Improved survival outcomes in clinically relevant patient subgroups from COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel-based chemotherapy.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 4-4 ◽  
Author(s):  
H. I. Scher ◽  
C. Logothetis ◽  
A. Molina ◽  
O. B. Goodman ◽  
C. N. Sternberg ◽  
...  
Keyword(s):  
Abiraterone Acetate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Androgen Synthesis ◽  
Phase Iii Study ◽  
Study Population ◽  
Grade 3 ◽  
Patient Subgroups

4 Background: 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. Methods: COU-AA-301 ( NCT00638690 ) is an international, randomized, double blind study of AA (1,000 mg + P 5 mg po BID) vs placebo + P administered to men with mCRPC progressing after docetaxel-based chemo. OS is the primary endpoint. Patients treated with previous ketoconazole or > 2 prior chemo regimens were excluded. Results: Data are drawn from a planned, stratified interim analysis, unblinded in August 2010, based on significant OS improvement in the AA + P treatment group compared to the placebo + P group [median OS 14.8 vs.10.9 months; HR = 0.646 (0.54-0.77), P < 0.0001]. A subgroup analysis for OS is presented in the table. Mineralocorticoid- related AEs were more common in the AA arm vs placebo: fluid retention 30.5% vs 22.3%, hypokalemia 17.1% vs 8.4%; but grade 3/4 hypokalemia (3.8% vs 0.8%), and grade 3/4 hypertension (1.3% vs 0.3%) were infrequent. LFT abnormalities were observed in 10.4% AA vs 8.1% placebo; and cardiac disorders were observed in 13.3% AA vs 10.4% placebo. Conclusions: AA significantly prolongs OS in patients with mCRPC who have progressed after docetaxel-based chemo. AA's favorable treatment effect on OS, observed across multiple patient subgroups (HR range 0.59 – 0.74 vs placebo + P), was consistent with the survival benefit for the overall study population. [Table: see text] [Table: see text]

Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 15-15 ◽  
Author(s):  
Kim N. Chi ◽  
Howard I. Scher ◽  
Arturo Molina ◽  
Christopher Logothetis ◽  
Robert J. Jones ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Androgen Synthesis ◽  
Survival Result ◽  
Phase Iii Study ◽  
Post Hoc

15 Background: AA, a selective androgen biosynthesis inhibitor, blocks the action of CYP17, thereby inhibiting adrenal and intratumoral androgen synthesis. AA has demonstrated improved overall survival (OS) by 4.6 months (mos) vs placebo (HR=0.74) in patients (pts) previously treated with D. Methods: COU-AA-301 is a randomized double-blind study of AA (1 g) + P (5 mg po BID) vs placebo + P administered to mCRPC pts post-D with a primary endpoint of OS. To evaluate the robustness of the primary survival results, we performed post hoc exploratory analyses to assess whether the timing of first and last dose of D and reason for D discontinuation impacted OS. Results: At the time of randomization, treatment arms were balanced with respect to baseline characteristics, prior D use, and reasons for discontinuation. In both arms, almost half (45%) discontinued D due to progressive disease (PD); the remainder discontinued D as part of planned treatment (37%), toxicity (12%), or for other reasons (5%) per investigator reporting. Median OS from first and last dose of D were longer with AA vs placebo (Table). Median OS was longer with AA vs placebo in pts who discontinued D for PD or for all other reasons. Conclusions: These exploratory analyses suggest that the survival benefit of AA in mCRPC was maintained when calculated from first or last dose of prior D, and whether or not pts discontinued D for PD. Pts in the AA arm of this study had a prolonged median OS of > 32 mos from the time of initial D therapy. Congruity among these analyses demonstrates the robustness of the primary survival result. [Table: see text]

Exploratory analysis of survival benefit and prior docetaxel (D) treatment in COU-AA-301, a phase III study of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4558-4558 ◽  
Author(s):  
Oscar B. Goodman ◽  
Kim N. Chi ◽  
Arturo Molina ◽  
Christopher Logothetis ◽  
Robert J. Jones ◽  
...  
Keyword(s):  
Abiraterone Acetate ◽  
Phase Iii ◽  
Double Blind Study ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Survival Result ◽  
Castration Resistant ◽  
Phase Iii Study ◽  
Previously Treated ◽  
Post Hoc

