DRUG EVALUATION For reprint orders, please contact: [email protected]
Ipilimumab in the treatment of prostate cancer
Zachary Reese‡,1, Ali Straubhar‡,2, Sumanta K Pal3 & Neeraj Agarwal*,1
ABSTRACT Ipilimumab (Yervoy®; Bristol-Myers Squibb, NY, USA) is a fully human
monoclonal antibody targeting CTLA-4 and is approved for the treatment of metastatic melanoma. Preclinical and clinical studies have shown its activity in a number of different cancer types, including prostate cancer. Recently, the results from a Phase III study of ipilimumab in prostate cancer patients with prior docetaxel therapy were reported. Although the study did not meet the primary end point of improved overall survival, prespecified subset analyses suggested that ipilimumab may be more active in men with lower disease burden, which suggests that immunotherapy should be tested early in men with castrationrefractory prostate cancer. Immune-related adverse events are common and most can be well managed with standard immunosuppressive algorithms. Prostate cancer is the most common noncutaneous malignancy and the second most common cause of cancer deaths among men [1] . More than 238,000 men were diagnosed with prostate cancer in 2013. Furthermore, approximately 29,000 men were estimated to have died of their disease, mainly because of progression to metastatic disease. Targeting gonadal androgen synthesis either by medical or surgical castration is the cornerstone of treatment for metastatic prostate cancer. However, responses are not durable and almost all men experience disease progression to castrate-resistant prostate cancer, despite castrate levels of testosterone [2] . Until 2010, the only systemic regimen known to extend survival of men with metastatic castration-resistant prostate cancer (mCRPC) was docetaxel-based chemotherapy [3,4] . Since then, the therapeutic landscape of mCRPC has rapidly changed with the arrival of multiple novel agents. In May 2010, regulatory approval of sipuleucel-T for mCRPC valdiated immune modulation as an effective strategy in prostate cancer. Since then, an androgen synthesis inhibitor (abiraterone acetate), an androgen signaling inhibitor (enzalutamide), a chemotherapeutic agent (cabazitaxel) and a radiopharmaceutical (radium-223) have been approved. Despite this dramatic expansion in the therapeutic armamentarium, all of the aforementioned agents provide incremental gains and extend median survival only by 3–5 months. There is a need to develop newer therapies without overlapping mechanisms of action and toxicities in order to improve these outcomes. Advances in the field of cancer immunology have led to an improved understanding of the interactions between the immune system and tumors, propelling the field of cancer immunotherapy to the forefront of clinical investigation. Prostate cancer cells express a number of tumor-associated antigens, including prostate acid phosphatase (PAP), prostate surface antigen (PSA) and prostate
KEYWORDS
• CTLA-4 • immunotherapy • ipilimumab • prostate
cancer
Division of Medical Oncology, Department of Medicine, University of Utah Huntsman Cancer Institute, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT 84112, USA 2 University of Utah School of Medicine, Salt Lake City, UT, USA 3 City of Hope Comprehensive Cancer Center, Duarte, CA, USA *Author for correspondence: Tel.: +1 801 585 0255; Fax: +1 801 585 0124; [email protected] ‡ Authors contributed equally 1
10.2217/FON.14.196 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(1), 27–37
part of
ISSN 1479-6694
27
Drug Evaluation Reese, Straubhar, Pal & Agarwal surface membrane antigen (PSMA), which can serve as targets for immunotherapy. Overview of the market Sipuleucel-T (Provenge® ; Dendreon, Inc., WA, USA), a first-of-its-kind cellular vaccine, consists of autologous dendritic cells enriched with a CD54 + dendritic cell fraction harvested by leukopheresis and exposed to a fusion protein (PA2024) comprised of PAP and GM-CSF and then reinfused, thereby inducing an immune response to PAP-expressing prostate cancer cells [5] . Based on data from the Phase III IMPACT trial including 512 men with asymptomatic or minimally symptomatic mCRPC, sipuleucel-T was approved in April 2010 for this population [5] . The IMPACT