- Email: [email protected]
Immunotherapy for Advanced Prostate Cancer
Annals of Oncology 23 (Supplement 9): ix38, 2012 doi:10.1093/annonc/mds378
re-inventing the medical treatment of advanced prostate cancer 46IN
active therapies should be on the shelf when treating an incurable disease is not. Striving for patients to receive as many active therapies as feasible seems reasonable in an era when predicting therapeutic response is more art than science. Disclosure: O. Sartor: Investigator and consultant for Algeta, Bayer, JNJ, Sanofi, and Dendreon. Consultant for Medivation and Astellas.
IMMUNOTHERAPY FOR ADVANCED PROSTATE CANCER 48IN
P.W. Kantoff Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA
abstracts
J.S. de Bono Division of Cancer Therapeutics, Institute of Cancer Research Royal Marsden Hospital, Sutton, UNITED KINGDOM Prostate cancer progression is associated with continued androgen receptor (AR) activation despite treatment with castration and/or currently available anti-androgens. Abiraterone, a rationally- designed inhibitor of CYP17A1 has been recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires co-administration with glucocorticoids to curtail side effects. Enzalutamide (MDV3100) is a novel AR antagonist that effectively blocks AR signaling when currently available AR antagonists are unable to do this and has shown impressive antitumor activity and a similar impact on overall survival as abiraterone. We now report that these two drugs in combination may be superior to either drug alone. We have hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We also found that prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone that are used to treat side-effects related to mineralocorticoid excess, also bound to and activated signaling through both wild-type and mutant AR. Activation of mutant AR was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone. Moreover, higher androgenic steroid concentrations resulted in decreased enzalutamide antitumour activity. Together, our findings provide a strong rationale for the clinical evaluation of combined CYP17A1 inhibition and AR antagonism by enzalutamide. Disclosure: J.S. de Bono: I am an employee of The Institute of Cancer Research that has a commercial interest in abiraterone. I have served as an advisor for J&J, Medivation, Astellas and Takeda.
49IN 47IN
HOW SHOULD WE USE CYTOTOXIC CHEMOTHERAPY IN THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER?
O. Sartor Department of Medicine: Section of Hematology & Medical Oncology and Department of Urology, Tulane Cancer Center, New Orleans, LA, UNITED STATES OF AMERICA The recent incremental advances in metastatic castrate-resistant prostate cancer (mCRPC) may one day translate into more meaningful change. Today mCRPC therapeutic choices are a sequential series of affairs with several either/or decisions. Optimal sequencing is unstudied and endless speculation abound as to which drug is best best for which patient. Combination therapies are in their infancy. In the past, the world of mCRPC was conveniently divided into the pre- and post-docetaxel space. That being said, the biologic basis for this was lacking and now we have new spaces such as the post-abiraterone/MDV3100 space that might in fact be more biologically meaningful. What do we do with patients progressing post-abiraterone or MDV3100? The data are sparse to date and so we gear up with new studies and read tea leaves in the interim. What is the role for cytotoxic chemotherapies today’s mCRPC therapeutic armamentarium? The new hormonal therapies are now marching forward with provovative data in the “pre-chemotherapy” space. Novel immunotherapies have seized imaginations. The new world of truly active bone-targeted radiopharmaceuticals has arrived. Several facts seem clear. 1) the newer hormonal therapies are not effective for very long in mCRPC and after they fail, the progression rate can be very rapid. Exotic new molecular mechanisms of resistance are discovered with regularity; the CRPC cells are truly devious little Darwinian machines. 2) Today, death from prostate cancer is a foregone conclusion for mCRPC patient. So does this help us answer how we use cytotoxic chemotherapy today? Perhaps it si reasonable to point out that both docetaxel and cabazitaxel are clearly active agents and that some but not all patients will tolerate them well. Currently many men die from prostate cancer without having had the opportunity to benefit from known active agents. The best responses to chemotherapy, as with any agent, occur in patients with the best performance status. The concept that therapies of lesser toxicity should be administered first is appropriate but the concept that