4558 Background: AA, a selective androgen biosynthesis inhibitor, blocks the action of CYP17, thereby inhibiting adrenal and intratumoral androgen production. AA has demonstrated improved overall survival (OS) by 4.6 months (mos) vs placebo (HR=0.74) in patients (pts) previously treated with D. Methods: COU-AA-301 is a randomized double blind study of AA (1 g) + P (5 mg po BID) vs placebo + P administered to mCRPC pts post-D with a primary endpoint of OS. To further evaluate primary survival result robustness, we performed post hoc exploratory analyses to assess whether the timing of first and last dose of D and reason for D discontinuation impacted OS. Results: At randomization, treatment arms were balanced with respect to baseline characteristics, prior D use, and reasons for discontinuation. In both arms, almost half (45%) discontinued D due to progressive disease (PD); remainder discontinued D after completing all planned cycles (37%), due to toxicity (12%), or for other reasons (5%) per investigator. Median OS from first and last dose of D were longer with AA vs placebo (Table). Median OS was longer with AA vs placebo in pts who discontinued D for PD, or for all other reasons. Conclusions: These exploratory analyses suggest that the OS benefit of AA in mCRPC was maintained when calculated from first or last dose of prior D, and whether or not pts discontinued D for PD. Pts in AA arm of this study had a prolonged median OS of > 32 mos from time of initial D therapy. Congruity among these analyses and lack of dependence on D timing demonstrate robustness of the primary survival result. [Table: see text]

Exploratory analysis of the visceral disease (VD) patient subset in COU-AA-301, a phase III study of abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC).

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 14-14 ◽  
Author(s):  
Oscar B. Goodman ◽  
Thomas W. Flaig ◽  
Arturo Molina ◽  
Peter Mulders ◽  
Henrik Suttmann ◽  
...  
Keyword(s):  
Objective Response ◽  
Response Rates ◽  
Abiraterone Acetate ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Negative Prognostic Factor ◽  
Psa Response ◽  
Phase Iii Study ◽  
Grade 3

14 Background: VD is a negative prognostic factor in mCRPC patients (pts) and may be less responsive to hormonal therapy. AA, a selective androgen biosynthesis inhibitor, inhibits androgen synthesis from adrenal and intratumoral sources. Improved overall survival (OS) with AA vs prednisone (P) was demonstrated in a randomized trial of pts with mCRPC post-docetaxel (D). Here we further assess the effect of AA on OS and other clinical outcomes in post-D mCRPC pts with VD (liver or lung, but not nodal-only metastases). Methods: In COU-AA-301, pts with mCRPC previously treated with D were randomized 2:1 to AA (1000 mg) + P (5 mg BID) (n=797) or placebo + P (n=398). The primary end point was OS. Data shown herein represent the updated analysis (775 events) of patients with (n=352) or without (n=843) VD. Results: The OS benefit of AA was similarly improved in patients with VD (4.6 m) and without VD (4.8 m) (Table). Treatment with AA led to significant 40% and 32% reductions in the risk of radiographic progression or death in patients with VD or without VD, respectively. Soft-tissue objective response rates were superior with AA in both groups. PSA response rates (50% reduction) were significantly improved by AA in both groups. Grade 3/4 adverse events (AEs) were similar in both groups. Hypertension, hypokalemia, and LFT abnormalities were observed with AA in pts with and without VD. Conclusions: AA has substantial anti-tumor activity and provides clinical benefit including improvements in OS and rPFS in post-D mCRPC pts with VD indicating it is a therapeutically active treatment option for CRPC pts. Safety/tolerability of AA in pts with VD was similar to that reported previously in mCRPC. Clinical trial information: NCT00638690. [Table: see text]

Phase III study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 687-687 ◽  
Author(s):  
Andrew J. Armstrong ◽  
Russell Zelig Szmulewitz ◽  
Daniel Peter Petrylak ◽  
Arnauld Villers ◽  
Arun Azad ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
High Volume ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Secondary Endpoints ◽  
Phase Iii Study ◽  
Grade 3

687 Background: ENZA, a potent androgen receptor inhibitor, has demonstrated benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). Efficacy of ENZA with ADT in men with mHSPC is unknown. Methods: ARCHES is a multinational, double-blind, phase 3 study (NCT02677896). Patients (pts) with mHSPC were randomized 1:1 to ENZA (160 mg/day) + ADT or PBO + ADT, stratified by disease volume (CHAARTED criteria) and prior docetaxel therapy. Primary endpoint was radiographic progression-free survival (rPFS) assessed centrally or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS). Treatment continued until disease progression or unacceptable toxicity. Results: 1150 men were randomized to ENZA (n=574) or PBO (n=576); baseline characteristics were balanced between groups. Overall, 67% had distant metastasis at initial diagnosis; 63% had high volume disease, 18% had prior docetaxel. Median follow-up was 14.4 mo. ENZA + ADT significantly improved rPFS (Table); similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, pattern of spread, region and prior docetaxel (HRs 0.24–0.53). Secondary endpoints improved with ENZA + ADT (Table); OS data are immature. Grade 3–4 adverse events (AEs) were reported in 23.6% of ENZA pts vs 24.7% of PBO pts with no unexpected AEs. Conclusions: ENZA + ADT significantly improved rPFS and other efficacy endpoints vs PBO + ADT in men with mHSPC, with a preliminary safety analysis that appears consistent with the safety profile of ENZA in previous CRPC clinical trials. Acknowledgements: Medical writing and editing assistance was provided by Stephanie Rippon, MBio, and Lauren Smith from Complete HealthVizion, funded by the study sponsors. This study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the co-developers of enzalutamide. Clinical trial information: NCT02677896. [Table: see text]

