology Group (SWOG) trial. Cancer 2008; 112:2393-400.
Clinical Genitourinary Cancer April 2014
18. Herrada J, Dieringer P, Logothetis CJ. Characterization of patients with androgenindependent prostate carcinoma whose serum prostate specific antigen decreased following flutamide withdrawal. J Urol 1996; 155:620-3. 19. Koh YT, Gray A, Higgins SA, et al. Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization. Prostate 2009; 69:571-4. 20. Bissada NK, Kaczmarek AT. Complete remission of hormone refractory adenocarcinoma of the prostate in response to withdrawal of diethylstilbestrol. J Urol 1995; 153:1944-5. 21. McNeel DG, Lin DW, Gardner T, et al. Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients with metastatic castrateresistant prostate cancer. J Clin Oncol 2012; 30 (abstract 4650). 22. Sheikh NA, Petrylak D, Kantoff PW, 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. Cancer Immunol Immunother 2013; 62:137-47. 23. Hepgur M, Dorff TB, Cai J, et al. Changes in circulating tumor cells (CTC) and markers of inflammation after sipuleucel-T treatment. J Clin Oncol 2013; 31 (abstract 40).
Durable Complete Remission From Castration-Resistant Prostate Cancer With Sipuleucel-T After Estrogen Withdrawal Tanya B. Dorff,1,2 Cy Wilkins,1 Mehmet Hepgur,1 David I. Quinn1,2 Clinical Practice Points Sipuleucel-T has been shown to prolong overall sur-
Withdrawal of hormonal therapies has been associ-
vival, without commonly affecting prostate-specific antigen (PSA) or inducing objective disease regression; however, objective responses do occur. The need to continue androgen deprivation after complete response to sipuleucel-T is uncertain.
ated with PSA and objective responses in men with prostate cancer; the optimal sequence for introduction and withdrawal of androgen-targeted agents and sipuleucel-T should be explored.
Clinical Genitourinary Cancer, Vol. 12, No. 2, e55-8 ª 2014 Elsevier Inc. All rights reserved. Keywords: Anti-androgen withdrawal response, Bone metastases, Estrogen withdrawal, Prostate cancer immunotherapy, Testosterone recovery
Introduction Prostate cancer is the leading cause of cancer for men in the United States, with an estimated 241,740 new diagnoses and 28,170 deaths in 2012.1 Metastatic prostate cancer is initially treated with androgen deprivation therapy (ADT), which initially controls disease in most patients. However all patients eventually develop progressive disease despite ADT, a condition called castration-resistant prostate cancer (CRPC).2 Until 2010, the primary treatment for CRPC was docetaxel chemotherapy, which had demonstrated a survival advantage in phase III clinical trials.3 Immunotherapy for prostate cancer emerged as a treatment option after preclinical studies demonstrated that tumor vaccines were able to induce antitumor immune responses.4 Phase I/II studies with sipuleucel-T supported further development of immunotherapy for prostate cancer.5 Sipuleucel-T was approved by the Food and Drug Administration in April 2010 for the treatment of asymptomatic or minimally symptomatic metastatic CRPC after randomized phase III clinical trials identified a significant improvement in overall survival for men treated with sipuleucel-T compared with placebo.6 However, progression-free survival at 12 weeks was similar in men treated with 1
Department of Medicine, USC Keck School of Medicine, Los Angeles, CA USC Norris Comprehensive Cancer Center, Los Angeles, CA
2
Submitted: Jul 20, 2013; Accepted: Nov 8, 2013; Epub: Nov 14, 2013 Address for correspondence: Tanya B. Dorff, MD, USC Keck School of Medicine, Department of Medicine, USC Norris Comprehensive Cancer Center, 1441 Eastlake Ave. #3440, Los Angeles, CA 90033 Fax: 323-865-0061; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2013.11.006
sipuleucel-T or placebo, and PSA responses were uncommon, with only a single objective partial response noted. Complete response to sipuleucel-T is extremely rare and limited to anecdotal reports.7,8 With multiple new agents demonstrating survival benefit in CRPC, it is becoming increasingly important to identify factors that might contribute to the achievement of an objective response after sipuleucel-T treatment. In this setting, we present a rare case of a complete PSA response after treatment with sipuleucel-T, accompanied by radiographic disease regression that persisted for more than 2 years, with a review of the literature to understand clinical factors that might have contributed to his excellent outcome.
