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716 PHASE III STUDY OF INTERMITTENT MAB VS CONTINUOS MAB
e288
THE JOURNAL OF UROLOGY姞
Vol. 185, No. 4S, Supplement, Monday, May 16, 2011
717
Location 8q24
SNP rs16901979
Non-Aggressive (%) N⫽1123 11.8
Aggressive (%) N⫽253 9.1
8q24
rs16902094
28.4
44.2
8q24
rs445114
89.1
93.7
0.03
8q24
rs6983267
80.4
83.0
0.34
8q24
rs1447295
25.6
22.1
0.26
P value 0.23
Source of Funding: Supported in part by the Urological Research Foundation, Prostate SPORE grant (P50 CA9038605S2) and the Robert H. Lurie Comprehensive Cancer Center Grant (P30 CA60553)
716 PHASE III STUDY OF INTERMITTENT MAB VS CONTINUOS MAB Fernando M. Calais da Silva*, Fernando Calais da Silva, Lisbon, Portugal; Aldo Bono, Varese, Italy; Peter Whelan, Leeds, United Kingdom; Maurizio Brausi, Modena, Italy; Anton Queimadelos, Santiago Compostela, Spain; Jose Portillo, Santander, Spain; Ziya Kirkali, Izmir, Turkey INTRODUCTION AND OBJECTIVES: Few randomised studies have compared intermittent hormonal therapy with continuous therapy for the treatment of advanced prostate cancer. The main publication in 2009 was based upon data with a median follow up of 51 months. We present updated results with extended follow up. The objective is to investigate if intermittent therapy is associated with a shorter survival time. METHODS: 766 patients with locally advanced or metastatic prostate cancer received a three month induction treatment. 626 patients whose PSA decreased below 4 ng/ml or to 80% below the initial value, were randomised. Intervention: Patients received cyproterone acetate (CPA) 200 mg for two weeks and then monthly depot injections of a LHRH analogue plus 200 mg of CPA daily during induction. Patients randomised to the intermittent arm ceased treatment while those randomised to the continuous arm received 200 mg of CPA daily sa LHRH analogue RESULTS: A total of 474 patients are known to have died, 90 are lost to follow up, of which 37 withdrew mainly for patient refusal and change of therapy. There was no difference in survival, p ⫽ 0.61, with hazard ratio 0.96 (95% CI 0.80 to 1.14) and 239 deaths on the intermittent and 235 on the continuous arm. A slight excess of cancer deaths in the intermittent treatment arm (136 versus 109) is balanced by a slight excess of cardiovascular deaths in the continuous arm (68 versus 62), and deaths from other causes (58 versus 41). The hazard ratio of a cancer death is 1.27 (95% CI 0.98, 1.64), p ⫽ 0.06 in the intermittent arm compared to the continuous, For cardiovascular deaths the hazard ratios are 1.05 (95% CI 0.75, 1.49), p ⫽ 0.77, continuous compared to intermittent, and for other deaths the hazard ratio for continuous compared to intermittent is 1.38 (95% CI 0.93, 2.06), p⫽0.11. The extended follow up has accumulated a further 135 deaths since the last analysis which used data up to 2005 and exceeds the number of events specified in the original power analysis. The extra 5 years of follow up now means that the study has accumulated almost 3000 person years at risk among the 626 randomised patients and the median follow up is now 57 months compared to 51 months in the publication. CONCLUSIONS: Intermittent therapy should be considered for use in routine practice since it is associated with no reduction in survival, no clinically meaningful impairment in quality of life, better sexual activity, and considerable economic benefit to individual and community. Source of Funding: None