trial demonstrated a significantly improved median overall survival with sipuleucel-T over placebo (25.8 vs 21.7 months; hazard ratio [HR]: 0.77; p = 0.02), with a 22% relative reduction in the risk of death in the sipuleucel-T group (HR: 0.78; p = 0.03) [5] . Regulatory approval of sipuleucel-T represents a significant advancement in the field of prostate cancer immunotherapy. However, the survival benefit with sipuleucel-T is modest at best and the field of prostate cancer immunotherapy continues to evolve. The inherent immunogenicity of viruses and the high level of gene expression seen with viral vectors may lead to an improved immune response against tumor antigens expressed by viruses [6] . One example is PROSTVAC®-VF (Bavarian Nordic, Denmark), which utilizes a heterologous prime/boost vaccination strategy. PROSTVAC-VF comprises two recombinant viral vectors (vaccinia vector and fowlpox vector), each encoding transgenes for PSA and TRICOM™. TRICOM consists of costimulatory molecules, including ICAM1 (CD54), B7.1 (CD80) and LFA-3 (CD58). Preclinical studies demonstrated TRICOM to be superior compared with a transgene containing only one or two of the costimulatory molecules [7] . In a placebo-controlled Phase II trial, men with minimally symptomatic, chemotherapynaive mCRPC (n = 122) were randomized to receive PROSTVAC-VF and GM-CSF or empty vectors plus saline injections [8] . The therapy was well tolerated. Although there was no difference in progression-free survival, the median overall survival was significantly improved (25.1 vs 16.6 months; estimated HR: 0.56; 95% CI: 0.37–0.85; p = 0.0061). Given
28
Future Oncol. (2015) 11(1)
these preliminary data, PROSTVAC-VF has the potential to expand the currently limited immunotherapeutic armamentarium against mCRPC. A Phase III trial of PROSTVAC-VF is being conducted in patients with asymptomatic or minimally symptomatic disease (NCT01322490). Monoclonal antibodies targeting specific proteins expressed on the surface of tumor cells exemplify passive immunotherapy and are approved in the treatment of several malignancies [9] . PSMA is a membrane glycoprotein that is markedly upregulated in prostate cancer [10] . Monoclonal antibodies targeting PSMA are in advanced phases of development. The naked anti-PSMA antibody, J591, demonstrated marginal antitumor activity [11] . Radioimmunoconjugates of J591 and radiopharmaceuticals (Y-90, Lu-177) have demonstrated more promising activity and tolerable cytopenia [12–16] . Between Y-90 and Lu-177, the latter has been favored for further development as it can be administered in higher doses with comparatively less radiation to the marrow, and because of its γ-emission, it enables imaging to be performed using the treatment doses [10] . An ongoing Phase II trial is evaluating 177Lu-J591 in combination with ketoconazole and hydrocortisone in non-mCRPC with rapidly rising PSA (PSA doubling time 10 μg/ml were maintained for 60 days with a single ipilimumab infusion. The mean (± SD) total body clearance was low at 0.01 l/h (± 0.004 l/h) and ranged from 0.005 to 0.017 l/h, with plasma concentrations maintained above 10 μg/ml for 60 days after a single infusion [21] . There was
Inhibition of T-cell activation
CTLA-4 impediment
T cell
T cell
T cell
APC
APC
APC
CD28
TCR
CTLA-4
Drug Evaluation
B7-1, B7-2
Peptide/MHC
CTLA-4 blocking antibody
Figure 1. Role of CTLA-4 in T-cell activation. (A) Binding of the peptide/MHC with the TCR is the first signal in T-cell activation. Costimulatory signaling via the binding of CD28 with B7 then triggers the optimal activation of T cells. (B) The expression of CTLA-4 is induced by T-cell activation. CTLA-4 competes with CD28 for the binding of B7, with CTLA-4 having a much higher affinity for B7. Binding between CTLA-4 and B7 provides an inhibitory signal that turns off or prevents T-cell activation. (C) CTLA-4-blocking antibodies prevent binding between CTLA-4 and B7, thus removing the inhibitory signal to T-cell activation. APC: Antigen-presenting cell; TCR: T-cell receptor.
future science group
www.futuremedicine.com
29
Drug Evaluation Reese, Straubhar, Pal & Agarwal considerable intersubject variability. No dose adjustments are necessary for renal impairment or mild hepatic impairment [22] .