Case Report A 55-year-old man was diagnosed with prostate cancer in 2006, with a baseline PSA of 19 ng/mL. Imaging revealed no evidence of metastatic disease. He underwent radical prostatectomy in September of 2006 and pathologic examination showed a Gleason 3þ4 adenocarcinoma, stage T3aN0. After a 9-month period of undetectable PSA, his PSA levels began to increase, reaching 2.38 ng/dL at 1 year after surgery. Combined ADT and radiation were recommended but the patient chose only ADT. In August of 2008 his PSA level began to increase despite castrate levels of testosterone. He received salvage radiation from September to December 2008 with PSA response to undetectable levels. Over the next 3 months, despite castrate levels of testosterone, his PSA again increased, and reached 7.46 ng/mL by March 2009. At that time, asymptomatic metastatic bone lesions were found in the sternum and ribs. Treatment was resumed with bicalutamide until September 2009
Clinical Genitourinary Cancer April 2014
- e55
Estrogen Withdrawal, Sipuleucel-T, and CR in CRPC when his PSA began to increase again; at that time bicalutamide was withdrawn and leuprolide injections were continued. After a 1-month washout period failed to reveal an antiandrogen withdrawal response, he was still asymptomatic, so treatment with estrogen transdermal patches was prescribed in October 2009 with a baseline PSA of 1.79 ng/mL. During estrogen therapy the patient’s PSA continued to increase slowly, reaching 2.92 ng/mL by July 2010. Estrogen was stopped, and after a 2-week washout period, sipuleucel-T was administered. There were no adverse events during his leukapheresis or infusion procedures, and his only reported complaint was minor fatigue, not interfering with his ability to work full time. His product parameters were: CD54þ upregulation ¼ 29.69, total nucleated cell (TNC) count ¼ 0.79 109, and CD54þ cell count ¼ 5.2 109. He had no detectable circulating tumor cells (CTCs) before or after treatment. Immediately after completing sipuleucel-T treatment, his PSA level decreased to 2.52 ng/mL with a testosterone level of 27 ng/dL. One month later his PSA level decreased to undetectable. He continued to have an undetectable PSA level, so in December 2010 leuprolide was stopped. A restaging bone scan in May 2011 showed regression of his bony metastatic disease. Despite normalization of his testosterone levels in August 2011, his PSA level remained undetectable
until August 2012. Repeat restaging scans in October 2012 showed continued regression of the bony metastases (Fig. 1).
Discussion Sipuleucel-T (Provenge, or APC8015) is a novel cancer vaccine developed from autologous dendritic cells incubated with an engineered fusion protein of prostatic acid phosphatase and granulocytemacrophage colony-stimulating factor. The treatment, consisting of 3 infusions of activated cells from 3 leukapheresis procedures, was found to prolong overall survival by 4.5 months compared with placebo among men with asymptomatic/minimally symptomatic metastatic CRPC.6 In general, sipuleucel-T is well tolerated, with minor side effects predominantly involving infusion reactions and complications of pheresis catheter placement (in men for whom peripheral access is not feasible).9 Although early studies noted occasional PSA declines, the phase III trials failed to identify prolonged progression-free survival.10,11 We report a case of objective response after sipuleucel-T treatment followed by remission lasting more than 26 months, despite testosterone recovery. PSA level declines > 50% are not common after sipuleucel-T treatment, as delineated in the Immunotherapy Prostate Adenocarcinoma Treatment (IMPACT) trial in which only 8 of 311 subjects (2.6%) treated with
Figure 1 Bone Scintigraphy. (A) Bone Scintigraphy on May 29, 2010. (B) Bone Scintigraphy on October 30, 2012
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-
Abbreviations: LAO ¼ left anterior oblique; RAO ¼ right anterior oblique; RPO ¼ right posterior oblique.
