The Experts below are selected from a list of 4710 Experts worldwide ranked by ideXlab platform
Charles J. Ryan - One of the best experts on this subject based on the ideXlab platform.
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Abiraterone Acetate and prednisone in chemotherapy-naïve prostate cancer patients: rationale, evidence and clinical utility.
Therapeutic advances in medical oncology, 2017Co-Authors: E. David Crawford, Neal D Shore, Daniel P. Petrylak, Celestia S. Higano, Charles J. RyanAbstract:Abiraterone Acetate 1000 mg/day, combined with prednisone 5 mg PO twice daily, is indicated for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Abiraterone Acetate is the oral prodrug of Abiraterone, a specific CYP17 inhibitor that blocks androgen biosynthesis within the adrenal glands, testes and tumor microenvironment. In a phase III trial of men with asymptomatic or minimally symptomatic, chemotherapy-naive mCRPC, treatment with oral Abiraterone Acetate plus prednisone led to a statistically significant improvement in the co-primary endpoints of overall survival and radiographic progression-free survival when compared with placebo plus prednisone. In long-term follow-up of phase III trials, the incidence of corticosteroid-associated adverse events was 25.5% in the Abiraterone Acetate plus prednisone arm compared with 23.3% in the placebo plus prednisone arm. The need for regular patient monitoring and appropriate management of symptoms during long-term use of prednisone must b...
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Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naïve Patients with Metastatic Castration Resistant Prostate Cancer.
The Journal of urology, 2015Co-Authors: Matthew R Smith, Arturo Molina, Thian Kheoh, Dana E Rathkopf, Peter F A Mulders, Joan Carles, Hendrik Van Poppel, Thomas W. Griffin, Charles J. RyanAbstract:Purpose: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of Abiraterone Acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysis (55% of total overall survival events) for the COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer) trial.Materials and Methods: Patients were stratified and randomized 1:1 to Abiraterone Acetate 1,000 mg plus prednisone/prednisolone 5 mg twice daily (Abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg twice daily (prednisone alone). Co-primary end points were radiographic progression-free and overall survival. Median time to event and HR were estimated using the Kaplan-Meier method and a Cox model, respectively.Results: A total of 350 elderly patients treated with Abiraterone-prednisone had significant improvemen...
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Abiraterone Acetate plus prednisone versus placebo plus prednisone in chemotherapy naive men with metastatic castration resistant prostate cancer cou aa 302 final overall survival analysis of a randomised double blind placebo controlled phase 3 study
Lancet Oncology, 2015Co-Authors: Charles J. Ryan, Cora N Sternberg, Karim Fizazi, Matthew R Smith, Christopher J Logothetis, Neal D Shore, Peter F A Mulders, Fred Saad, Kurt Miller, Eric J SmallAbstract:Summary Background Abiraterone Acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of Abiraterone Acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. Methods In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either Abiraterone Acetate (1000 mg once daily) plus prednisone (5 mg twice daily; Abiraterone Acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. Findings At a median follow-up of 49·2 months (IQR 47·0–51·8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the Abiraterone Acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received Abiraterone Acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the Abiraterone Acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the Abiraterone Acetate group than in the placebo group (34·7 months [95% CI 32·7–36·8] vs 30·3 months [28·7–33·3]; hazard ratio 0·81 [95% CI 0·70–0·93]; p=0·0033). The most common grade 3–4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the Abiraterone Acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [ vs 17 [3%]). Interpretation In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with Abiraterone Acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of Abiraterone Acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Funding Janssen Research & Development.
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Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with Abiraterone Acetate
Prostate cancer and prostatic diseases, 2014Co-Authors: Won Seog Kim, Arturo Molina, C M Haqq, Eric J Small, Jeremy O. Jones, Marc I. Diamond, Charles J. RyanAbstract:Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with Abiraterone Acetate
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Abiraterone Acetate for the treatment of prostate cancer.
Expert opinion on pharmacotherapy, 2012Co-Authors: Charles J. Ryan, Michael L ChengAbstract:Introduction: Prostate cancer is the second leading cause of cancer death in men in the United States. The disease is driven by androgen receptor (AR) signaling, and the majority of patients initially respond to androgen deprivation therapies. The lethal form of this disease occurs when metastatic lesions progress in the setting of low testosterone levels, in what is conventionally referred to as castration-resistant prostate cancer (CRPC). Recent insights suggest that CRPC continues to rely on an active AR pathway for cell survival and growth. Areas covered: This review summarizes the rationale, mechanism of action and relevant clinical data of Abiraterone Acetate, an oral androgen biosynthesis inhibitor, in the management of CRPC. Expert opinion: Abiraterone Acetate is an oral, well-tolerated drug that targets a newly elucidated paradigm of continued AR activation in CRPC. Abiraterone Acetate is approved in CRPC patients who have received docetaxel, and recent data suggest that the drug will also be eff...
