Oral Presentation COSA-IPOS Joint Scientific Meeting 2012

Abiraterone acetate (AA) in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC): results of interim analysis (IA) of COU-AA-302, a randomized phase 3 study (#156)

Paul de Souza 1 , Matthew R Smith 2 , Johann S de Bono 3 , Arturo Molina 4 , Christopher Logothetis 5 , Karim Fizazi 6 , Josep M Piulats 7 , Siobhan Ng 8 , Joan Carles 9 , Peter FA Mulders 10 , Paul Mainwaring 11 , Thian Kheoh 4 , Thomas Griffin 4 , Eric J Small 12 , Howard I Scher 13 , Dana Rathkopf 13 , Charles J Ryan 12
  1. University of Western Sydney School of Medicine, Ingham Institute, Liverpool, NSW, Australia
  2. Massachusetts General Hospital Cancer Center, Boston, MA, USA
  3. Royal Marsden Hospital, Sutton, UK
  4. Janssen Research & Development, Los Angeles, CA, USA
  5. MD Anderson Cancer Center, Houston, TX, USA
  6. Institut Gustave Roussy, University of Paris Sud, Villejuif, France
  7. Institut Català d'Oncologia de l'Hospitalet, Barcelona, Spain
  8. St. John of God Hospital, Subiaco, Australia
  9. Hospital Universitari Vall d´Hebron, Barcelona, Spain
  10. Radboud University Medical Centre, Nijmegen, Netherlands
  11. Haematology and Oncology Clinics of Australia, Brisbane, Australia
  12. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
  13. Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Aims: AA is an androgen biosynthesis inhibitor that blocks CYP17 activity and improves overall survival(OS) in mCRPC patients post-docetaxel. Study COU-AA-302 evaluated the co-primary endpoints of radiographic progression-free survival(rPFS) and OS, in AA+prednisone(P) versus placebo(PL)+P in chemotherapy-naïve, asymptomatic or mildly symptomatic mCRPC patients.

Methods: 1088 patients (151 centers; 12 countries) were randomized 1:1 to AA(1 g)+P(5 mg BID) or PL+P; 132 patients enrolled across 18 sites in Australia. Median time-to-event endpoints were estimated using Kaplan-Meier method including LR statistic for inference. Lan-DeMets α-spending function was used for OS, with pre-specified alpha level 0.0008.

Results: Median follow up = 22.2 months. Clinical cutoff date(rPFS) was 20 Dec 2010 and 20 Dec 2011(other analyses). Median time for rPFS and OS was not reached(NR) for AA+P, while for PL+P these were 8.3 months, HR(95%CI) 0.43(0.35, 0.52), p<0.0001, and 27.2 months, HR(95%CI) 0.75(0.61, 0.93), p=0.0097, respectively. Median time to opiate use (cancer-related pain) was NR for AA+P and 23.7 months for PL+P, HR(95%CI) 0.69(0.57, 0.83), p=0.0001. Median time to chemotherapy initiation, to ECOG-PS deterioration and to PSA progression were statistically significant and favored AA+P versus PL+P, HR(95%CI):0.58(0.49, 0.69), p<0.0001; 0.82(0.71, 0.94), p=0.0053; and 0.49(0.42, 0.57), p<0.0001, respectively. Grade 3/4 AEs (AA+P, PL+P) (%): hypertension 3.9 versus 3.0; hypokalemia 2.4 versus 1.9; ALT↑ 5.4 versus 0.7; AST↑ 3.0 versus 0.9.

Conclusions: The Independent Data Monitoring Committee concluded that OS, rPFS and secondary endpoints favored AA arm and unanimously recommended unblinding the study and crossing patients from PL to AA at IA (43% of total events). IA results confirmed acceptable tolerability/safety profile of AA. This is the first randomized trial to demonstrate both OS and rPFS benefits in chemotherapy-naïve patients with mCRPC and that inhibition of persistent extragonadal androgen synthesis significantly delays initiation of cytotoxic chemotherapy. 

  1. Funding: Supported by Janssen Research & Development.