Comment
Radium-223 is a bone-homing, α-emitting radiopharmaceutical approved for the treatment of men with castrate-resistant prostate cancer with bone metastases.1 In The Lancet Oncology, Oliver Sartor and colleagues2 now extend their findings by reporting the effects of radium-223 on bone-specific symptoms. The ALSYMPCA trial1 is unique because it included patients with bone metastases only, and did not bias the results of the study with routine radiographic imaging that might have driven post-treatment interventions. The newly reported findings complement the previously reported increase in overall survival1 of patients treated with radium-223 with the improvement of symptom-free survival too. Symptomatic skeletal-related events developed in 202 (33%) of 614 patients treated with radium-223 compared with 116 (38%) of 307 patients in the placebo group; however, the clinically meaningful benefit of radium-223 was best portrayed in the delay in time to symptomatic progression between groups: in the radium-223 group median time to symptomatic progression was 15·6 months (95% CI 13·5–18·0) compared with 9·8 months (7·3–23·7) in the placebo group (hazard ratio [HR]=0·66, 95% CI 0·52–0·83; p=0·00037). This delay rivals that achieved with second-generation androgen biosynthesis inhibitors in similar patients.3 As a result of this study, a new and safe method has been added to the inventory of available effective agents for advanced prostate cancer, and establish a new therapeutic paradigm by confirming the merits of bone targeting in men with advanced prostate cancer. The ALSYMPCA trial builds on past efforts to use radiopharmaceuticals in the treatment of bonemetastatic castrate-resistant prostate cancer. Strontium-89, the first class β-emitting radiopharmaceutical to relieve pain, lengthens time to symptomatic progression.4 Similar findings have been reported with samarium, but strontium and samarium are myelosuppressive, which limits their clinical utility. Radium-223, as a short-range α-emitting radiopharmaceutical, provides meaningful benefit without proportional haematological toxic effects. From a pragmatic clinical perspective, this profile broadens its potential clinical application by allowing the
development of combinations with other agents and permitting repetitive dosing. The investigators should be credited for selecting men likely to benefit, and showing that, in addition to prolongation of survival, patients benefitted from a reduction in cancerassociated symptoms. The absence of dose-limiting haematological toxic effects, and the lack of a proportional decrease in serum concentration of prostate-specific antigen (PSA) raises intriguing questions about the mechanisms of action of radium-223. The bone marrow is a frequent site in which prostate cancer cells are detected, and serum PSA concentration is a marker associated with cancer cell load within individual patients. The short range of α-particles possibly accounts for the reduced haematological toxic effects (the bone marrow is spared) but might not extend to areas where some cancers reside. Attributing the clinical benefits to radiation-induced cytoreduction in the absence of a decrease in serum PSA concentration is challenging. Other clinically effective therapeutics studied in men with castrate-resistant prostate cancer share the radium-223 response profile. For example, sipuleucel-T (Provenge, Dendreon Corporation, WA, USA), an approved prostate cancer vaccine, and cabozantinib, a VEGFR2/cMET-inhibiting tyrosine kinase inhibitor, have remarkable effects on bone scan results, serum alkaline phosphatase concentration, and bone pain, but less effect on serum PSA concentration.5–7 The small reduction in serum PSA concentration compels us to consider alternative hypotheses to account for the clinical efficacy of radium-223. Although speculative, plausible mechanisms include selective killing of nonPSA-expressing clones within range of the α-particles or indirect effects on tumour lethality through the modulation of the tumour microenvironment. What has become clear is that serum PSA concentration is neither predictive nor prognostic in the setting of metastatic castrate-resistant prostate cancer. An urgent need exists to identify, and build on, the mechanisms that explain the clinical efficacy of these agents, to identify predictive and companion markers that can be used to select who will benefit from radium-223, and to continue to monitor its efficacy .
www.thelancet.com/oncology Published online May 14, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70217-7
Simon Fraser/Medical Physics, RVI, Newcastle Upon-Tyne/Science Photo Library
Prostate cancer bone metastases: not so systemic after all
Lancet Oncol 2014 Published Online May 14, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70217-7 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(14)70183-4
1
Comment
Christopher J Logothetis
3
University of Texas, M D Anderson Cancer Center, Genitourinary Medical Oncology, Holcombe Blvd, Houston, TX 77030, USA [email protected]
4
I have received grants, personal fees, and non-financial support from Astellas Pharma, Novartis, Bristol-Myers Squibb, Johnson & Johnson, Exelixis, and Pfizer. 1
2
2
Parker C, Nilsson S, Heinrich D, et al, for the ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–23. Sartor O, Coleman R, Nilsson S, et al. Effect of Radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014; published May 14, 2014. http://dx.doi.org/10.1016/S1470-2045(14)70183-4.