Matthew R Smith - One of the best experts on this subject based on the ideXlab platform.
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a phase iii randomized placebo controlled double blind study of niraparib plus Abiraterone Acetate and prednisone versus Abiraterone Acetate and prednisone in patients with metastatic prostate cancer nct03748641
Journal of Clinical Oncology, 2020Co-Authors: Dana E Rathkopf, Matthew R Smith, Gerhardt Attard, Eleni Efstathiou, David Olmos, Eric J Small, Paul Sieber, Curtis Dunshee, Deborah Ricci, Jason S SimonAbstract:TPS257Background: Preclinical data suggest synergistic antitumor activity when the PARP inhibitor (PARPi) niraparib is combined with the androgen pathway inhibitor Abiraterone Acetate. (1) The addi...
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clinical outcomes from androgen signaling directed therapy after treatment with Abiraterone Acetate and prednisone in patients with metastatic castration resistant prostate cancer post hoc analysis of cou aa 302
European Urology, 2017Co-Authors: Matthew R Smith, Karim Fizazi, Thian Kheoh, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Peter De PorreAbstract:Abstract In the COU-AA-302 trial, Abiraterone Acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone Acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone Acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone Acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone Acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone Acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone Acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone Acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone Acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone Acetate plus prednisone or enzalutamide following initial therapy with Abiraterone Acetate plus prednisone.
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Clinical Outcomes from Androgen Signaling–directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302
European urology, 2017Co-Authors: Matthew R Smith, Karim Fizazi, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Thian KheohAbstract:Abstract In the COU-AA-302 trial, Abiraterone Acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone Acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone Acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone Acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone Acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone Acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone Acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone Acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone Acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone Acetate plus prednisone or enzalutamide following initial therapy with Abiraterone Acetate plus prednisone.
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Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naïve Patients with Metastatic Castration Resistant Prostate Cancer.
The Journal of urology, 2015Co-Authors: Matthew R Smith, Arturo Molina, Thian Kheoh, Dana E Rathkopf, Peter F A Mulders, Joan Carles, Hendrik Van Poppel, Thomas W. Griffin, Charles J. RyanAbstract:Purpose: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of Abiraterone Acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysis (55% of total overall survival events) for the COU-AA-302 (Abiraterone Acetate in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer) trial.Materials and Methods: Patients were stratified and randomized 1:1 to Abiraterone Acetate 1,000 mg plus prednisone/prednisolone 5 mg twice daily (Abiraterone-prednisone) vs placebo plus prednisone/prednisolone 5 mg twice daily (prednisone alone). Co-primary end points were radiographic progression-free and overall survival. Median time to event and HR were estimated using the Kaplan-Meier method and a Cox model, respectively.Results: A total of 350 elderly patients treated with Abiraterone-prednisone had significant improvemen...
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Abiraterone Acetate plus prednisone versus placebo plus prednisone in chemotherapy naive men with metastatic castration resistant prostate cancer cou aa 302 final overall survival analysis of a randomised double blind placebo controlled phase 3 study
Lancet Oncology, 2015Co-Authors: Charles J. Ryan, Cora N Sternberg, Karim Fizazi, Matthew R Smith, Christopher J Logothetis, Neal D Shore, Peter F A Mulders, Fred Saad, Kurt Miller, Eric J SmallAbstract:Summary Background Abiraterone Acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of Abiraterone Acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. Methods In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either Abiraterone Acetate (1000 mg once daily) plus prednisone (5 mg twice daily; Abiraterone Acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. Findings At a median follow-up of 49·2 months (IQR 47·0–51·8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the Abiraterone Acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received Abiraterone Acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the Abiraterone Acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the Abiraterone Acetate group than in the placebo group (34·7 months [95% CI 32·7–36·8] vs 30·3 months [28·7–33·3]; hazard ratio 0·81 [95% CI 0·70–0·93]; p=0·0033). The most common grade 3–4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the Abiraterone Acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [ vs 17 [3%]). Interpretation In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with Abiraterone Acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of Abiraterone Acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Funding Janssen Research & Development.
