Review Article Current and Emerging Immunotherapies for Castration-resistant Prostate Cancer Fred Saad and Kurt Miller Despite advances in castration-resistant prostate cancer (CRPC) treatment, therapies that provide long-term survival are still needed. In 2010, sipuleucel-T was approved for CRPC on the basis of improved overall survival. Recently, new immunotherapeutic approaches have emerged with perhaps the most exciting being immune-checkpoint inhibition. Here, we provide an overview of immunotherapies for CRPC, with a focus on immune-checkpoint inhibition with ipilimumab. We consider how experience with ipilimumab in melanoma might inform future use in CRPC and describe ongoing phase 3 trials. Finally, we discuss the potential for improved antitumor activity when ipilimumab is combined with hormonal or bone-targeted agents. UROLOGY -: -e-, 2015. 2015 Elsevier Inc.
P
rostate cancer is the second most common cancer in men worldwide and the fifth leading cause of cancer-related deaths in men.1 An estimated 1.1 million men worldwide were diagnosed with prostate cancer in 2012, and 307,000 deaths from this disease were reported.1 Patients with advanced-stage prostate cancer are typically managed with radiotherapy, surgery, and/or androgen-deprivation therapy, which aim to reduce testosterone to castrate levels and reduce tumor burden.2 Although most patients initially respond to treatment, many eventually develop castration-resistant prostate cancer (CRPC), a clinical state in which disease progression occurs despite surgical or chemical castration.2 CRPC is not a single, homogenous disorder, but rather a spectrum of clinical states ranging from asymptomatic or minimally symptomatic, nonmetastatic disease to symptomatic disease with metastases. Although each patient’s disease course may be different in terms of timing, there is a general progression from asymptomatic to symptomatic disease and potentially death. Until recently, treatment options for metastatic CRPC (mCRPC) were limited to docetaxel-based chemotherapy. In 2005, docetaxel in combination with prednisone was approved by the US Food and Drug Administration (FDA) on the basis of an overall survival (OS) benefit, which was The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical expertise. Professional medical writing assistance was provided by Jennifer DiNieri and professional editing assistance was provided by Matthew Dougherty at StemScientific and was funded by Bristol-Myers Squibb. Neither BristolMyers Squibb nor StemScientific influenced the content of the manuscript, nor did the authors receive financial compensation for authoring the article. Financial Disclosure: Fred Saad has served as a consultant and received research funding from Bristol-Myers Squibb, Astellas, Janssen, Bavarian Nordic, Sanofi, and Millennium. Kurt Miller is a paid consultant for Bayer, Bristol-Myers Squibb, Astellas, Janssen, Novartis, and Roche. From the Division of Urology, Department of Surgery, Centre Hospitalier de I’Universite de Montreal, Montreal, Quebec, Canada; and the Department of Urology, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany Address correspondence to: Fred Saad, M.D., Division of Urology, Department of Surgery, Centre Hospitalier de I’Universite de Montreal, Montreal, Quebec, Canada H2L 4M1. E-mail: [email protected] Submitted: September 30, 2014, accepted (with revisions): December 19, 2014
ª 2015 Elsevier Inc. All Rights Reserved
