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647 PHASE 1–2 STUDY OF MDV3100 IN PRE- AND POST-DOCETAXEL ADVANCED PROSTATE CANCER: LONG-TERM EFFICACY RESULTS
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THE JOURNAL OF UROLOGY姞
Vol. 185, No. 4S, Supplement, Sunday, May 15, 2011
647 PHASE 1–2 STUDY OF MDV3100 IN PRE- AND POST-DOCETAXEL ADVANCED PROSTATE CANCER: LONG-TERM EFFICACY RESULTS Celestia Higano*, Seattle, WA; Tomasz Beer, Portland, OR; Evan Yu, Seattle, WA; Mary-Ellen Taplin, Boston, MA; Eleni Efstathiou, Houston, TX; Aseem Anand, New York, NY; Mohammad Hirmand, San Francisco, CA; Martin Fleisher, Howard Scher, New York, NY INTRODUCTION AND OBJECTIVES: MDV3100 is a novel androgen receptor (AR) antagonist with activity against prostate cancer (PCa) cells that overexpress AR. MDV3100 slows growth and induces cell death in bicalutamide-resistant tumors via 3 complementary actions: AR direct antagonism, inhibition of nuclear translocation of the AR complex, and inhibition of DNA binding by the AR (Tran C et al. Science. 2009;324:787). AR partial agonism has not been seen with MDV3100 in vitro. Preliminary antitumor activity and adverse events have been reported in advanced PCa from a phase 1–2 study of MDV3100 (Scher HI et al. Lancet. 2010;375:1437). Long-term follow-up for time to prostate-specific antigen (PSA) and radiographic progression from this study are presented here. METHODS: Patients (pts) with progressive castration-resistant PCa were enrolled in sequential cohorts of 3– 6 pts; MDV3100 doses were 30, 60, 150, 240, 360, 480, and 600 mg/day. After confirming dose tolerability, enrollment was expanded for doses ⱖ60 mg/day to include approximately 24 pts per dose cohort who were chemotherapynaive (chemo-naive; n⫽12) or previously treated with docetaxel (postchemo; n⫽12). RESULTS: 140 pts were enrolled, 18 (13%) of whom continue on active treatment (chemo-naive, n⫽16; post-chemo, n⫽2) with a median of 131 weeks of therapy. The median time on treatment is 51 weeks for chemo-naive (n⫽65) and 17 weeks for post-chemo (n⫽75) pts. The median time to PSA progression, defined as a ⱖ25% increase in PSA from baseline, was not met for chemo-naive pts and was 33 weeks for post-chemo pts. Median time to PSA progression by Prostate Cancer Clinical Trials Working Group 2 criteria was 41 and 20 weeks for chemo-naive and post-chemo pts, respectively. Median time to radiological progression is shown in the Figure. CONCLUSIONS: In this phase 1–2 study, MDV3100 demonstrated durable antitumor activity in chemo-naive and post-chemo pts with advanced PCa. To confirm these promising results, MDV3100 is being evaluated in 2 ongoing global phase 3 studies in pts with advanced progressive PCa: the AFFIRM study in pts previously treated with docetaxel, and the PREVAIL study in asymptomatic or mildly symptomatic chemo-naive pts who have progressed following androgen deprivation therapy.
Source of Funding: Medivation, Inc. and supported in part by the Department of Defense Prostate Cancer Research Program (PC051382) and the Prostate Cancer Foundation.
648 BENEFIT OF DENOSUMAB THERAPY IN PATIENTS WITH BONE METASTASES FROM CASTRATE RESISTANT PROSTATE CANCER: A NUMBER-NEEDED-TO-TREAT (NNT) ANALYSIS Kurt Miller*, Berlin, Germany; Karim Fizazi, Paris, France; Matthew Smith, Boston, MA; Jose Pablo Moroto, Barcelona, Spain; Laurence Klotz, Toronto, Canada; Janet Brown, Leeds, United Kingdom; Teuvo LJ Tammela, Tampere, Finland; Neal Shore, Myrtle Beach, SC; Chunlei Ke, Karen Chung, Carsten Goessl, Thousand Oaks, CA INTRODUCTION AND OBJECTIVES: Denosumab, a fully human monoclonal anti-RANKL antibody, was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in a randomized trial of prostate cancer patients with bone metastases. The number needed to treat (NNT) is a widely used method of expressing the benefit from a particular intervention. The NNT quantifies the benefit of a treatment by describing how many patients or patient-years of treatment are needed to prevent 1 undesirable event (eg, SRE) or achieve 1 beneficial outcome. METHODS: In this randomized, double-blind, double-dummy study, eligible castrate-resistant prostate cancer patients with bone metastases were randomized to receive either subcutaneous denosumab 120 mg (N ⫽ 950) or intravenous ZA 4 mg (N ⫽ 951) every 4 weeks. Supplemental calcium ⱖ 500 mg and vitamin D ⱖ 400 IU were recommended for all patients. The NNT for denosumab compared with ZA was calculated using first and subsequent SREs and was reported in patient-years, which describes the benefit of treatment regardless of treatment duration. RESULTS: In this head-to-head trial, denosumab reduced the risk of SREs by 18% vs ZA; P ⫽ 0.008. Seven hundred eighty SREs occurred in 1,045 patient-years in the denosumab arm; 943 SREs occurred in 996 patient-years in the ZA treatment arm. On average, compared with ZA, the NNT analysis demonstrates that treatment of 5 patients with denosumab would prevent an additional SRE (first or subsequent) per year. CONCLUSIONS: The low NNT for each SRE prevented suggests relatively high therapeutic efficacy for denosumab in men with prostate cancer and bone metastases compared to ZA. Source of Funding: Amgen Inc.