(CD25, CD44, CD45RO, CD69 and MHC class II molecules). ●●Clinical efficacy
●●Preclinical studies & pharmacodynamics
The end result of T-cell receptor stimulation is determined by competing inhibitory signals from CTLA-4 and costimulatory signals from CD28 [23] . Ipilimumab-mediated blockade of CTLA-4 led to T-cell proliferation via the loss of inhibitory signals. CTLA-4-deficient mice have been shown to develop a rapidly progressive lymphoproliferative disorder that is fatal by 3–4 weeks of age [24,25] . Significant tumor responses and regression have been demonstrated after CTLA-4 blockade in mice injected with murine colon cancer cell lines [26] . Similar findings were also seen in murine fibrosarcoma and ovarian cancer models [27] . By contrast, antiCTLA-4 therapy by itself was not sufficient to produce a response in some poorly immunogenic tumors, such as B16 melanoma, SM1 mammary carcinoma, EL4 lymphoma, M109 lung cancer and MOPC-315 plasmacytoma models [28,29] . In an early preclinical study in prostate cancer, CTLA-4 blockade was sufficient to induce partial or complete regression of subcutaneous implants of tumor cell lines derived from the transgenic adenocarcinoma of the mouse prostate (TRAMP) model [30] . Following this, the potential of CTLA-4 blockade in the treatment of primary prostate cancer in TRAMP mice was studied [31] . TRAMP mice treated with either the CTLA-4 antibody (intraperitoneal injections of 100 μg of anti-CTLA-4 antibodies) or irradiated tumor cell vaccines alone showed no reduction in tumor incidence or tumor grade; however, the combination of both treatments resulted in a significant reduction in both criteria. Histological analysis of treated tumors showed an accumulation of inflammatory cells, thus supporting the role of immune modulation in tumor response. In a Phase I study of ipilimumab in prostate cancer, in which 14 men with mCRPC were treated with ipilimumab, there was an increase in CD4 T cells (but not in CD8 T cells) coexpressing MHC class II molecules for up to 28 days [21] . However, there was no change in the erythrocyte sedimentation rate, levels of complement proteins (C3, C4 or CH50) or antinuclear antibodies, composition of lymphocyte subpopulations (by flow cytometry) or change in the T-cell surface activation markers
30
Future Oncol. (2015) 11(1)
Phase I/II studies of ipilimumab in prostate cancer Ipilimumab monotherapy in mCRPC
In the first study to document the safety and immune effects of an anti-CTLA-4 antibody in men with prostate cancer, 14 men with mCRPC were treated with a single dose of 3 mg/kg of ipilimumab in addition to the continuation of androgen-deprivation therapy [21] . In total, 50% of patients had received previous chemotherapy. Two patients experienced a decline in PSA of ≥50% (lasting 60 and 135 days) and eight patients experienced a decline of 13 months. Among the 28 tumor-evaluable patients, one had a complete response and six had stable disease lasting for 2.8–6.1 months. Phase III studies of ipilimumab in prostate cancer
Two large, placebo-controlled, Phase III trials of ipilimumab have completed accrual in chemotherapy-naive or post-docetaxel mCRPC patients. The results of the Phase III trial in the post-docetaxel mCRPC setting were recently reported [38] . Men with mCRPC were randomized (1:1) to receive bone-directed radiotherapy at 8 Gy prior to either 10 mg/kg ipilimumab (n = 399) or placebo (n = 400) every 3 weeks for four doses, followed by one dose every 3 months in patients with nonprogressive disease. Notable inclusion criteria were: the presence of one or more bone metastasis that could be irradiated or warranted irradiation in the clinical judgment of the investigator; castrate level of serum testosterone; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and progression ≤6 months after receiving docetaxel. Exclusion criteria included prior treatment with more than two cytotoxic chemotherapy regimens for mCRPC and the presence of brain metastases, autoimmune disease or known HIV or hepatitis B or C infection. A total of 799 patients with mCRPC were randomized in a 1:1 fashion to receive bone-directed radiotherapy followed by either ipilimumab at 10 mg/kg or placebo every 3 weeks for up to four doses (intravenous infusion for 90 min each). Patients with nonprogressing disease could receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months. Within 2 days prior to the first dose of ipilimumab/placebo, radiotherapy was delivered as a single dose at 8 Gy to at least one and up to five bone fields based on investigator discretion. Palliative radiotherapy was allowed to any bone lesion while on the study. The stratification factors used for randomization were ECOG performance status (0 vs 1), alkaline phosphatase (