demonstrated in 2 phase 3 studies.3-5 Subsequently, docetaxel-based chemotherapy became the standard of care for patients with mCRPC, although its use was limited by patient or physician reluctance, particularly in an asymptomatic setting. Recently, the FDA approved 4 new agents (cabazitaxel, abiraterone acetate, enzalutamide, and radium-223 (Table 1; Fig. 1) based on demonstrated OS benefit in phase 3 studies.6-9 Cabazitaxel, a taxane chemotherapy agent, was the first agent to demonstrate improved survival in mCRPC patients in a postdocetaxel setting.6 Abiraterone acetate, a selective inhibitor of the enzyme CYP17, which plays a role in androgen biosynthesis, is approved by the FDA for the treatment of mCRPC patients in prechemotherapy and postchemotherapy settings.7,10 Enzalutamide, a competitive inhibitor of the androgen receptor, is FDA-approved for docetaxelexperienced patients with mCRPC8 and was recently shown to decrease the risk of disease progression and death in chemotherapy-naïve mCRPC patients.11 Radium-223, an a-emitting radiopharmaceutical, is approved for CRPC patients with bone metastases.9 Despite the improved therapeutic options for CRPC, there remains a need for treatments that can provide durable disease control and long-term survival benefit. Among the many strategies that are being investigated to address this need, immunotherapy is a compelling approach. Research suggests that prostate cancer is an immunologically modulated malignancy, and therefore, may be sensitive to immunotherapy. For example, data from studies that have evaluated the cellular composition of prostate tumors suggest that immune cell populations infiltrate the prostate gland.12,13 Infiltrating leukocytes detected in prostate tumors include natural killer cells, effector cells, and regulatory T cells, suggesting that both the innate and adaptive branches of the immune system may play a role in mounting an attack against prostate cancer cells.14 Although immunotherapy for prostate cancer has been associated with disappointing results in the past, there is renewed interest because of the recent success of http://dx.doi.org/10.1016/j.urology.2014.12.029 0090-4295/15
1
2
Table 1. Results of completed phase 3 trials in advanced prostate cancer Study ID Chemotherapy TAX 327
Patient Population mCRPC
SWOG 99-16 NCT00004001
mCRPC
TROPIC NCT00417079
mCRPC, postdocetaxel
Agents that target the androgen receptor pathway COU-AA-301 mCRPC, postdocetaxel NCT00638690
COU-AA-302 NCT00887198
mCRPC, chemonaïve
Study Arms Arm 1: D1 þ P (n ¼ 334*) Arm 2: D3 þ P (n ¼ 335*) Arm 3: M þ P (n ¼ 337*) Arm 1: D þ E (n ¼ 338y) Arm 2: M þ P (n ¼ 336y) Arm 1: C þ P (n ¼ 378*) Arm 2: M þ P (n ¼ 377*)
Primary Analysis
Subgroup Analysis: þ/ VM
mOS
mOS
D1 þ P ¼ 17.8 mo D3 þ P ¼ 19.2 mo M þ P ¼ 16.3 mo mOS
VM ¼ 18.9 mo þVM ¼ 13.1 mo
D þ E ¼ 17.5 mo M þ P ¼ 15.6 mo mOS
Reference Berthold 20083
Pts with VMs were enrolled in this study, but no subgroup analysis was performed
Petrylak 20044
HR for pts þ/ measurable diseasex
de Bono 20106
C þ P ¼ 15.1 mo M þ P ¼ 12.7 mo
Measurable disease ¼ 0.72 þMeasurable disease ¼ 0.68
Arm 1: Abi þ P (n ¼ 797*) Arm 2: Pb þ P (n ¼ 398*)
mOS
mOS
de Bono 20117
Abi þ P ¼ 14.8 mo Pb þ P ¼ 10.9 mo
Arm 1: Abi þ P (n ¼ 546*) Arm 2: Pb þ P (n ¼ 542*)
Median radiographic PFS
VM B Abi þ P ¼ 15.4 mo B Pb þ P ¼ 11.2 mo þVM B Abi þ P ¼ 12.6 mo B Pb þ P ¼ 8.4 mo Pts with VMs were excluded
Ryan 201310
mOS
Beer 201411
Abi þ P ¼ 16.5 mo Pb þ P ¼ 8.3 mo
mOS
PREVAIL NCT01212991
mCRPC, chemonaïve
Arm 1: Enza (n ¼ 872z) Arm 2: Pb (n ¼ 845z)
Abi þ P ¼ not reached Pb þ P ¼ 27.2 mo Rate of radiographic PFS Enza ¼ 65% Pb ¼ 14%
UROLOGY
mOS
-
AFFIRM NCT00974311
CRPC, postdocetaxel
Arm 1: Enza (n ¼ 800*) Arm 2: Pb (n ¼ 399*)
Enza ¼ not reached Pb ¼ 31.0 mo mOS
(-), 2015
Enza ¼ 18.4 mo Pb ¼ 13.6 mo
VM B Enza ¼ not reached B Pb ¼ 30.2 mo þVM B Enza ¼ 27.8 mo B Pb ¼ 22.8 mo mOS
Scher 20128
VM B Enza ¼ not reached B Pb ¼ 14.2 mo Continued
Abi, abiraterone acetate; C, cabazitaxel; D, docetaxel; D1, docetaxel once every week; D3, docetaxel every 3 weeks; E, estramustine; Enza, enzalutamide; HR, hazard ratio; ID, identifier; Ipi, ipilimumab; M, mitoxantrone; mCRPC, metastatic castration-resistant prostate cancer; mOS, median overall survival; P, prednisone; Pb, placebo; PC, prostate cancer; PFS, progression-free survival; pts, patients; Rad-223, radium-223; RT, radiotherapy; VM, visceral metastases. * Number of randomized patients. y Number of treatment-eligible patients. z Number of patients who enrolled. x Defined as documented disease progression by RECIST criteria and at least one visceral or soft-tissue metastatic lesion.