EVALUATION OF PROSTATE-SPECIFIC ANTIGEN KINETICS DURING ZOLEDRONIC ACID THERAPY FOR BONE METASTASES IN PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER Fred Saad*, Montre´al, Canada; Jose Perez, Florham Park, NJ; Richard Cook, Waterloo, Canada; Scott Segal, Florham Park, NJ INTRODUCTION AND OBJECTIVES: Prevention of skeletalrelated events (SREs) has become an integral component of care in castration-resistant prostate cancer (CRPC), and zoledronic acid (ZOL) is an established therapy in this setting. Prostate-specific antigen (PSA) is an established marker for monitoring PC patients (pts). However, correlative information on PSA and SRE risks and the effects of ZOL on PSA kinetics is currently limited. Therefore, exploratory analyses of the ZOL phase III trial database were performed. METHODS: In the phase III trial of ZOL (Saad et al. JNCI. 2002/2004), CRPC pts with bone metastases (mets; N ⫽ 643) were randomized to ZOL or placebo (PBO) q 3 wk. PSA levels during the first 3 mo on study were evaluated in linear and logarithmic (log) models. Relative risks (RR) of SREs, bone disease progression (BDP), and death were calculated per 1 log (ng/mL) PSA increase. PSA kinetics models were stratified using prognostic factors established in the ZOL phase III trial (Cook et al. CCR. 2006) and a CRPC nomogram (Halabi et al. JCO. 2003). Time-dependent PSA values were carried forward for up to 168 days. Baseline PSA models used the study median (PSA 77.3 ng/mL) as the high/low cutpoint. RESULTS: Baseline PSA data were available for 434 ZOL- and 202 PBO-treated pts. In multivariate linear models of PSA kinetics over the first 3 mo, PSA velocity (coefficient of time in model for log[PSA] vs time) ranged from 0.134 – 0.155 log(ng/mL)/mo (ZOL) and 0.148 – 0.188 log(ng/mL)/mo (PBO), with no statistically significant treatment difference. In the overall population (n ⫽ 636), PSA increases correlated with significantly increased risks of death (RR ⫽ 1.596), BDP (RR ⫽ 1.159), and first SRE (RR ⫽ 1.264; RRs are for 1 log [ng/mL] increase; P ⬍ .0001 for all). The associated increases in BDP risk per 1 log (ng/mL) PSA increase were RR ⫽ 1.097 (ZOL) and RR ⫽ 1.295 (PBO). The cumulative incidence of SREs was lower overall for ZOL vs PBO. Pts with high baseline PSA had higher SRE risks in both groups (RR ⫽ 2.03 for PBO and 1.40 for ZOL). CONCLUSIONS: PSA is an important prognostic tool for survival in the CRPC bone mets setting, and these analyses showed that PSA is also prognostic for BDP and SREs. Consistent with its boneprotective effects, ZOL reduced the risk of SREs. Further analyses of PSA progression in earlier PC settings are planned. Source of Funding: Statistical analyses funded by Novartis Pharmaceuticals Corporation
718 LONG-TERM FOLLOW-UP OF A MULTICENTER PHASE II STUDY OF ABIRATERONE ACETATE (AA) ⴙ LOW-DOSE PREDNISONE (P) IN CHEMOTHERAPY-NAIVE MCRPC DEMONSTRATING RADIOGRAPHIC FLARES DISCORDANT WITH SEROLOGIC MEASURES OF RESPONSE Charles J. Ryan*, San Francisco, CA; Eleni Efstathiou, Houston, TX; Shreya Shah, Berkeley, CA; Matthew R. Smith, Mary-Ellen Taplin, Glenn J. Bubley, Boston, MA; Christopher J. Logothetis, Houston, TX; Thian Kheoh, Los Angeles, CA; Christine Kilian, San Francisco, CA; Christopher M. Haqq, Arturo Molina, Los Angeles, CA; Eric J. Small, San Francisco, CA INTRODUCTION AND OBJECTIVES: AA is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical and early clinical studies suggest that AA potently inhibits persistent androgen synthesis from adrenal and intratumoral sources, thus suppressing an important growth stimulus for mCRPC. AA ⫹ P has recently been shown to improve overall survival in mCRPC progressing after docetaxel (De Bono et al, ESMO 2010).