Ipilimumab in the treatment of prostate cancer
Zachary Reese‡,1, Ali Straubhar‡,2, Sumanta K Pal3 & Neeraj Agarwal*,1
ABSTRACT Ipilimumab (Yervoy®; Bristol-Myers Squibb, NY, USA) is a fully human
monoclonal antibody targeting CTLA-4 and is approved for the treatment of metastatic melanoma. Preclinical and clinical studies have shown its activity in a number of different cancer types, including prostate cancer. Recently, the results from a Phase III study of ipilimumab in prostate cancer patients with prior docetaxel therapy were reported. Although the study did not meet the primary end point of improved overall survival, prespecified subset analyses suggested that ipilimumab may be more active in men with lower disease burden, which suggests that immunotherapy should be tested early in men with castrationrefractory prostate cancer. Immune-related adverse events are common and most can be well managed with standard immunosuppressive algorithms. Prostate cancer is the most common noncutaneous malignancy and the second most common cause of cancer deaths among men [1] . More than 238,000 men were diagnosed with prostate cancer in 2013. Furthermore, approximately 29,000 men were estimated to have died of their disease, mainly because of progression to metastatic disease. Targeting gonadal androgen synthesis either by medical or surgical castration is the cornerstone of treatment for metastatic prostate cancer. However, responses are not durable and almost all men experience disease progression to castrate-resistant prostate cancer, despite castrate levels of testosterone [2] . Until 2010, the only systemic regimen known to extend survival of men with metastatic castration-resistant prostate cancer (mCRPC) was docetaxel-based chemotherapy [3,4] . Since then, the therapeutic landscape of mCRPC has rapidly changed with the arrival of multiple novel agents. In May 2010, regulatory approval of sipuleucel-T for mCRPC valdiated immune modulation as an effective strategy in prostate cancer. Since then, an androgen synthesis inhibitor (abiraterone acetate), an androgen signaling inhibitor (enzalutamide), a chemotherapeutic agent (cabazitaxel) and a radiopharmaceutical (radium-223) have been approved. Despite this dramatic expansion in the therapeutic armamentarium, all of the aforementioned agents provide incremental gains and extend median survival only by 3–5 months. There is a need to develop newer therapies without overlapping mechanisms of action and toxicities in order to improve these outcomes. Advances in the field of cancer immunology have led to an improved understanding of the interactions between the immune system and tumors, propelling the field of cancer immunotherapy to the forefront of clinical investigation. Prostate cancer cells express a number of tumor-associated antigens, including prostate acid phosphatase (PAP), prostate surface antigen (PSA) and prostate
KEYWORDS
• CTLA-4 • immunotherapy • ipilimumab • prostate
cancer
Division of Medical Oncology, Department of Medicine, University of Utah Huntsman Cancer Institute, 2000 Circle of Hope, Ste 2123, Salt Lake City, UT 84112, USA 2 University of Utah School of Medicine, Salt Lake City, UT, USA 3 City of Hope Comprehensive Cancer Center, Duarte, CA, USA *Author for correspondence: Tel.: +1 801 585 0255; Fax: +1 801 585 0124; [email protected] ‡ Authors contributed equally 1
10.2217/FON.14.196 © 2015 Future Medicine Ltd
Future Oncol. (2015) 11(1), 27–37
part of
ISSN 1479-6694
27
