Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer.
OBJECTIVE
To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC).


PATIENTS AND METHODS
Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons.


RESULTS
An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review.


CONCLUSIONS
Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.
['Sonpavde|Guru|G|', 'Pond|Gregory R|GR|', 'Armstrong|Andrew J|AJ|', 'Galsky|Matthew D|MD|', 'Leopold|Lance|L|', 'Wood|Brian A|BA|', 'Wang|Shaw-Ling|SL|', 'Paolini|Jolanda|J|', 'Chen|Isan|I|', 'Chow-Maneval|Edna|E|', 'Mooney|David J|DJ|', 'Lechuga|Mariajose|M|', 'Smith|Matthew R|MR|', 'Michaelson|M Dror|MD|']
D000971:Antineoplastic Combined Chemotherapy Protocols D018450:Disease Progression D018572:Disease-Free Survival D000077143:Docetaxel D055808:Drug Discovery D006072:Gossypol D006801:Humans D007211:Indoles D008297:Male D011241:Prednisone D064129:Prostatic Neoplasms, Castration-Resistant D011758:Pyrroles D011859:Radiography D012189:Retrospective Studies D000077210:Sunitinib D015996:Survival Rate D043823:Taxoids D013997:Time Factors
radiographic progression Prostate Cancer Working Group (PCWG)-2 metastatic castration-resistant prostate cancer overall survival (OS)