THE JOURNAL OF UROLOGY姞
Vol. 185, No. 4S, Supplement, Monday, May 16, 2011
717
Location 8q24
SNP rs16901979
Non-Aggressive (%) N⫽1123 11.8
Aggressive (%) N⫽253 9.1
8q24
rs16902094
28.4
44.2
8q24
rs445114
89.1
93.7
0.03
8q24
rs6983267
80.4
83.0
0.34
8q24
rs1447295
25.6
22.1
0.26
P value 0.23
Source of Funding: Supported in part by the Urological Research Foundation, Prostate SPORE grant (P50 CA9038605S2) and the Robert H. Lurie Comprehensive Cancer Center Grant (P30 CA60553)
716 PHASE III STUDY OF INTERMITTENT MAB VS CONTINUOS MAB Fernando M. Calais da Silva*, Fernando Calais da Silva, Lisbon, Portugal; Aldo Bono, Varese, Italy; Peter Whelan, Leeds, United Kingdom; Maurizio Brausi, Modena, Italy; Anton Queimadelos, Santiago Compostela, Spain; Jose Portillo, Santander, Spain; Ziya Kirkali, Izmir, Turkey INTRODUCTION AND OBJECTIVES: Few randomised studies have compared intermittent hormonal therapy with continuous therapy for the treatment of advanced prostate cancer. The main publication in 2009 was based upon data with a median follow up of 51 months. We present updated results with extended follow up. The objective is to investigate if intermittent therapy is associated with a shorter survival time. METHODS: 766 patients with locally advanced or metastatic prostate cancer received a three month induction treatment. 626 patients whose PSA decreased below 4 ng/ml or to 80% below the initial value, were randomised. Intervention: Patients received cyproterone acetate (CPA) 200 mg for two weeks and then monthly depot injections of a LHRH analogue plus 200 mg of CPA daily during induction. Patients randomised to the intermittent arm ceased treatment while those randomised to the continuous arm received 200 mg of CPA daily sa LHRH analogue RESULTS: A total of 474 patients are known to have died, 90 are lost to follow up, of which 37 withdrew mainly for patient refusal and change of therapy. There was no difference in survival, p ⫽ 0.61, with hazard ratio 0.96 (95% CI 0.80 to 1.14) and 239 deaths on the intermittent and 235 on the continuous arm. A slight excess of cancer deaths in the intermittent treatment arm (136 versus 109) is balanced by a slight excess of cardiovascular deaths in the continuous arm (68 versus 62), and deaths from other causes (58 versus 41). The hazard ratio of a cancer death is 1.27 (95% CI 0.98, 1.64), p ⫽ 0.06 in the intermittent arm compared to the continuous, For cardiovascular deaths the hazard ratios are 1.05 (95% CI 0.75, 1.49), p ⫽ 0.77, continuous compared to intermittent, and for other deaths the hazard ratio for continuous compared to intermittent is 1.38 (95% CI 0.93, 2.06), p⫽0.11. The extended follow up has accumulated a further 135 deaths since the last analysis which used data up to 2005 and exceeds the number of events specified in the original power analysis. The extra 5 years of follow up now means that the study has accumulated almost 3000 person years at risk among the 626 randomised patients and the median follow up is now 57 months compared to 51 months in the publication. CONCLUSIONS: Intermittent therapy should be considered for use in routine practice since it is associated with no reduction in survival, no clinically meaningful impairment in quality of life, better sexual activity, and considerable economic benefit to individual and community. Source of Funding: None