VM ¼ 0.73 þVM ¼ 1.20 Ipi þ RT ¼ 11.2 mo Pb þ RT ¼ 10.0 mo
Kwon 201437 HR
Arm 1: Ipi þ RT (n ¼ 399*) Arm 2: Pb þ RT (n ¼ 400*)
(-), 2015
mCRPC, postdocetaxel Immunotherapy CA184-043 NCT00861614
Rad-223 ¼ 14.9 mo Pb ¼ 11.3 mo
Arm 1: Rad-223 (n ¼ 614*) Arm 2: Pb (n ¼ 307*)
mOS
Parker 20139 -
Bone-targeted therapy ALSYMPCA CRPC and bone NCT00699751 metastases
mOS
Pts with VM were excluded from this study
Reference Subgroup Analysis: þ/ VM
þVM B Enza ¼ 13.4 mo B Pb ¼ 9.5 mo
Primary Analysis Study Arms Patient Population Study ID
Table 1. Continued
UROLOGY
immune-checkpoint inhibition in other tumor types. The goal of this review is to educate urologists and other interested readers on current and emerging immunotherapies for CRPC. We will emphasize immunecheckpoint inhibition, as this approach is expected to play an increasingly important role in CRPC treatment. This review is divided into 4 main sections. The first focuses on vaccine-based strategies and other select immunotherapies, including sipuleucel-T, GVAX (Cell Genesys Inc, San Francisco, CA), PROSTVAC (PROSTVAC, Mountain View, CA), and tasquinimod. In this section, we review data from clinical trials that support the current or future use of these agents in the treatment of CRPC. The section second focuses on immune-checkpoint inhibition with ipilimumab, which is currently approved for the treatment of metastatic melanoma and is the subject of a large development program in CRPC. In this section, we summarize findings from the melanoma experience with ipilimumab and consider how these data may inform the future use of this agent for prostate cancer. The third section focuses on the potential of ipilimumab as a treatment for mCRPC. In this section, we review data from study CA184-043, the first phase 3 trial of ipilimumab outside of the melanoma setting. We consider how data from this study have generated hypotheses for further evaluation of ipilimumab in mCRPC patients. In particular, we describe the ongoing phase 3 study, CA184-095, designed to evaluate the role of ipilimumab in chemotherapy-naïve patients with asymptomatic or minimally symptomatic CRPC. The fourth section focuses on the potential for combining or sequencing immune-checkpoint inhibitors with hormonal and bone-targeting agents to improve antitumor activity.