Clinical Genitourinary Cancer April 2014
Tanya B. Dorff et al sipuleucel-T had a PSA level decline 50%, compared with 2 of 153 subjects (1.3%) taking placebo.6 Complete response is extremely rare and was reported in a single patient from the phase II sipuleucelT trials.7 Our patient’s PSA level decreased from 2.92 ng/mL to undetectable levels within 2 months of vaccine administration and continued to be undetectable after testosterone recovery. This patient’s baseline PSA of 2.92 ng/mL would have placed him in the lowest quartile of patients in the phase III IMPACT trial. A subgroup analysis of IMPACT data demonstrated that greater benefit from sipuleucel-T was observed in the patients with lowest baseline PSA levels.12 Current paradigms favor incorporating sipuleucel-T treatment early in metastatic CRPC, when the disease burden is lowest and before extensive use of corticosteroids or chemotherapy could potentially attenuate the ability to induce an immune response.13 Treatment in the setting of low PSA might have contributed to his positive response, although a previously reported complete response occurred in a patient with a baseline PSA level of 224 ng/mL.7 The ability of ADT to evoke immune responses is well known. Clinical studies suggest that ADT enhances immune responses to vaccines by partially reversing age-related thymic involution and augmenting B-cell development.14 Exposure to ADT has been associated with generation of new antibodies against prostate cancer antigens.15,16 However, whether this occurs on withdrawal of hormonal therapies has not been well studied. Withdrawal of androgen-targeted therapies has been associated with clinical responses, making it plausible that immune activation could occur.17,18 Recently, Graff et al reported a complete PSA response in a patient who was treated with sipuleucel-T concurrent with enzalutamide, after the patient had responded to and then begun to experience progression while taking enzalutamide.8 The optimal sequence of application or withdrawal of hormonal therapies in relationship to immunotherapy is not known.19 In both of the previously published cases of complete response to sipuleucel-T, castration therapy was maintained. Recovery of testosterone might have affected the duration of our patient’s remission. As described in the Case Report section, our patient with CRPC with metastases to bone was refractory to several lines of ADT. He then received 10 months of transdermal estrogen therapy with modest effect. Estrogen was withdrawn before sipuleucel-T treatment because of an increasing level of PSA and concern for hypercoagulability interfering with leukapheresis. We recognize this as a possible confounding variable to explain the patient’s dramatic response. Although the phenomenon of antiandrogen withdrawal response has been well documented,17,18 few publications have reported the effect of estrogen withdrawal on PSA kinetics or prostate cancer. In 1995, Bissada and Kaczmarek reported a case of a patient with advanced adenocarcinoma of the prostate who had progression of disease while taking diethylstilbestrol but durable complete remission lasting 3 years after its withdrawal.20 For antiandrogens, withdrawal responses occur in approximately 20% of patients, with a median duration of less than 14.5 months.17 In our case, it is possible that estrogen withdrawal contributed to our patient’s response; however, the timing makes response to sipuleucel-T a more plausible explanation, or raises the possibility of a synergistic effect. Markers of response to sipuleucel-T treatment are needed, because disease progression is not visibly affected before patients go on to subsequent lines of therapy. Eosinophilia, CD54
upregulation, CD54þ cell count, and TNC count are emerging as potential biomarkers that correlate with benefit from sipuleucel-T treatment.21,22 This patient’s CD54þ upregulation result was 29.69, which is slightly greater than the median value reported by Sheikh at al from the IMPACT population.22 However, our patient’s TNC and CD54þ cell count were lower than the 25th percentile reported by Sheikh et al. Therefore, immunologic parameters did not delineate our patient’s marked response. Circulating tumor cells are a commercially available biomarker with strong prognostic significance, independent of PSA, in men with CRPC. Although CTC data were not reported as part of the IMPACT trial, we found declines in CTC counts after sipuleucel-T treatment in 7 of 18 patients who had detectable pretreatment CTCs.23 Further evaluation of CTC changes and other biomarkers of response are needed to assist physicians and patients in optimal use of sipuleucel-T and subsequent therapies.
Conclusion We present a case of a durable complete remission in a man with metastatic CRPC after withdrawal of estrogen and sipuleucel-T treatment. We believe that immune activation by sipuleucel-T was a significant contributor to the patient’s response and ability to remain in remission despite normalization of testosterone levels.
Acknowledgments Supported by the USC Norris Comprehensive Cancer Center Core Grant P30 CA014089.
Disclosure Doctors Dorff and Quinn have served as paid consultants to Dendreon. Doctors Hepgur and Wilkins have no disclosures to report.
