Neutropenia as a potential pharmacodynamic marker for docetaxel-based chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC).

51 Background: Data suggest docetaxel clearance is increased in castrate men. An association of docetaxel-induced grade ≥3 neutropenia with overall survival (OS) may provide a rationale for tailored dosing in mCRPC. Methods: The association of cycle 1 neutropenia with OS was examined in a randomized phase II trial of 221 men with mCRPC receiving docetaxel-prednisone combined with placebo or AT-101 (bcl-2 inhibitor), which performed weekly blood cell counts during the first cycle. Patients from both arms were combined as no outcome or neutropenia differences were observed. OS was calculated from randomization by the Kaplan-Meier method and Cox proportional hazards regression models were used to estimate the association with OS. Results: The difference in OS between men with day 8 ≥grade 3 neutropenia and those with ≤grade 2 neutropenia was significant after adjusting for stratification factors (HR: 0.64, p= 0.048). Excluding men with delayed cycle 2 yielded a more significant association of grade 3-4 neutropenia on day 8 with survival (Table). Men with ≥grade 3 neutropenia and ≥30% PSA decline by day 90 had improved OS compared with men exhibiting neither (HR: 0.51, p=0.014). Conclusions: In mCRPC receiving docetaxel, ≥grade 3 neutropenia on day 8 was prognostic for improved OS, suggesting its potential utility as a pharmacodynamic marker in this hypothesis-generating analysis. Since the association was stronger after excluding patients that experienced dose delays, grade 3 neutropenia may confer a more favorable therapeutic index than grade 4 neutropenia. The exploration of dose modulation of docetaxel to attain ≥grade 3 neutropenia on day 8 may be warranted. [Table: see text]