HOW SHOULD WE UTILIZE BONE TREATMENTS: BISPHOSPHONATES, DENOSUMAB AND RADIUM-223
C. Parker Academic Urology, Royal Marsden Hospital NHS Foundation Trust, Sutton, UNITED KINGDOM How should we utilize bone treatments: Bisphosphonates, denosumab and radium-223? Bone metastases are a prominent feature of CRPC, and can lead to significant skeletal-related events (SREs) such as spinal cord compression, pathological fracture, and the need for surgery or external-beam radiotherapy. Zoledronate, a bisphosphonate, reduces the risk of SREs (1) and has been widely, although not universally, regarded as a standard treatment for metastatic CRPC. More recently, denosumab, an antibody targeted at the RANK-ligand, has shown greater efficacy for SRE prevention with an acceptable toxicity profile (2), and has also been licensed for use. Radium-223, a bone-targetted alpha emitter, has been reported not only to reduce the risk of SREs, but also to improve overall survival. Although radium-223 is the first bone-targetted agent to improve overall survival in CRPC, it is not yet licensed for clinical use. I will review the clinical trial data concerning these bone-targetted agents in CRPC, and give my personal view as to how they should be used. References 1. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B; Zoledronic Acid Prostate Cancer Study Group. J Natl Cancer Inst. 2002 Oct 2;94 (19):1458-68. 2. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. Lancet. 2011 Mar 5;377 (9768):813-22. 3. Overall survival benefit of radium-223 chloride (Alpharadin™) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): A phase III randomized trial (ALSYMPCA). C. Parker, D. Heinrich, J.M. O’Sullivan, S. Fosså, A. Chodacki, T. Demkow, A. Cross, B. Bolstad, J. Garcia-Vargas, and O. Sartor. Eur J Cancer 47:Supp 2, Sept 2011 p3 Disclosure: C. Parker: Advisory board membership for Amgen, BMS, Bayer, Dendreon, Janssen and Takeda
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 30, 2016
While the concept of immunotherapy for cancer has been proposed for many years, proof of principle did not exist. In the context of prostate cancer, the allogeneic cell based agent, GVAX has been tested. GVAX consists of a platform of irradiated hormone sensitive (LNCaP) and hormone resistant (PC-3) prostate cancer cell lines transduced with a replication-defective retrovirus bearing GM-CSF. Unfortunately, two phase III studies in men with metastatic castration resistant prostate cancer (CRPC) failed to demonstrate a survival advantage. More recently, the improved survival observed with sipuleucel-T, an autologous antigen presenting cell (APC)-based agent, for the treatment of patients with metastatic CRPC supports immunotherapy as a valid approach for this disease. Sipuleucel-T uses a fusion antigen of prostatic acid phosphatase and GM-CSF. Evidence exists to support activation of APCs and T cells in an antigen specific fashion and that the degree of activation correlates with overall survival. PROSTVAC-VF TRICOM, a poxvirus vector based PSA antigen targeted vaccine showed promising results in a randomized Phase II study and is now being tested in a international Phase III study. The CTLA-4 inhibiting human monoclonal antibody, ipilimumab, has extended survival in advanced melanoma. Early phase I clinical trials of ipilimumab have yielded clinical and PSA responses in advanced CRPC. A Phase I/II trial was conducted using ipilimumab 10 mg/ kg every 3 weeks x 4 with or without prior priming by single fraction of radiation to a metastatic bony site. Results were promising enough to launch 2 phase III clinical trials in men with metastatic CRPC who were either chemo-naive or following prior chemotherapy. The outcomes of these 2 studies are pending. Disclosure: P.W. Kantoff: Amgen USA consultant (con), Bayer con, Bellicum con, BIND Biosciences SAB, BN Immunotherapeutics con, Celgene DSMB, Dendreon con, Genetech con, Progenics Pharmaceuticals con, Janssen con, Takeda/Millenium DSMB, Oncogenex DSMB, Tokai con
INTEGRATING NOVEL ENDOCRINE THERAPIES: SEQUENTIAL OR CONCOMITANT TREATMENT?
re-inventing the medical treatment of advanced prostate cancer 46IN
active therapies should be on the shelf when treating an incurable disease is not. Striving for patients to receive as many active therapies as feasible seems reasonable in an era when predicting therapeutic response is more art than science. Disclosure: O. Sartor: Investigator and consultant for Algeta, Bayer, JNJ, Sanofi, and Dendreon. Consultant for Medivation and Astellas.