VACCINE-BASED AND OTHER IMMUNOTHERAPY The goal of vaccine-based immunotherapy is to stimulate a specific antitumor immune response against 1 tumor antigens while minimizing collateral damage to normal tissues.15 To accomplish this goal, vaccine-based immunotherapies often use prostate-specific or tumor-specific antigens (eg, prostate-specific antigen [PSA], prostatic acid phosphatase, or prostate stem cell antigen), to direct therapeutic effects. Equally important is the use of an effective delivery system to promote antitumor immune responses. Although many antigen delivery vehicles are available, few studies have directly compared these approaches. The 4 main types of vaccine-based immunotherapies studied in CRPC can be classified as autologous, cellbased, viral vectorebased, and DNA vaccines.15 Autologous vaccines, such as sipuleucel-T (Provenge, Dendreon Corp, Seattle, WA), are derived from a patient’s own tumor cells, which can be grown in vitro and transfected with agents such as tumor antigens or cytokines before being reintroduced to the patient. Cell-based vaccines, such as GVAX, use autogenic or allogenic 3
Figure 1. Current and emerging* treatment approaches for patients with mCRPC. *Selected potential future approaches only are shown. CTLA-4, cytotoxic T-lymphocyteeassociated antigen 4; IPI, ipilimumab; MHC, major histocompatibility complex; TCR, T-cell receptor. Figures reprinted with permission from the following copyright holders: Bottom left: “For the National Cancer Institute ª 2013 Terese Winslow LLC, U.S. Govt, has certain rights”; Bottom right: (denosumab) von Moos, R and Haynes, I. Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment? J Clin Med. 2013;2:89-102 and (zoledronic acid). Source: Roodman GD. Treatment of myeloma bone disease. www.clinicaloptions.com/oncology.
tumor cells to generate an immune response. This treatment strategy stimulates multiple antigens, which may decrease the likelihood of tumor evasion. Viral vectorebased vaccines, such as PROSTVAC, mimic natural infection and can induce a potent immune response. In this approach, a gene encoding a specific antigen is packaged into a recombinant viral vector, which is then administered to the patient as a live, attenuated virus. Deoxyribonucleic acid (DNA) vaccination is an approach in which DNA for a specific antigen is injected into the patient, in an attempt to transduce cells at the injection site, leading to the production of immunogenic protein and subsequent antitumor immune response. DNA vaccines are easy to produce and administer but have a low rate of cell transfection. As described in the following section, immunotherapy with vaccine-based approaches (sipuleucel-T, GVAX, PROSTVAC) and other novel agents (tasquinimod) has yielded mixed results in CRPC, and the role of these immunotherapies in the future treatment of CRPC remains to be determined. Sipuleucel-T Sipuleucel-T is an autologous vaccine designed to induce an immune response against prostatic acid phosphatase, an antigen that is expressed by >95% of prostate cancer cells.16 Sipuleucel-T is derived from a patient’s own immune cells, which are cultured and activated in vitro, and 4
then reintroduced into the patient to stimulate an antitumor immune response.16 In 2010, sipuleucel-T became the first therapeutic cancer vaccine to be approved by the FDA. FDA approval was based on improved OS, which was demonstrated in the double-blind, placebocontrolled, multicenter, phase 3 IMPACT trial.17 In this study of men with asymptomatic or minimally symptomatic mCRPC, sipuleucel-T prolonged survival by 4.1 months compared with placebo (25.8 months with sipuleucel-T vs 21.7 months with placebo [HR, 0.78; P ¼ .03]); no statistically significant difference between groups was observed in PSA response or progression-free survival (PFS).17 Sipuleucel-T was generally well tolerated in this study, with low-grade adverse events (AEs) such as fever and chills associated with drug infusion. An exploratory analysis was conducted by Schellhammer et al18 to evaluate the prognostic and predictive value of baseline variables in mCRPC patients enrolled in the IMACT trial. This analysis showed that the strongest baseline prognostic factor was PSA, and the sipuleucel-T treatment effect appeared to be greater with a decline in baseline PSA. When subdivided into quartiles, median OS (mOS) improved from 13 months in the lowest PSA baseline quartile to 2.8 months in the highest quartile. These results demonstrate that a greater treatment benefit with sipuleucel-T occurs in patients with more favorable baseline prognostic factors. Overall, these results reflect UROLOGY