A hypothesis-generating exploratory analysis of efficacy and safety of abiraterone acetate (AA) in African American (Af Am) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 55-55
Author(s):  
Eleni Efstathiou ◽  
Vasily J. Assikis ◽  
Scott A. North ◽  
John Showel ◽  
Thomas E. Hutson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Safety Profile ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Double Blind Study ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer ◽  
Double Blind ◽  
Psa Response ◽  
Grade 3

55 Background: The reported increased prostate cancer lethality in Af Ams has been attributed by some to altered androgen receptor (AR) signaling. We compared toxicity, PSA response, time-to-PSA progression (TTPP), and radiographic progression-free survival (rPFS) in Af Am vs non Af Am pts with CRPC treated with AA + prednisone (P) vs placebo + P. We hypothesized that differences in response to AA may be observed if differences in AR signaling exist in Af Ams. Methods: COU-AA-301 is a randomized double blind study of AA (1000 mg + P 5 mg po BID) vs placebo + P post-docetaxel. Results: TTPP, rPFS, and PSA response rate were higher with AA vs placebo. In Af Am pts, treatment emergent AEs (TEAEs) for AA vs placebo occurred in 96.4% vs 100.0% of pts (50.0% and 66.7%, respectively, grade 3/4); serious TEAEs occurred in 42.9% and 33.3% of pts (28.6% and 26.7%, respectively, grade 3/4). The safety profile of AA appears comparable between the Af Am and overall study populations. Conclusions: Although the small number of Af Am pts in this study precludes formal conclusions regarding efficacy and safety of AA in this pt population, the overall trend suggests these pts experienced clinical benefit from AA with a safety profile comparable to the overall study population. These findings do not appear to support the hypothesis that AR signaling accounts for the increased lethality of prostate cancer seen in Af Ams. Further studies of AA in Af Am pts are planned to understand the potential benefit in this population. Additional efforts are needed to increase participation of Af Am pts in clinical trials. [Table: see text]

Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (18_suppl) ◽  
pp. LBA4518-LBA4518 ◽  
Author(s):  
Charles J. Ryan ◽  
Matthew Raymond Smith ◽  
Johann Sebastian De Bono ◽  
Arturo Molina ◽  
Christopher Logothetis ◽  
...  
Keyword(s):  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Abiraterone Acetate ◽  
Primary Objective ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Androgen Synthesis ◽  
Strong Trend ◽  
Secondary Endpoints ◽  
Grade 3

LBA4518 Background: AA is an androgen biosynthesis inhibitor that inhibits CYP17 and improves overall survival (OS) in post-docetaxel mCRPC. The primary objective of COU-AA-302 was to compare clinical benefit of AA + prednisone (P) vs placebo (PL) + P in chemo-naive, asymptomatic/mildly symptomatic mCRPC pts. Methods: 1088 pts (151 centers; 12 countries) were randomized 1:1 to AA (1 g) + P (5 mg BID) or PL + P. Co-primary endpoints: radiographic progression-free survival (rPFS) and OS. Median times estimated using K-M method including LR statistic for inference. The Lan-DeMets α-spending function was used for OS. Results:The Independent Data Monitoring Committee concluded that the OS, rPFS and secondary endpoints (Table) all favored the AA arm and unanimously recommended unblinding the study and crossing pts from PL to AA at IA (43% of total events). Median follow up = 22.2 mos. Grade 3/4 AEs (AA + P, PL + P) (%): hypertension 3.9 vs 3.0; hypokalemia 2.4 vs 1.9; ALT↑ 5.4 vs 0.7; AST↑ 3.0 vs 0.9. Conclusions:AA + P produced a statistically significant improvement in rPFS and a strong trend for increased OS at this IA. AA resulted in clinically and statistically significant effects on all secondary endpoints. IA results confirmed the acceptable tolerability/safety profile of AA. This is the first randomized trial to demonstrate both OS and rPFS benefits in chemo-naive mCRPC and that inhibition of persistent extragonadal androgen synthesis significantly delays initiation of cytotoxic chemo. While median OS (AA arm) has not been reached, median PL arm OS (27.2 mos) is the longest measured in any phase III mCRPC study. [Table: see text]

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