Giandomenico Roviello - One of the best experts on this subject based on the ideXlab platform.
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Corticosteroid switch after progression on Abiraterone Acetate plus prednisone
International Journal of Clinical Oncology, 2020Co-Authors: Giandomenico Roviello, Navid Sobhani, Silvia Paola Corona, Alberto D’angeloAbstract:Introduction Abiraterone Acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on Abiraterone Acetate plus prednisone or prednisolone. Materials and Methods The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option. Results A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during Abiraterone Acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223. Conclusion Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with Abiraterone Acetate plus prednisone or prednisolone.
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Corticosteroid switch after progression on Abiraterone Acetate plus prednisone.
International journal of clinical oncology, 2019Co-Authors: Giandomenico Roviello, Navid Sobhani, Silvia Paola Corona, Alberto D'angeloAbstract:Abiraterone Acetate plus prednisone is approved in metastatic castration-resistant prostate cancer. There is some evidence in favour of the steroid switch from prednisone to dexamethasone in patients who progressed whilst on Abiraterone Acetate plus prednisone or prednisolone. The aim of this review is to discuss the results from the clinical studies available, examining potential mechanisms of action and patient selection criteria for this treatment option. A total of four studies were evaluated. Among possible eligibility criteria for steroid switch, we found: PSA progression without any radiological or clinical progression during Abiraterone Acetate + prednisone; no high-grade adverse events related to CYP-17 inhibition; and unfitness for chemotherapy or radium-223. Although large randomized prospective trials are warranted, steroid switch seems to offer a good option for certain patients treated with Abiraterone Acetate plus prednisone or prednisolone.
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Corticosteroid switch in heavily pre-treated castration-resistant prostate cancer patients progressed on Abiraterone Acetate plus prednisone.
Investigational new drugs, 2018Co-Authors: Giandomenico Roviello, Roberto Petrioli, Alberto Bonetta, Raffaele Conca, Maria Grazia Rodriquenz, Michele AietaAbstract:The aim of this retrospective study is to evaluate the activity and safety of a steroidal switch from prednisone to dexamethasone in patients with advanced, heavily pre-treated, castration-resistant prostate cancer (CRPC) who progressed on Abiraterone Acetate. Treatment consisted of oral daily Abiraterone plus dexamethasone (0.5 mg once daily) administered until disease progression or unacceptable toxicity. Thirty-six patients were evaluated: all men underwent a prior treatment with enzalutamide. A PSA decrease ≥50% was observed in 11% of patients; median progression-free survival was 10.8 weeks (95% CI: 9.2–16), and median survival was 17.6 weeks (95% CI: 15.8–28.8). Better efficacy and survival were observed in the subgroup of patients treated with Abiraterone Acetate prior for a period >3 months; treatment was well tolerated, and no grade 3–4 toxicities were observed. Our findings did not suggest the use of steroid switch in all CRPC who were heavily pre-treated. However, the switch could be an option for patients who responded well to prior Abiraterone Acetate treatment.
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Role of chemotherapy in the treatment of metastatic castration-resistant prostate cancer patients who have progressed after Abiraterone Acetate
Cancer Chemotherapy and Pharmacology, 2015Co-Authors: Roberto Petrioli, Edoardo Francini, Letizia Laera, Anna Ida Fiaschi, Roberto Ponchietti, Giandomenico RovielloAbstract:Abiraterone Acetate is a novel irreversible inhibitor of CYP17 that was recently approved for men with post-chemotherapy or chemo-naive castration-resistant prostate cancer. Unfortunately, this agent is not curative, and patients often ultimately develop resistance. However, men who progress after treatment with this new hormonal agent may be considered for another line of chemotherapy-based treatment. In 2004, docetaxel (D) and prednisone were found to improve survival compared with older regimens. More recently, cabazitaxel (C), a novel taxane chemotherapy, has been found to prolong survival in patients who exhibit disease progression during or after D chemotherapy. Here, we review the first clinical studies in which castration-resistant prostate cancer patients received chemotherapy with D or C after progression during Abiraterone Acetate treatment.
Eric J Small - One of the best experts on this subject based on the ideXlab platform.