-
(-), 2015
an emerging theme for immunotherapy: The use of immunotherapy should be included as early as possible in any treatment regimen for mCRPC or other advanced cancers. GVAX GVAX is a cell-based vaccine derived from 2 prostate cancer cell lines, LNCaP and PC3, genetically modified to secrete granulocyte-macrophage colony-stimulating factor, an immunostimulatory cytokine. In a phase 1/2 dose-escalating study of patients with metastatic prostate cancer, GVAX was associated with a tolerable safety profile, PSA decrease and stabilization, and a median survival time of 35.0 months with high-dose treatment.19 These results prompted the initiation of 2 phase 3 studies, which were terminated early because of a lack of efficacy or because of increased mortality. In the first phase 3 study (VITAL-1), which evaluated GVAX monotherapy vs docetaxel/prednisone, futility analysis indicated that the trial had a
P
rostate cancer is the second most common cancer in men worldwide and the fifth leading cause of cancer-related deaths in men.1 An estimated 1.1 million men worldwide were diagnosed with prostate cancer in 2012, and 307,000 deaths from this disease were reported.1 Patients with advanced-stage prostate cancer are typically managed with radiotherapy, surgery, and/or androgen-deprivation therapy, which aim to reduce testosterone to castrate levels and reduce tumor burden.2 Although most patients initially respond to treatment, many eventually develop castration-resistant prostate cancer (CRPC), a clinical state in which disease progression occurs despite surgical or chemical castration.2 CRPC is not a single, homogenous disorder, but rather a spectrum of clinical states ranging from asymptomatic or minimally symptomatic, nonmetastatic disease to symptomatic disease with metastases. Although each patient’s disease course may be different in terms of timing, there is a general progression from asymptomatic to symptomatic disease and potentially death. Until recently, treatment options for metastatic CRPC (mCRPC) were limited to docetaxel-based chemotherapy. In 2005, docetaxel in combination with prednisone was approved by the US Food and Drug Administration (FDA) on the basis of an overall survival (OS) benefit, which was The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical expertise. Professional medical writing assistance was provided by Jennifer DiNieri and professional editing assistance was provided by Matthew Dougherty at StemScientific and was funded by Bristol-Myers Squibb. Neither BristolMyers Squibb nor StemScientific influenced the content of the manuscript, nor did the authors receive financial compensation for authoring the article. Financial Disclosure: Fred Saad has served as a consultant and received research funding from Bristol-Myers Squibb, Astellas, Janssen, Bavarian Nordic, Sanofi, and Millennium. Kurt Miller is a paid consultant for Bayer, Bristol-Myers Squibb, Astellas, Janssen, Novartis, and Roche. From the Division of Urology, Department of Surgery, Centre Hospitalier de I’Universite de Montreal, Montreal, Quebec, Canada; and the Department of Urology, Charite Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany Address correspondence to: Fred Saad, M.D., Division of Urology, Department of Surgery, Centre Hospitalier de I’Universite de Montreal, Montreal, Quebec, Canada H2L 4M1. E-mail: [email protected] Submitted: September 30, 2014, accepted (with revisions): December 19, 2014
ª 2015 Elsevier Inc. All Rights Reserved
