A reproducible quantitative definition of radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer was highly consistent and highly associated with overall survival in the Cougar-Abiraterone Acetate Study 302.

The findings could have implications for the interim measurement of treatment response in future studies, according to Dr. Michael J. Morris of Memorial Sloan Kettering Cancer Center, New York, and his colleagues.

Radiographic progression-free survival (rPFS) – defined in the Cougar-Abiraterone Acetate Study 302 (COU-AA-302) as the time from randomization to the first occurrence of progression by bone scan, progression by computed tomography or magnetic resonance imaging as defined by modified RECIST 1.0, or death resulting from any cause – was highly positively associated with overall survival in the randomized, placebo-controlled phase III study of 1,088 patients with metastatic castration-resistant prostate cancer (mCRPC) who were assigned to receive treatment with abiraterone plus prednisone or prednisone alone (Spearman’s correlation coefficient, 0.72), Dr. Morris and his colleagues reported online Jan. 26 in the Journal of Clinical Oncology.

Most men with mCRPC will succumb to the disease as a result of overwhelming osseous metastases; thus, approved treatments are prescribed to control or relieve pain and to delay or prevent skeletal-related events or death.

“There has long been a need to develop additional time-to-event endpoints short of [overall survival] to accelerate drug development,” the authors wrote, noting that the need is particularly urgent given the recent approval of numerous life-prolonging therapies for mCRPC (J. Clin. Oncol. 2015 Jan. 26 [doi:10.1200/JCO.2014.55.3875]).

A specific unmet need is a reproducible assay that can be interpreted and reported consistently and quantitatively as a biomarker in the assessment of bone disease with radionuclide bone scans, the investigators said.

A Prostate Cancer Working Group 2 (PCSG2) proposal to use a time-to-event progression endpoint for bone scan interpretation – with progression defined as two or more new lesions on an initial posttreatment bone scan, followed by two additional lesions on the subsequent scan – was evaluated along with a bone scan data capture assay developed through the Prostate Cancer Clinical Consortium in COU-AA-302.

Chemotherapy-naive patients were randomly assigned to receive 1,000 mg abiraterone plus prednisone daily or prednisone alone. At the first interim analysis for overall survival, independent review recorded 401 rPFS events. A 57% reduction in radiographic progression or death was seen in the abiraterone-treated group vs. the prednisone group (hazard ratio, 0.43); when rPFS was based on investigator-reviewed assessments of scans at that analysis, the decrease in the hazard of radiographic progression or death in the abiraterone group vs. the prednisone-only group was similar at 51% (hazard ratio, 0.49), the investigators reported.

At the second interim analysis for overall survival, 607 rPFS events were observed on investigator review. Treatment with abiraterone plus prednisone led to a 47% reduction in the risk of radiographic progression or death, compared with prednisone (hazard ratio, 0.53). This finding also closely matched the findings from the independent review at the first interim analysis.

Of note, the definition of radiographic progression used in the study prevented premature treatment discontinuation in 166 of 229 patients (72%) with two or more new lesions on their initial scan, because they did not develop two additional new lesions as of the subsequent scan, the investigators said.

The study – the first to use rPFS as a registration endpoint for evaluating chemotherapy-naive mCRPC patients per Food and Drug Administration approval of a supplemental new drug application – provides the highest level of evidence to date that rPFS is highly associated with overall survival in such patients, they said, noting that “the rigor of the independently validated data showing significant benefit in rPFS and a strong trend in [overall survival] as co-primary endpoints in combination with clinically relevant secondary endpoints” supported the regulatory approval of abiraterone acetate plus prednisone in chemotherapy-naive mCRPC patients.

“The results suggest that this objective, prospectively defined endpoint may serve as a response indicator biomarker that is evaluable in future studies,” they said, adding that while the findings demonstrate a highly positive association between rPFS and overall survival in mCRPC, they do not provide support for the use of rPFS as a substitute for overall survival.

This study was supported by Ortho Biotech Oncology Research and Development, the Prostate Cancer Clinical Trials Consortium, sponsored by the Department of Defense, and by Janssen Global Services, which provided writing assistance. Dr. Morris reported having no disclosures; his coauthors reported holding employment or leadership positions, serving in consultant or advisory roles, having stock ownership, and/or receiving honoraria or research funding from numerous pharmaceutical and other companies.