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a phase iii randomized placebo controlled double blind study of niraparib plus Abiraterone Acetate and prednisone versus Abiraterone Acetate and prednisone in patients with metastatic prostate cancer nct03748641
Journal of Clinical Oncology, 2020Co-Authors: Dana E Rathkopf, Matthew R Smith, Gerhardt Attard, Eleni Efstathiou, David Olmos, Eric J Small, Paul Sieber, Curtis Dunshee, Deborah Ricci, Jason S SimonAbstract:TPS257Background: Preclinical data suggest synergistic antitumor activity when the PARP inhibitor (PARPi) niraparib is combined with the androgen pathway inhibitor Abiraterone Acetate. (1) The addi...
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clinical outcomes from androgen signaling directed therapy after treatment with Abiraterone Acetate and prednisone in patients with metastatic castration resistant prostate cancer post hoc analysis of cou aa 302
European Urology, 2017Co-Authors: Matthew R Smith, Karim Fizazi, Thian Kheoh, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Peter De PorreAbstract:Abstract In the COU-AA-302 trial, Abiraterone Acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone Acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone Acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone Acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone Acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone Acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone Acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone Acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone Acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone Acetate plus prednisone or enzalutamide following initial therapy with Abiraterone Acetate plus prednisone.
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Clinical Outcomes from Androgen Signaling–directed Therapy after Treatment with Abiraterone Acetate and Prednisone in Patients with Metastatic Castration-resistant Prostate Cancer: Post Hoc Analysis of COU-AA-302
European urology, 2017Co-Authors: Matthew R Smith, Karim Fizazi, Dana E Rathkopf, Johann S De Bono, Neal D Shore, Peter F A Mulders, Eric J Small, Fred Saad, Thian KheohAbstract:Abstract In the COU-AA-302 trial, Abiraterone Acetate plus prednisone significantly increased overall survival for patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). Limited information exists regarding response to subsequent androgen signaling–directed therapies following Abiraterone Acetate plus prednisone in patients with mCRPC. We investigated clinical outcomes associated with subsequent Abiraterone Acetate plus prednisone (55 patients) and enzalutamide (33 patients) in a post hoc analysis of COU-AA-302. Prostate-specific antigen (PSA) response was assessed. Median time to PSA progression was estimated using the Kaplan-Meier method. The PSA response rate (≥50% PSA decline, unconfirmed) was 44% and 67%, respectively. The median time to PSA progression was 3.9 mo (range 2.6–not estimable) for subsequent Abiraterone Acetate plus prednisone and 2.8 mo (range 1.8–not estimable) for subsequent enzalutamide. The majority of patients (68%) received intervening chemotherapy before subsequent Abiraterone Acetate plus prednisone or enzalutamide. While acknowledging the limitations of post hoc analyses and high censoring (>75%) in both treatment groups, these results suggest that subsequent therapy with Abiraterone Acetate plus prednisone or enzalutamide for patients who progressed on Abiraterone Acetate is associated with limited clinical benefit. Patient summary This analysis showed limited clinical benefit for subsequent Abiraterone Acetate plus prednisone or enzalutamide in patients with metastatic castration-resistant prostate cancer following initial treatment with Abiraterone Acetate plus prednisone. This analysis does not support prioritization of subsequent Abiraterone Acetate plus prednisone or enzalutamide following initial therapy with Abiraterone Acetate plus prednisone.