References 1. Siegel R, Naishadham M, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62:10-29. 2. Perlmutter MA, Lepor H. Androgen deprivation therapy in the treatment of advanced prostate cancer. Rev Urol 2007; 9:S3-8. 3. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502-12. 4. Laus R. Dendritic cells immunotherapy of prostate cancer: preclinical models and early clinical experience. Cancer Res Therapy Control 2001; 11:1-10. 5. Beinart G, Rini BI, Weinberg V. Antigen-presenting cells 8015 (Provenge) in patients with androgen dependent, biochemically relapsed prostate cancer. Clin Prostate Cancer 2005; 4:55-60. 6. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363:411-22. 7. Burch PA, Croghan GA, Gastineau DA, et al. Immunotherapy (APC8015, Provenge) targeting prostatic acid phosphatase can induce durable remission of metastatic androgen-independent prostate cancer: a phase 2 trial. Prostate 2004; 60: 197-204. 8. Graff JN, Drake CG, Beer TM. Complete biochemical (prostate-specific antigen) response to sipuleucel-T with enzalutamide in castration-resistant prostate cancer: a case report with implications for future research. Urology 2013; 81:381-3. 9. Flanigan RC, Polcari AJ, Shore ND, et al. An analysis of leukapheresis and central venous catheter use in the randomized, placebo-controlled, phase 3 IMPACT trial of sipuleucel-T for metastatic castrate resistant prostate cancer. J Urol 2013; 189: 521-6. 10. Shore ND, Mantz CA, Dosoretz DE, et al. Building on sipuleucel-T for immunologic treatment of castration-resistant prostate cancer. Cancer Control 2013; 20:7-16. 11. Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 clinical trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer 2009; 115:3670-9. 12. Schellhammer PF, Chodak G, Whitmore JB, et al. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the
Clinical Genitourinary Cancer April 2014
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Estrogen Withdrawal, Sipuleucel-T, and CR in CRPC 13. 14. 15. 16. 17.
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immunotherapy for prostate adenocarcinoma treatment (IMPACT) trial. Urol 2013; 81:1297-302. Crawford DE, Kibel A, Shore N. Optimal timing for treatment of metastatic castration-resistant prostate cancer (MCRPC): sequencing and identifying parameters of early progression with sipuleucel-T. J Urol 2013; 189:393-4. Aragon-Ching JB, Williams KM, Gulley JL. Impact of androgen deprivation therapy on the immune system: implications for combination therapy of prostate cancer. Front Biosci 2007; 12:4957-71. Morse MD, McNeel DG. Prostate cancer patients on androgen deprivation therapy develop persistent changes in adaptive immune response. Hum Immunol 2010; 71:496-504. Nesslinger NJ, Sahota RA, Stone B, et al. Standard treatments induce antigenspecific immune responses in prostate cancer. Clin Cancer Res 2007; 13: 1493-502. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castraterefractory prostate cancer: a Southwest Oncology Group (SWOG) trial. Cancer 2008; 112:2393-400.
Clinical Genitourinary Cancer April 2014
18. Herrada J, Dieringer P, Logothetis CJ. Characterization of patients with androgenindependent prostate carcinoma whose serum prostate specific antigen decreased following flutamide withdrawal. J Urol 1996; 155:620-3. 19. Koh YT, Gray A, Higgins SA, et al. Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization. Prostate 2009; 69:571-4. 20. Bissada NK, Kaczmarek AT. Complete remission of hormone refractory adenocarcinoma of the prostate in response to withdrawal of diethylstilbestrol. J Urol 1995; 153:1944-5. 21. McNeel DG, Lin DW, Gardner T, et al. Correlation of increased eosinophil count following sipuleucel-T treatment with outcome in patients with metastatic castrateresistant prostate cancer. J Clin Oncol 2012; 30 (abstract 4650). 22. Sheikh NA, Petrylak D, Kantoff PW, 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. Cancer Immunol Immunother 2013; 62:137-47. 23. Hepgur M, Dorff TB, Cai J, et al. Changes in circulating tumor cells (CTC) and markers of inflammation after sipuleucel-T treatment. J Clin Oncol 2013; 31 (abstract 40).