EVALUATION OF PROSTATE-SPECIFIC ANTIGEN KINETICS DURING ZOLEDRONIC ACID THERAPY FOR BONE METASTASES IN PATIENTS WITH CASTRATION-RESISTANT PROSTATE CANCER Fred Saad*, Montre´al, Canada; Jose Perez, Florham Park, NJ; Richard Cook, Waterloo, Canada; Scott Segal, Florham Park, NJ INTRODUCTION AND OBJECTIVES: Prevention of skeletalrelated events (SREs) has become an integral component of care in castration-resistant prostate cancer (CRPC), and zoledronic acid (ZOL) is an established therapy in this setting. Prostate-specific antigen (PSA) is an established marker for monitoring PC patients (pts). However, correlative information on PSA and SRE risks and the effects of ZOL on PSA kinetics is currently limited. Therefore, exploratory analyses of the ZOL phase III trial database were performed. METHODS: In the phase III trial of ZOL (Saad et al. JNCI. 2002/2004), CRPC pts with bone metastases (mets; N ⫽ 643) were randomized to ZOL or placebo (PBO) q 3 wk. PSA levels during the first 3 mo on study were evaluated in linear and logarithmic (log) models. Relative risks (RR) of SREs, bone disease progression (BDP), and death were calculated per 1 log (ng/mL) PSA increase. PSA kinetics models were stratified using prognostic factors established in the ZOL phase III trial (Cook et al. CCR. 2006) and a CRPC nomogram (Halabi et al. JCO. 2003). Time-dependent PSA values were carried forward for up to 168 days. Baseline PSA models used the study median (PSA 77.3 ng/mL) as the high/low cutpoint. RESULTS: Baseline PSA data were available for 434 ZOL- and 202 PBO-treated pts. In multivariate linear models of PSA kinetics over the first 3 mo, PSA velocity (coefficient of time in model for log[PSA] vs time) ranged from 0.134 – 0.155 log(ng/mL)/mo (ZOL) and 0.148 – 0.188 log(ng/mL)/mo (PBO), with no statistically significant treatment difference. In the overall population (n ⫽ 636), PSA increases correlated with significantly increased risks of death (RR ⫽ 1.596), BDP (RR ⫽ 1.159), and first SRE (RR ⫽ 1.264; RRs are for 1 log [ng/mL] increase; P ⬍ .0001 for all). The associated increases in BDP risk per 1 log (ng/mL) PSA increase were RR ⫽ 1.097 (ZOL) and RR ⫽ 1.295 (PBO). The cumulative incidence of SREs was lower overall for ZOL vs PBO. Pts with high baseline PSA had higher SRE risks in both groups (RR ⫽ 2.03 for PBO and 1.40 for ZOL). CONCLUSIONS: PSA is an important prognostic tool for survival in the CRPC bone mets setting, and these analyses showed that PSA is also prognostic for BDP and SREs. Consistent with its boneprotective effects, ZOL reduced the risk of SREs. Further analyses of PSA progression in earlier PC settings are planned. Source of Funding: Statistical analyses funded by Novartis Pharmaceuticals Corporation
718 LONG-TERM FOLLOW-UP OF A MULTICENTER PHASE II STUDY OF ABIRATERONE ACETATE (AA) ⴙ LOW-DOSE PREDNISONE (P) IN CHEMOTHERAPY-NAIVE MCRPC DEMONSTRATING RADIOGRAPHIC FLARES DISCORDANT WITH SEROLOGIC MEASURES OF RESPONSE Charles J. Ryan*, San Francisco, CA; Eleni Efstathiou, Houston, TX; Shreya Shah, Berkeley, CA; Matthew R. Smith, Mary-Ellen Taplin, Glenn J. Bubley, Boston, MA; Christopher J. Logothetis, Houston, TX; Thian Kheoh, Los Angeles, CA; Christine Kilian, San Francisco, CA; Christopher M. Haqq, Arturo Molina, Los Angeles, CA; Eric J. Small, San Francisco, CA INTRODUCTION AND OBJECTIVES: AA is a selective androgen biosynthesis inhibitor that blocks the action of CYP17. Preclinical and early clinical studies suggest that AA potently inhibits persistent androgen synthesis from adrenal and intratumoral sources, thus suppressing an important growth stimulus for mCRPC. AA ⫹ P has recently been shown to improve overall survival in mCRPC progressing after docetaxel (De Bono et al, ESMO 2010).