Radiographic progression-free survival as a response biomarker in metastatic castration-resistant prostate cancer: COU-AA-302 results

Abstract

Purpose: Progression-free survival (PFS) in metastatic castration-resistant prostate cancer (mCRPC) trials has been inconsistently defined and poorly associated with overall survival (OS). A reproducible quantitative definition of radiographic PFS (rPFS) was tested for association with a coprimary end point of OS in a randomized trial of abiraterone in patients with mCRPC.

Patients and methods: rPFS was defined as ≥ two new lesions on an 8-week bone scan plus two additional lesions on a confirmatory scan, ≥ two new confirmed lesions on any scan ≥ 12 weeks after random assignment, and/or progression in nodes or viscera on cross-sectional imaging, or death. rPFS was assessed by independent review at 15% of deaths and by investigator review at 15% and 40% of deaths. rPFS and OS association was evaluated by Spearman's correlation.

Results: A total of 1,088 patients were randomly assigned to abiraterone plus prednisone or prednisone alone. At first interim analysis, the hazard ratio (HR) by independent review was 0.43 (95% CI, 0.35 to 0.52; P < .001; abiraterone plus prednisone: median rPFS, not estimable; prednisone: median rPFS, 8.3 months). Similar HRs were obtained by investigator review at the first two interim analyses (HR, 0.49; 95% CI, 0.41 to 0.60; P < .001 and HR, 0.53; 95% CI, 0.45 to 0.62; P < .001, respectively), validating the imaging data assay used. Spearman's correlation coefficient between rPFS and OS was 0.72.

Conclusion: rPFS was highly consistent and highly associated with OS, providing initial prospective evidence on further developing rPFS as an intermediate end point in mCRPC trials.

Trial registration: ClinicalTrials.gov NCT00887198.

Fig 1.

Study profile. Adapted Prostate Cancer Working Group criteria identified a substantial number of patients with ≥ two new lesions at 8 weeks compared with baseline for whom progression was not confirmed by having ≥ two additional new lesions on subsequent scan (total, 166 [72%] of 229; abiraterone, 92 [85%] of 108; prednisone, 74 [61%] of 121). ITT, intent to treat; PD, progressive disease.

Fig 2.

Radiographic progression-free survival as assessed by blinded independent review (December 2010), blinded independent and investigator review (December 2010), and blinded independent and investigator review (December 2011).

Fig 3.

Survival of patients with early bone scan progression (by 2 + 2 criteria) who failed to document progression (n = 166) versus those with documented progression on subsequent bone scan (n = 63). PD, progressive disease.