demonstrated in 2 phase 3 studies.3-5 Subsequently, docetaxel-based chemotherapy became the standard of care for patients with mCRPC, although its use was limited by patient or physician reluctance, particularly in an asymptomatic setting. Recently, the FDA approved 4 new agents (cabazitaxel, abiraterone acetate, enzalutamide, and radium-223 (Table 1; Fig. 1) based on demonstrated OS benefit in phase 3 studies.6-9 Cabazitaxel, a taxane chemotherapy agent, was the first agent to demonstrate improved survival in mCRPC patients in a postdocetaxel setting.6 Abiraterone acetate, a selective inhibitor of the enzyme CYP17, which plays a role in androgen biosynthesis, is approved by the FDA for the treatment of mCRPC patients in prechemotherapy and postchemotherapy settings.7,10 Enzalutamide, a competitive inhibitor of the androgen receptor, is FDA-approved for docetaxelexperienced patients with mCRPC8 and was recently shown to decrease the risk of disease progression and death in chemotherapy-naïve mCRPC patients.11 Radium-223, an a-emitting radiopharmaceutical, is approved for CRPC patients with bone metastases.9 Despite the improved therapeutic options for CRPC, there remains a need for treatments that can provide durable disease control and long-term survival benefit. Among the many strategies that are being investigated to address this need, immunotherapy is a compelling approach. Research suggests that prostate cancer is an immunologically modulated malignancy, and therefore, may be sensitive to immunotherapy. For example, data from studies that have evaluated the cellular composition of prostate tumors suggest that immune cell populations infiltrate the prostate gland.12,13 Infiltrating leukocytes detected in prostate tumors include natural killer cells, effector cells, and regulatory T cells, suggesting that both the innate and adaptive branches of the immune system may play a role in mounting an attack against prostate cancer cells.14 Although immunotherapy for prostate cancer has been associated with disappointing results in the past, there is renewed interest because of the recent success of http://dx.doi.org/10.1016/j.urology.2014.12.029 0090-4295/15
1
2
Table 1. Results of completed phase 3 trials in advanced prostate cancer Study ID Chemotherapy TAX 327
Patient Population mCRPC
SWOG 99-16 NCT00004001
mCRPC
TROPIC NCT00417079
mCRPC, postdocetaxel
Agents that target the androgen receptor pathway COU-AA-301 mCRPC, postdocetaxel NCT00638690
COU-AA-302 NCT00887198
mCRPC, chemonaïve
Study Arms Arm 1: D1 þ P (n ¼ 334*) Arm 2: D3 þ P (n ¼ 335*) Arm 3: M þ P (n ¼ 337*) Arm 1: D þ E (n ¼ 338y) Arm 2: M þ P (n ¼ 336y) Arm 1: C þ P (n ¼ 378*) Arm 2: M þ P (n ¼ 377*)
Primary Analysis
Subgroup Analysis: þ/ VM
mOS
mOS
D1 þ P ¼ 17.8 mo D3 þ P ¼ 19.2 mo M þ P ¼ 16.3 mo mOS
VM ¼ 18.9 mo þVM ¼ 13.1 mo
D þ E ¼ 17.5 mo M þ P ¼ 15.6 mo mOS
Reference Berthold 20083
Pts with VMs were enrolled in this study, but no subgroup analysis was performed
Petrylak 20044
HR for pts þ/ measurable diseasex
de Bono 20106
C þ P ¼ 15.1 mo M þ P ¼ 12.7 mo
Measurable disease ¼ 0.72 þMeasurable disease ¼ 0.68
Arm 1: Abi þ P (n ¼ 797*) Arm 2: Pb þ P (n ¼ 398*)
mOS
mOS
de Bono 20117
Abi þ P ¼ 14.8 mo Pb þ P ¼ 10.9 mo
Arm 1: Abi þ P (n ¼ 546*) Arm 2: Pb þ P (n ¼ 542*)
Median radiographic PFS
VM B Abi þ P ¼ 15.4 mo B Pb þ P ¼ 11.2 mo þVM B Abi þ P ¼ 12.6 mo B Pb þ P ¼ 8.4 mo Pts with VMs were excluded
Ryan 201310
mOS
Beer 201411
Abi þ P ¼ 16.5 mo Pb þ P ¼ 8.3 mo
mOS
PREVAIL NCT01212991
mCRPC, chemonaïve
Arm 1: Enza (n ¼ 872z) Arm 2: Pb (n ¼ 845z)
Abi þ P ¼ not reached Pb þ P ¼ 27.2 mo Rate of radiographic PFS Enza ¼ 65% Pb ¼ 14%
UROLOGY
mOS
-
AFFIRM NCT00974311
CRPC, postdocetaxel
Arm 1: Enza (n ¼ 800*) Arm 2: Pb (n ¼ 399*)
Enza ¼ not reached Pb ¼ 31.0 mo mOS
(-), 2015
Enza ¼ 18.4 mo Pb ¼ 13.6 mo
VM B Enza ¼ not reached B Pb ¼ 30.2 mo þVM B Enza ¼ 27.8 mo B Pb ¼ 22.8 mo mOS
Scher 20128
VM B Enza ¼ not reached B Pb ¼ 14.2 mo Continued
Abi, abiraterone acetate; C, cabazitaxel; D, docetaxel; D1, docetaxel once every week; D3, docetaxel every 3 weeks; E, estramustine; Enza, enzalutamide; HR, hazard ratio; ID, identifier; Ipi, ipilimumab; M, mitoxantrone; mCRPC, metastatic castration-resistant prostate cancer; mOS, median overall survival; P, prednisone; Pb, placebo; PC, prostate cancer; PFS, progression-free survival; pts, patients; Rad-223, radium-223; RT, radiotherapy; VM, visceral metastases. * Number of randomized patients. y Number of treatment-eligible patients. z Number of patients who enrolled. x Defined as documented disease progression by RECIST criteria and at least one visceral or soft-tissue metastatic lesion.