IMMUNOTHERAPY FOR ADVANCED PROSTATE CANCER 48IN
P.W. Kantoff Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, UNITED STATES OF AMERICA
abstracts
J.S. de Bono Division of Cancer Therapeutics, Institute of Cancer Research Royal Marsden Hospital, Sutton, UNITED KINGDOM Prostate cancer progression is associated with continued androgen receptor (AR) activation despite treatment with castration and/or currently available anti-androgens. Abiraterone, a rationally- designed inhibitor of CYP17A1 has been recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires co-administration with glucocorticoids to curtail side effects. Enzalutamide (MDV3100) is a novel AR antagonist that effectively blocks AR signaling when currently available AR antagonists are unable to do this and has shown impressive antitumor activity and a similar impact on overall survival as abiraterone. We now report that these two drugs in combination may be superior to either drug alone. We have hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We also found that prednisolone plasma levels in CRPC patients were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone that are used to treat side-effects related to mineralocorticoid excess, also bound to and activated signaling through both wild-type and mutant AR. Activation of mutant AR was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone. Moreover, higher androgenic steroid concentrations resulted in decreased enzalutamide antitumour activity. Together, our findings provide a strong rationale for the clinical evaluation of combined CYP17A1 inhibition and AR antagonism by enzalutamide. Disclosure: J.S. de Bono: I am an employee of The Institute of Cancer Research that has a commercial interest in abiraterone. I have served as an advisor for J&J, Medivation, Astellas and Takeda.
49IN 47IN
HOW SHOULD WE USE CYTOTOXIC CHEMOTHERAPY IN THE TREATMENT OF CASTRATION-RESISTANT PROSTATE CANCER?
O. Sartor Department of Medicine: Section of Hematology & Medical Oncology and Department of Urology, Tulane Cancer Center, New Orleans, LA, UNITED STATES OF AMERICA The recent incremental advances in metastatic castrate-resistant prostate cancer (mCRPC) may one day translate into more meaningful change. Today mCRPC therapeutic choices are a sequential series of affairs with several either/or decisions. Optimal sequencing is unstudied and endless speculation abound as to which drug is best best for which patient. Combination therapies are in their infancy. In the past, the world of mCRPC was conveniently divided into the pre- and post-docetaxel space. That being said, the biologic basis for this was lacking and now we have new spaces such as the post-abiraterone/MDV3100 space that might in fact be more biologically meaningful. What do we do with patients progressing post-abiraterone or MDV3100? The data are sparse to date and so we gear up with new studies and read tea leaves in the interim. What is the role for cytotoxic chemotherapies today’s mCRPC therapeutic armamentarium? The new hormonal therapies are now marching forward with provovative data in the “pre-chemotherapy” space. Novel immunotherapies have seized imaginations. The new world of truly active bone-targeted radiopharmaceuticals has arrived. Several facts seem clear. 1) the newer hormonal therapies are not effective for very long in mCRPC and after they fail, the progression rate can be very rapid. Exotic new molecular mechanisms of resistance are discovered with regularity; the CRPC cells are truly devious little Darwinian machines. 2) Today, death from prostate cancer is a foregone conclusion for mCRPC patient. So does this help us answer how we use cytotoxic chemotherapy today? Perhaps it si reasonable to point out that both docetaxel and cabazitaxel are clearly active agents and that some but not all patients will tolerate them well. Currently many men die from prostate cancer without having had the opportunity to benefit from known active agents. The best responses to chemotherapy, as with any agent, occur in patients with the best performance status. The concept that therapies of lesser toxicity should be administered first is appropriate but the concept that