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Abiraterone Acetate plus prednisone versus placebo plus prednisone in chemotherapy naive men with metastatic castration resistant prostate cancer cou aa 302 final overall survival analysis of a randomised double blind placebo controlled phase 3 study
Lancet Oncology, 2015Co-Authors: Charles J. Ryan, Cora N Sternberg, Karim Fizazi, Matthew R Smith, Christopher J Logothetis, Neal D Shore, Peter F A Mulders, Fred Saad, Kurt Miller, Eric J SmallAbstract:Summary Background Abiraterone Acetate plus prednisone significantly improved radiographic progression-free survival compared with placebo plus prednisone in men with chemotherapy-naive castration-resistant prostate cancer at the interim analyses of the COU-AA-302 trial. Here, we present the prespecified final analysis of the trial, assessing the effect of Abiraterone Acetate plus prednisone on overall survival, time to opiate use, and use of other subsequent therapies. Methods In this placebo-controlled, double-blind, randomised phase 3 study, 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive prostate cancer stratified by Eastern Cooperative Oncology performance status (0 vs 1) were randomly assigned with a permuted block allocation scheme via a web response system in a 1:1 ratio to receive either Abiraterone Acetate (1000 mg once daily) plus prednisone (5 mg twice daily; Abiraterone Acetate group) or placebo plus prednisone (placebo group). Coprimary endpoints were radiographic progression-free survival and overall survival analysed in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00887198. Findings At a median follow-up of 49·2 months (IQR 47·0–51·8), 741 (96%) of the prespecified 773 death events for the final analysis had been observed: 354 (65%) of 546 patients in the Abiraterone Acetate group and 387 (71%) of 542 in the placebo group. 238 (44%) patients initially receiving prednisone alone subsequently received Abiraterone Acetate plus prednisone as crossover per protocol (93 patients) or as subsequent therapy (145 patients). Overall, 365 (67%) patients in the Abiraterone Acetate group and 435 (80%) in the placebo group received subsequent treatment with one or more approved agents. Median overall survival was significantly longer in the Abiraterone Acetate group than in the placebo group (34·7 months [95% CI 32·7–36·8] vs 30·3 months [28·7–33·3]; hazard ratio 0·81 [95% CI 0·70–0·93]; p=0·0033). The most common grade 3–4 adverse events of special interest were cardiac disorders (41 [8%] of 542 patients in the Abiraterone Acetate group vs 20 [4%] of 540 patients in the placebo group), increased alanine aminotransferase (32 [6%] vs four [ vs 17 [3%]). Interpretation In this randomised phase 3 trial with a median follow-up of more than 4 years, treatment with Abiraterone Acetate prolonged overall survival compared with prednisone alone by a margin that was both clinically and statistically significant. These results further support the favourable safety profile of Abiraterone Acetate in patients with chemotherapy-naive metastatic castration-resistant prostate cancer. Funding Janssen Research & Development.
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Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with Abiraterone Acetate
Prostate cancer and prostatic diseases, 2014Co-Authors: Won Seog Kim, Arturo Molina, C M Haqq, Eric J Small, Jeremy O. Jones, Marc I. Diamond, Charles J. RyanAbstract:Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with Abiraterone Acetate
Neeraj Agarwal - One of the best experts on this subject based on the ideXlab platform.
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Germline Variant in SLCO2B1 and Response to Abiraterone Acetate Plus Prednisone (AA) in New-onset Metastatic Castration-resistant Prostate Cancer (mCRPC)
Molecular cancer therapeutics, 2018Co-Authors: Andrew W. Hahn, David M. Gill, Austin Poole, Roberto Nussenzveig, Sara Wilson, James M. Farnham, Robert A. Stephenson, Lisa A. Cannon-albright, Benjamin L. Maughan, Neeraj AgarwalAbstract:There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently unavailable. A recent translational study suggested that SLCO2B1 genotype could predict response to Abiraterone Acetate for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line Abiraterone Acetate in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah (Salt Lake City, UT). Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line Abiraterone Acetate in men with mCRPC. We performed a prespecified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on Abiraterone Acetate. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild-type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line Abiraterone Acetate for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared with the homozygous wild-type group (8.9 months vs. 6.3 months; HR, 0.46; 95% confidence interval, 0.23-0.94; P = 0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line Abiraterone Acetate in men with mCRPC.
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inherited variants in sult1e1 and response to Abiraterone Acetate by men with metastatic castration refractory prostate cancer
The Journal of Urology, 2016Co-Authors: Neeraj Agarwal, David M. Gill, James M. Farnham, Robert A. Stephenson, Anitha Alex, Shiven B Patel, Tyler Howard Buckley, Lisa A CannonalbrightAbstract:Purpose: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to Abiraterone Acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy.Materials and Methods: We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway. The purpose was to investigate them for an association with time to treatment failure in 68 white men with metastatic, castration refractory prostate cancer undergoing treatment with Abiraterone Acetate. Cox proportional hazard analysis was used with Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation as covariates. Each single nucleotide polymorphism was assessed using an allele carriage genetic model in which carriage of 1 or ...
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Abiraterone Acetate: a promising drug for the treatment of castration-resistant prostate cancer
Future oncology (London England), 2010Co-Authors: Neeraj Agarwal, Thomas E. Hutson, Nicholas J. Vogelzang, SonpavdeAbstract:Abiraterone Acetate (CB7630), a pregnenolone analog, is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosysnthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. In clinical studies, Abiraterone Acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of Abiraterone Acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, Abiraterone Acetate is being tested in a Phase III trial for men with progressive ca...