VM ¼ 0.73 þVM ¼ 1.20 Ipi þ RT ¼ 11.2 mo Pb þ RT ¼ 10.0 mo
Kwon 201437 HR
Arm 1: Ipi þ RT (n ¼ 399*) Arm 2: Pb þ RT (n ¼ 400*)
(-), 2015
mCRPC, postdocetaxel Immunotherapy CA184-043 NCT00861614
Rad-223 ¼ 14.9 mo Pb ¼ 11.3 mo
Arm 1: Rad-223 (n ¼ 614*) Arm 2: Pb (n ¼ 307*)
mOS
Parker 20139 -
Bone-targeted therapy ALSYMPCA CRPC and bone NCT00699751 metastases
mOS
Pts with VM were excluded from this study
Reference Subgroup Analysis: þ/ VM
þVM B Enza ¼ 13.4 mo B Pb ¼ 9.5 mo
Primary Analysis Study Arms Patient Population Study ID
Table 1. Continued
UROLOGY
immune-checkpoint inhibition in other tumor types. The goal of this review is to educate urologists and other interested readers on current and emerging immunotherapies for CRPC. We will emphasize immunecheckpoint inhibition, as this approach is expected to play an increasingly important role in CRPC treatment. This review is divided into 4 main sections. The first focuses on vaccine-based strategies and other select immunotherapies, including sipuleucel-T, GVAX (Cell Genesys Inc, San Francisco, CA), PROSTVAC (PROSTVAC, Mountain View, CA), and tasquinimod. In this section, we review data from clinical trials that support the current or future use of these agents in the treatment of CRPC. The section second focuses on immune-checkpoint inhibition with ipilimumab, which is currently approved for the treatment of metastatic melanoma and is the subject of a large development program in CRPC. In this section, we summarize findings from the melanoma experience with ipilimumab and consider how these data may inform the future use of this agent for prostate cancer. The third section focuses on the potential of ipilimumab as a treatment for mCRPC. In this section, we review data from study CA184-043, the first phase 3 trial of ipilimumab outside of the melanoma setting. We consider how data from this study have generated hypotheses for further evaluation of ipilimumab in mCRPC patients. In particular, we describe the ongoing phase 3 study, CA184-095, designed to evaluate the role of ipilimumab in chemotherapy-naïve patients with asymptomatic or minimally symptomatic CRPC. The fourth section focuses on the potential for combining or sequencing immune-checkpoint inhibitors with hormonal and bone-targeting agents to improve antitumor activity.
VACCINE-BASED AND OTHER IMMUNOTHERAPY The goal of vaccine-based immunotherapy is to stimulate a specific antitumor immune response against 1 tumor antigens while minimizing collateral damage to normal tissues.15 To accomplish this goal, vaccine-based immunotherapies often use prostate-specific or tumor-specific antigens (eg, prostate-specific antigen [PSA], prostatic acid phosphatase, or prostate stem cell antigen), to direct therapeutic effects. Equally important is the use of an effective delivery system to promote antitumor immune responses. Although many antigen delivery vehicles are available, few studies have directly compared these approaches. The 4 main types of vaccine-based immunotherapies studied in CRPC can be classified as autologous, cellbased, viral vectorebased, and DNA vaccines.15 Autologous vaccines, such as sipuleucel-T (Provenge, Dendreon Corp, Seattle, WA), are derived from a patient’s own tumor cells, which can be grown in vitro and transfected with agents such as tumor antigens or cytokines before being reintroduced to the patient. Cell-based vaccines, such as GVAX, use autogenic or allogenic 3
Figure 1. Current and emerging* treatment approaches for patients with mCRPC. *Selected potential future approaches only are shown. CTLA-4, cytotoxic T-lymphocyteeassociated antigen 4; IPI, ipilimumab; MHC, major histocompatibility complex; TCR, T-cell receptor. Figures reprinted with permission from the following copyright holders: Bottom left: “For the National Cancer Institute ª 2013 Terese Winslow LLC, U.S. Govt, has certain rights”; Bottom right: (denosumab) von Moos, R and Haynes, I. Where Do Bone-Targeted Agents RANK in Breast Cancer Treatment? J Clin Med. 2013;2:89-102 and (zoledronic acid). Source: Roodman GD. Treatment of myeloma bone disease. www.clinicaloptions.com/oncology.