HOW SHOULD WE UTILIZE BONE TREATMENTS: BISPHOSPHONATES, DENOSUMAB AND RADIUM-223
C. Parker Academic Urology, Royal Marsden Hospital NHS Foundation Trust, Sutton, UNITED KINGDOM How should we utilize bone treatments: Bisphosphonates, denosumab and radium-223? Bone metastases are a prominent feature of CRPC, and can lead to significant skeletal-related events (SREs) such as spinal cord compression, pathological fracture, and the need for surgery or external-beam radiotherapy. Zoledronate, a bisphosphonate, reduces the risk of SREs (1) and has been widely, although not universally, regarded as a standard treatment for metastatic CRPC. More recently, denosumab, an antibody targeted at the RANK-ligand, has shown greater efficacy for SRE prevention with an acceptable toxicity profile (2), and has also been licensed for use. Radium-223, a bone-targetted alpha emitter, has been reported not only to reduce the risk of SREs, but also to improve overall survival. Although radium-223 is the first bone-targetted agent to improve overall survival in CRPC, it is not yet licensed for clinical use. I will review the clinical trial data concerning these bone-targetted agents in CRPC, and give my personal view as to how they should be used. References 1. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B; Zoledronic Acid Prostate Cancer Study Group. J Natl Cancer Inst. 2002 Oct 2;94 (19):1458-68. 2. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, Goessl C. Lancet. 2011 Mar 5;377 (9768):813-22. 3. Overall survival benefit of radium-223 chloride (Alpharadin™) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): A phase III randomized trial (ALSYMPCA). C. Parker, D. Heinrich, J.M. O’Sullivan, S. Fosså, A. Chodacki, T. Demkow, A. Cross, B. Bolstad, J. Garcia-Vargas, and O. Sartor. Eur J Cancer 47:Supp 2, Sept 2011 p3 Disclosure: C. Parker: Advisory board membership for Amgen, BMS, Bayer, Dendreon, Janssen and Takeda
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
Downloaded from http://annonc.oxfordjournals.org/ by guest on March 30, 2016
While the concept of immunotherapy for cancer has been proposed for many years, proof of principle did not exist. In the context of prostate cancer, the allogeneic cell based agent, GVAX has been tested. GVAX consists of a platform of irradiated hormone sensitive (LNCaP) and hormone resistant (PC-3) prostate cancer cell lines transduced with a replication-defective retrovirus bearing GM-CSF. Unfortunately, two phase III studies in men with metastatic castration resistant prostate cancer (CRPC) failed to demonstrate a survival advantage. More recently, the improved survival observed with sipuleucel-T, an autologous antigen presenting cell (APC)-based agent, for the treatment of patients with metastatic CRPC supports immunotherapy as a valid approach for this disease. Sipuleucel-T uses a fusion antigen of prostatic acid phosphatase and GM-CSF. Evidence exists to support activation of APCs and T cells in an antigen specific fashion and that the degree of activation correlates with overall survival. PROSTVAC-VF TRICOM, a poxvirus vector based PSA antigen targeted vaccine showed promising results in a randomized Phase II study and is now being tested in a international Phase III study. The CTLA-4 inhibiting human monoclonal antibody, ipilimumab, has extended survival in advanced melanoma. Early phase I clinical trials of ipilimumab have yielded clinical and PSA responses in advanced CRPC. A Phase I/II trial was conducted using ipilimumab 10 mg/ kg every 3 weeks x 4 with or without prior priming by single fraction of radiation to a metastatic bony site. Results were promising enough to launch 2 phase III clinical trials in men with metastatic CRPC who were either chemo-naive or following prior chemotherapy. The outcomes of these 2 studies are pending. Disclosure: P.W. Kantoff: Amgen USA consultant (con), Bayer con, Bellicum con, BIND Biosciences SAB, BN Immunotherapeutics con, Celgene DSMB, Dendreon con, Genetech con, Progenics Pharmaceuticals con, Janssen con, Takeda/Millenium DSMB, Oncogenex DSMB, Tokai con
INTEGRATING NOVEL ENDOCRINE THERAPIES: SEQUENTIAL OR CONCOMITANT TREATMENT?