Drug Evaluation Reese, Straubhar, Pal & Agarwal surface membrane antigen (PSMA), which can serve as targets for immunotherapy. Overview of the market Sipuleucel-T (Provenge® ; Dendreon, Inc., WA, USA), a first-of-its-kind cellular vaccine, consists of autologous dendritic cells enriched with a CD54 + dendritic cell fraction harvested by leukopheresis and exposed to a fusion protein (PA2024) comprised of PAP and GM-CSF and then reinfused, thereby inducing an immune response to PAP-expressing prostate cancer cells [5] . Based on data from the Phase III IMPACT trial including 512 men with asymptomatic or minimally symptomatic mCRPC, sipuleucel-T was approved in April 2010 for this population [5] . The IMPACT trial demonstrated a significantly improved median overall survival with sipuleucel-T over placebo (25.8 vs 21.7 months; hazard ratio [HR]: 0.77; p = 0.02), with a 22% relative reduction in the risk of death in the sipuleucel-T group (HR: 0.78; p = 0.03) [5] . Regulatory approval of sipuleucel-T represents a significant advancement in the field of prostate cancer immunotherapy. However, the survival benefit with sipuleucel-T is modest at best and the field of prostate cancer immunotherapy continues to evolve. The inherent immunogenicity of viruses and the high level of gene expression seen with viral vectors may lead to an improved immune response against tumor antigens expressed by viruses [6] . One example is PROSTVAC®-VF (Bavarian Nordic, Denmark), which utilizes a heterologous prime/boost vaccination strategy. PROSTVAC-VF comprises two recombinant viral vectors (vaccinia vector and fowlpox vector), each encoding transgenes for PSA and TRICOM™. TRICOM consists of costimulatory molecules, including ICAM1 (CD54), B7.1 (CD80) and LFA-3 (CD58). Preclinical studies demonstrated TRICOM to be superior compared with a transgene containing only one or two of the costimulatory molecules [7] . In a placebo-controlled Phase II trial, men with minimally symptomatic, chemotherapynaive mCRPC (n = 122) were randomized to receive PROSTVAC-VF and GM-CSF or empty vectors plus saline injections [8] . The therapy was well tolerated. Although there was no difference in progression-free survival, the median overall survival was significantly improved (25.1 vs 16.6 months; estimated HR: 0.56; 95% CI: 0.37–0.85; p = 0.0061). Given
28
Future Oncol. (2015) 11(1)
these preliminary data, PROSTVAC-VF has the potential to expand the currently limited immunotherapeutic armamentarium against mCRPC. A Phase III trial of PROSTVAC-VF is being conducted in patients with asymptomatic or minimally symptomatic disease (NCT01322490). Monoclonal antibodies targeting specific proteins expressed on the surface of tumor cells exemplify passive immunotherapy and are approved in the treatment of several malignancies [9] . PSMA is a membrane glycoprotein that is markedly upregulated in prostate cancer [10] . Monoclonal antibodies targeting PSMA are in advanced phases of development. The naked anti-PSMA antibody, J591, demonstrated marginal antitumor activity [11] . Radioimmunoconjugates of J591 and radiopharmaceuticals (Y-90, Lu-177) have demonstrated more promising activity and tolerable cytopenia [12–16] . Between Y-90 and Lu-177, the latter has been favored for further development as it can be administered in higher doses with comparatively less radiation to the marrow, and because of its γ-emission, it enables imaging to be performed using the treatment doses [10] . An ongoing Phase II trial is evaluating 177Lu-J591 in combination with ketoconazole and hydrocortisone in non-mCRPC with rapidly rising PSA (PSA doubling time 10 μg/ml were maintained for 60 days with a single ipilimumab infusion. The mean (± SD) total body clearance was low at 0.01 l/h (± 0.004 l/h) and ranged from 0.005 to 0.017 l/h, with plasma concentrations maintained above 10 μg/ml for 60 days after a single infusion [21] . There was
Inhibition of T-cell activation
CTLA-4 impediment
T cell
T cell
T cell
APC
APC
APC
CD28
TCR
CTLA-4
Drug Evaluation
B7-1, B7-2
Peptide/MHC
CTLA-4 blocking antibody
Figure 1. Role of CTLA-4 in T-cell activation. (A) Binding of the peptide/MHC with the TCR is the first signal in T-cell activation. Costimulatory signaling via the binding of CD28 with B7 then triggers the optimal activation of T cells. (B) The expression of CTLA-4 is induced by T-cell activation. CTLA-4 competes with CD28 for the binding of B7, with CTLA-4 having a much higher affinity for B7. Binding between CTLA-4 and B7 provides an inhibitory signal that turns off or prevents T-cell activation. (C) CTLA-4-blocking antibodies prevent binding between CTLA-4 and B7, thus removing the inhibitory signal to T-cell activation. APC: Antigen-presenting cell; TCR: T-cell receptor.
future science group
www.futuremedicine.com
29
Drug Evaluation Reese, Straubhar, Pal & Agarwal considerable intersubject variability. No dose adjustments are necessary for renal impairment or mild hepatic impairment [22] .