tumor cells to generate an immune response. This treatment strategy stimulates multiple antigens, which may decrease the likelihood of tumor evasion. Viral vectorebased vaccines, such as PROSTVAC, mimic natural infection and can induce a potent immune response. In this approach, a gene encoding a specific antigen is packaged into a recombinant viral vector, which is then administered to the patient as a live, attenuated virus. Deoxyribonucleic acid (DNA) vaccination is an approach in which DNA for a specific antigen is injected into the patient, in an attempt to transduce cells at the injection site, leading to the production of immunogenic protein and subsequent antitumor immune response. DNA vaccines are easy to produce and administer but have a low rate of cell transfection. As described in the following section, immunotherapy with vaccine-based approaches (sipuleucel-T, GVAX, PROSTVAC) and other novel agents (tasquinimod) has yielded mixed results in CRPC, and the role of these immunotherapies in the future treatment of CRPC remains to be determined. Sipuleucel-T Sipuleucel-T is an autologous vaccine designed to induce an immune response against prostatic acid phosphatase, an antigen that is expressed by >95% of prostate cancer cells.16 Sipuleucel-T is derived from a patient’s own immune cells, which are cultured and activated in vitro, and 4
then reintroduced into the patient to stimulate an antitumor immune response.16 In 2010, sipuleucel-T became the first therapeutic cancer vaccine to be approved by the FDA. FDA approval was based on improved OS, which was demonstrated in the double-blind, placebocontrolled, multicenter, phase 3 IMPACT trial.17 In this study of men with asymptomatic or minimally symptomatic mCRPC, sipuleucel-T prolonged survival by 4.1 months compared with placebo (25.8 months with sipuleucel-T vs 21.7 months with placebo [HR, 0.78; P ¼ .03]); no statistically significant difference between groups was observed in PSA response or progression-free survival (PFS).17 Sipuleucel-T was generally well tolerated in this study, with low-grade adverse events (AEs) such as fever and chills associated with drug infusion. An exploratory analysis was conducted by Schellhammer et al18 to evaluate the prognostic and predictive value of baseline variables in mCRPC patients enrolled in the IMACT trial. This analysis showed that the strongest baseline prognostic factor was PSA, and the sipuleucel-T treatment effect appeared to be greater with a decline in baseline PSA. When subdivided into quartiles, median OS (mOS) improved from 13 months in the lowest PSA baseline quartile to 2.8 months in the highest quartile. These results demonstrate that a greater treatment benefit with sipuleucel-T occurs in patients with more favorable baseline prognostic factors. Overall, these results reflect UROLOGY
-
(-), 2015
an emerging theme for immunotherapy: The use of immunotherapy should be included as early as possible in any treatment regimen for mCRPC or other advanced cancers. GVAX GVAX is a cell-based vaccine derived from 2 prostate cancer cell lines, LNCaP and PC3, genetically modified to secrete granulocyte-macrophage colony-stimulating factor, an immunostimulatory cytokine. In a phase 1/2 dose-escalating study of patients with metastatic prostate cancer, GVAX was associated with a tolerable safety profile, PSA decrease and stabilization, and a median survival time of 35.0 months with high-dose treatment.19 These results prompted the initiation of 2 phase 3 studies, which were terminated early because of a lack of efficacy or because of increased mortality. In the first phase 3 study (VITAL-1), which evaluated GVAX monotherapy vs docetaxel/prednisone, futility analysis indicated that the trial had a