5
6
7
Logothetis CJ, Basch E, Molina A,et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with AA-301 randomised trial. Lancet Oncology 2012; 13: 1210–17. Porter AT. Strontium 89 (Metastron) in the treatment of prostate cancer metastatic to bone. Eur Urol 1994; 26 (suppl 1): 20–25. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39–46. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813–22. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2013; 31: 412–19.
www.thelancet.com/oncology Published online May 14, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70217-7
Radium-223 is a bone-homing, α-emitting radiopharmaceutical approved for the treatment of men with castrate-resistant prostate cancer with bone metastases.1 In The Lancet Oncology, Oliver Sartor and colleagues2 now extend their findings by reporting the effects of radium-223 on bone-specific symptoms. The ALSYMPCA trial1 is unique because it included patients with bone metastases only, and did not bias the results of the study with routine radiographic imaging that might have driven post-treatment interventions. The newly reported findings complement the previously reported increase in overall survival1 of patients treated with radium-223 with the improvement of symptom-free survival too. Symptomatic skeletal-related events developed in 202 (33%) of 614 patients treated with radium-223 compared with 116 (38%) of 307 patients in the placebo group; however, the clinically meaningful benefit of radium-223 was best portrayed in the delay in time to symptomatic progression between groups: in the radium-223 group median time to symptomatic progression was 15·6 months (95% CI 13·5–18·0) compared with 9·8 months (7·3–23·7) in the placebo group (hazard ratio [HR]=0·66, 95% CI 0·52–0·83; p=0·00037). This delay rivals that achieved with second-generation androgen biosynthesis inhibitors in similar patients.3 As a result of this study, a new and safe method has been added to the inventory of available effective agents for advanced prostate cancer, and establish a new therapeutic paradigm by confirming the merits of bone targeting in men with advanced prostate cancer. The ALSYMPCA trial builds on past efforts to use radiopharmaceuticals in the treatment of bonemetastatic castrate-resistant prostate cancer. Strontium-89, the first class β-emitting radiopharmaceutical to relieve pain, lengthens time to symptomatic progression.4 Similar findings have been reported with samarium, but strontium and samarium are myelosuppressive, which limits their clinical utility. Radium-223, as a short-range α-emitting radiopharmaceutical, provides meaningful benefit without proportional haematological toxic effects. From a pragmatic clinical perspective, this profile broadens its potential clinical application by allowing the
development of combinations with other agents and permitting repetitive dosing. The investigators should be credited for selecting men likely to benefit, and showing that, in addition to prolongation of survival, patients benefitted from a reduction in cancerassociated symptoms. The absence of dose-limiting haematological toxic effects, and the lack of a proportional decrease in serum concentration of prostate-specific antigen (PSA) raises intriguing questions about the mechanisms of action of radium-223. The bone marrow is a frequent site in which prostate cancer cells are detected, and serum PSA concentration is a marker associated with cancer cell load within individual patients. The short range of α-particles possibly accounts for the reduced haematological toxic effects (the bone marrow is spared) but might not extend to areas where some cancers reside. Attributing the clinical benefits to radiation-induced cytoreduction in the absence of a decrease in serum PSA concentration is challenging. Other clinically effective therapeutics studied in men with castrate-resistant prostate cancer share the radium-223 response profile. For example, sipuleucel-T (Provenge, Dendreon Corporation, WA, USA), an approved prostate cancer vaccine, and cabozantinib, a VEGFR2/cMET-inhibiting tyrosine kinase inhibitor, have remarkable effects on bone scan results, serum alkaline phosphatase concentration, and bone pain, but less effect on serum PSA concentration.5–7 The small reduction in serum PSA concentration compels us to consider alternative hypotheses to account for the clinical efficacy of radium-223. Although speculative, plausible mechanisms include selective killing of nonPSA-expressing clones within range of the α-particles or indirect effects on tumour lethality through the modulation of the tumour microenvironment. What has become clear is that serum PSA concentration is neither predictive nor prognostic in the setting of metastatic castrate-resistant prostate cancer. An urgent need exists to identify, and build on, the mechanisms that explain the clinical efficacy of these agents, to identify predictive and companion markers that can be used to select who will benefit from radium-223, and to continue to monitor its efficacy .
www.thelancet.com/oncology Published online May 14, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70217-7
Simon Fraser/Medical Physics, RVI, Newcastle Upon-Tyne/Science Photo Library
Prostate cancer bone metastases: not so systemic after all
Lancet Oncol 2014 Published Online May 14, 2014 http://dx.doi.org/10.1016/ S1470-2045(14)70217-7 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(14)70183-4
1
Comment
Christopher J Logothetis
3
University of Texas, M D Anderson Cancer Center, Genitourinary Medical Oncology, Holcombe Blvd, Houston, TX 77030, USA [email protected]
4
I have received grants, personal fees, and non-financial support from Astellas Pharma, Novartis, Bristol-Myers Squibb, Johnson & Johnson, Exelixis, and Pfizer. 1
2
2
Parker C, Nilsson S, Heinrich D, et al, for the ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213–23. Sartor O, Coleman R, Nilsson S, et al. Effect of Radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014; published May 14, 2014. http://dx.doi.org/10.1016/S1470-2045(14)70183-4.
5
6
7
Logothetis CJ, Basch E, Molina A,et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with AA-301 randomised trial. Lancet Oncology 2012; 13: 1210–17. Porter AT. Strontium 89 (Metastron) in the treatment of prostate cancer metastatic to bone. Eur Urol 1994; 26 (suppl 1): 20–25. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012; 379: 39–46. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011; 377: 813–22. Smith DC, Smith MR, Sweeney C, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol 2013; 31: 412–19.
www.thelancet.com/oncology Published online May 14, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70217-7