(CD25, CD44, CD45RO, CD69 and MHC class II molecules). ●●Clinical efficacy
●●Preclinical studies & pharmacodynamics
The end result of T-cell receptor stimulation is determined by competing inhibitory signals from CTLA-4 and costimulatory signals from CD28 [23] . Ipilimumab-mediated blockade of CTLA-4 led to T-cell proliferation via the loss of inhibitory signals. CTLA-4-deficient mice have been shown to develop a rapidly progressive lymphoproliferative disorder that is fatal by 3–4 weeks of age [24,25] . Significant tumor responses and regression have been demonstrated after CTLA-4 blockade in mice injected with murine colon cancer cell lines [26] . Similar findings were also seen in murine fibrosarcoma and ovarian cancer models [27] . By contrast, antiCTLA-4 therapy by itself was not sufficient to produce a response in some poorly immunogenic tumors, such as B16 melanoma, SM1 mammary carcinoma, EL4 lymphoma, M109 lung cancer and MOPC-315 plasmacytoma models [28,29] . In an early preclinical study in prostate cancer, CTLA-4 blockade was sufficient to induce partial or complete regression of subcutaneous implants of tumor cell lines derived from the transgenic adenocarcinoma of the mouse prostate (TRAMP) model [30] . Following this, the potential of CTLA-4 blockade in the treatment of primary prostate cancer in TRAMP mice was studied [31] . TRAMP mice treated with either the CTLA-4 antibody (intraperitoneal injections of 100 μg of anti-CTLA-4 antibodies) or irradiated tumor cell vaccines alone showed no reduction in tumor incidence or tumor grade; however, the combination of both treatments resulted in a significant reduction in both criteria. Histological analysis of treated tumors showed an accumulation of inflammatory cells, thus supporting the role of immune modulation in tumor response. In a Phase I study of ipilimumab in prostate cancer, in which 14 men with mCRPC were treated with ipilimumab, there was an increase in CD4 T cells (but not in CD8 T cells) coexpressing MHC class II molecules for up to 28 days [21] . However, there was no change in the erythrocyte sedimentation rate, levels of complement proteins (C3, C4 or CH50) or antinuclear antibodies, composition of lymphocyte subpopulations (by flow cytometry) or change in the T-cell surface activation markers
30
Future Oncol. (2015) 11(1)
Phase I/II studies of ipilimumab in prostate cancer Ipilimumab monotherapy in mCRPC
In the first study to document the safety and immune effects of an anti-CTLA-4 antibody in men with prostate cancer, 14 men with mCRPC were treated with a single dose of 3 mg/kg of ipilimumab in addition to the continuation of androgen-deprivation therapy [21] . In total, 50% of patients had received previous chemotherapy. Two patients experienced a decline in PSA of ≥50% (lasting 60 and 135 days) and eight patients experienced a decline of 13 months. Among the 28 tumor-evaluable patients, one had a complete response and six had stable disease lasting for 2.8–6.1 months. Phase III studies of ipilimumab in prostate cancer
Two large, placebo-controlled, Phase III trials of ipilimumab have completed accrual in chemotherapy-naive or post-docetaxel mCRPC patients. The results of the Phase III trial in the post-docetaxel mCRPC setting were recently reported [38] . Men with mCRPC were randomized (1:1) to receive bone-directed radiotherapy at 8 Gy prior to either 10 mg/kg ipilimumab (n = 399) or placebo (n = 400) every 3 weeks for four doses, followed by one dose every 3 months in patients with nonprogressive disease. Notable inclusion criteria were: the presence of one or more bone metastasis that could be irradiated or warranted irradiation in the clinical judgment of the investigator; castrate level of serum testosterone; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and progression ≤6 months after receiving docetaxel. Exclusion criteria included prior treatment with more than two cytotoxic chemotherapy regimens for mCRPC and the presence of brain metastases, autoimmune disease or known HIV or hepatitis B or C infection. A total of 799 patients with mCRPC were randomized in a 1:1 fashion to receive bone-directed radiotherapy followed by either ipilimumab at 10 mg/kg or placebo every 3 weeks for up to four doses (intravenous infusion for 90 min each). Patients with nonprogressing disease could receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months. Within 2 days prior to the first dose of ipilimumab/placebo, radiotherapy was delivered as a single dose at 8 Gy to at least one and up to five bone fields based on investigator discretion. Palliative radiotherapy was allowed to any bone lesion while on the study. The stratification factors used for randomization were ECOG performance status (0 vs 1), alkaline phosphatase (