THE JOURNAL OF UROLOGY姞
Vol. 185, No. 4S, Supplement, Sunday, May 15, 2011
647 PHASE 1–2 STUDY OF MDV3100 IN PRE- AND POST-DOCETAXEL ADVANCED PROSTATE CANCER: LONG-TERM EFFICACY RESULTS Celestia Higano*, Seattle, WA; Tomasz Beer, Portland, OR; Evan Yu, Seattle, WA; Mary-Ellen Taplin, Boston, MA; Eleni Efstathiou, Houston, TX; Aseem Anand, New York, NY; Mohammad Hirmand, San Francisco, CA; Martin Fleisher, Howard Scher, New York, NY INTRODUCTION AND OBJECTIVES: MDV3100 is a novel androgen receptor (AR) antagonist with activity against prostate cancer (PCa) cells that overexpress AR. MDV3100 slows growth and induces cell death in bicalutamide-resistant tumors via 3 complementary actions: AR direct antagonism, inhibition of nuclear translocation of the AR complex, and inhibition of DNA binding by the AR (Tran C et al. Science. 2009;324:787). AR partial agonism has not been seen with MDV3100 in vitro. Preliminary antitumor activity and adverse events have been reported in advanced PCa from a phase 1–2 study of MDV3100 (Scher HI et al. Lancet. 2010;375:1437). Long-term follow-up for time to prostate-specific antigen (PSA) and radiographic progression from this study are presented here. METHODS: Patients (pts) with progressive castration-resistant PCa were enrolled in sequential cohorts of 3– 6 pts; MDV3100 doses were 30, 60, 150, 240, 360, 480, and 600 mg/day. After confirming dose tolerability, enrollment was expanded for doses ⱖ60 mg/day to include approximately 24 pts per dose cohort who were chemotherapynaive (chemo-naive; n⫽12) or previously treated with docetaxel (postchemo; n⫽12). RESULTS: 140 pts were enrolled, 18 (13%) of whom continue on active treatment (chemo-naive, n⫽16; post-chemo, n⫽2) with a median of 131 weeks of therapy. The median time on treatment is 51 weeks for chemo-naive (n⫽65) and 17 weeks for post-chemo (n⫽75) pts. The median time to PSA progression, defined as a ⱖ25% increase in PSA from baseline, was not met for chemo-naive pts and was 33 weeks for post-chemo pts. Median time to PSA progression by Prostate Cancer Clinical Trials Working Group 2 criteria was 41 and 20 weeks for chemo-naive and post-chemo pts, respectively. Median time to radiological progression is shown in the Figure. CONCLUSIONS: In this phase 1–2 study, MDV3100 demonstrated durable antitumor activity in chemo-naive and post-chemo pts with advanced PCa. To confirm these promising results, MDV3100 is being evaluated in 2 ongoing global phase 3 studies in pts with advanced progressive PCa: the AFFIRM study in pts previously treated with docetaxel, and the PREVAIL study in asymptomatic or mildly symptomatic chemo-naive pts who have progressed following androgen deprivation therapy.
Source of Funding: Medivation, Inc. and supported in part by the Department of Defense Prostate Cancer Research Program (PC051382) and the Prostate Cancer Foundation.
648 BENEFIT OF DENOSUMAB THERAPY IN PATIENTS WITH BONE METASTASES FROM CASTRATE RESISTANT PROSTATE CANCER: A NUMBER-NEEDED-TO-TREAT (NNT) ANALYSIS Kurt Miller*, Berlin, Germany; Karim Fizazi, Paris, France; Matthew Smith, Boston, MA; Jose Pablo Moroto, Barcelona, Spain; Laurence Klotz, Toronto, Canada; Janet Brown, Leeds, United Kingdom; Teuvo LJ Tammela, Tampere, Finland; Neal Shore, Myrtle Beach, SC; Chunlei Ke, Karen Chung, Carsten Goessl, Thousand Oaks, CA INTRODUCTION AND OBJECTIVES: Denosumab, a fully human monoclonal anti-RANKL antibody, was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in a randomized trial of prostate cancer patients with bone metastases. The number needed to treat (NNT) is a widely used method of expressing the benefit from a particular intervention. The NNT quantifies the benefit of a treatment by describing how many patients or patient-years of treatment are needed to prevent 1 undesirable event (eg, SRE) or achieve 1 beneficial outcome. METHODS: In this randomized, double-blind, double-dummy study, eligible castrate-resistant prostate cancer patients with bone metastases were randomized to receive either subcutaneous denosumab 120 mg (N ⫽ 950) or intravenous ZA 4 mg (N ⫽ 951) every 4 weeks. Supplemental calcium ⱖ 500 mg and vitamin D ⱖ 400 IU were recommended for all patients. The NNT for denosumab compared with ZA was calculated using first and subsequent SREs and was reported in patient-years, which describes the benefit of treatment regardless of treatment duration. RESULTS: In this head-to-head trial, denosumab reduced the risk of SREs by 18% vs ZA; P ⫽ 0.008. Seven hundred eighty SREs occurred in 1,045 patient-years in the denosumab arm; 943 SREs occurred in 996 patient-years in the ZA treatment arm. On average, compared with ZA, the NNT analysis demonstrates that treatment of 5 patients with denosumab would prevent an additional SRE (first or subsequent) per year. CONCLUSIONS: The low NNT for each SRE prevented suggests relatively high therapeutic efficacy for denosumab in men with prostate cancer and bone metastases compared to ZA. Source of Funding: Amgen Inc.