Effect of sorafenib on chemotherapy resistance and refractoriness in castration-resistant prostate cancer (CRPC)

Abstract

e16105 Background: There is no standard for CRPC once chemotherapy fails. In studies employing docetaxel (D), 35–39% of pts did not complete therapy due to progression and only 45–50% had a PSA response. This implies that many pts develop resistance to D. Sorafenib is a multi kinase inhibitor with antiangiogenesis properties. We hypothesized that sorafenib could overcome chemotherapy resistance in these pts. Methods: Eligible pts must have progressed while on either D or mitoxantrone (M). They received sorafenib at 400 mg orally twice/daily in addition to the chemotherapy agent they were on. Sorefinib/chemotherapy combination was given for a maximum of 6 cycles followed by sorafenib monotherapy until progression. Primary end point was safety of the sorafenib/chemotherapy combination. Secondary end points included the overall clinical benefit calculated as the sum of complete response (CR), partial response (PR), and stable disease (SD), toxicity, and time to disease progression (TTP). Results: To date, 15 pts have been enrolled; 14 are evaluable. Eleven pts were on D and 4 on M. Median age was 68 (range 61–83), median PSA was 111.2 ng/ml (13.6–1703.9). Nine pts (60%) had visceral and bone disease. Median PSA-DT pre-study was 2 months (0.5–6) and median time from last chemotherapy to starting study was 4 weeks. Median number of given cycles was 6.5 (2–12). Six pts did not require dose reduction, 2 others were re-escalated to the full dose. Sorafenib was safely combined with chemotherapy with 6 pts experiencing grade 3 fatigue, 3 developing grade 3 hand/foot syndrome, and 1 experiening grade 3 diarrhea. Eleven pts (73%) had SD radiographically that lasted a median of 6.7 months. In all, 6 out of 14 pts (42%) had a PSA decline after adding sorafenib and 3 (21%) had stable PSA. Of these 9 pts (PR+SD), 2 never doubled their PSA. Two pts had PSA decline after withdrawing sorafenib. Median TTP for PSA was 3.75 months. PSA responses did not correlate with radiographic changes or clinical benefit. With a median follow-up of 8 months, 5 pts (33%) remain alive with 1 continuing on therapy without progression. Conclusions: Sorafenib overcomes chemotherapy-refractoriness and failures in CRPC. [Table: see text]