BACKGROUND: Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting. METHODS: We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (≥ 50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models. RESULTS: One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P = 0.089). Median TTPP was 7.2 months (95% CI = 4.5 - 17.2) in the D-naïve group versus 2.6 mo (95% CI = 1.9 - 3.5) in the D-pretreated group (P < 0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI = 2.5 - 4.8) for D-pretreated men (P < 0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR = 2.32; 95% CI = 1.19 - 4.50; P = 0.013) and marginally significant for PFS (HR = 1.90; 95% CI = 0.94 - 3.84; P = 0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n = 34), results suggested a trend towards shorter duration of response in D-pretreated patients. CONCLUSIONS: The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents.
BACKGROUND: Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting. METHODS: We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (≥ 50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models. RESULTS: One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P = 0.089). Median TTPP was 7.2 months (95% CI = 4.5 - 17.2) in the D-naïve group versus 2.6 mo (95% CI = 1.9 - 3.5) in the D-pretreated group (P < 0.0001). Median PFS was not reached for D-naïve men and was 3.3 mo (95% CI = 2.5 - 4.8) for D-pretreated men (P < 0.0001). After adjusting for potential confounders including prior abiraterone use, differences remained statistically significant for TTPP (HR = 2.32; 95% CI = 1.19 - 4.50; P = 0.013) and marginally significant for PFS (HR = 1.90; 95% CI = 0.94 - 3.84; P = 0.073) in multivariable analyses. Among patients who achieved a PSA response to enzalutamide (n = 34), results suggested a trend towards shorter duration of response in D-pretreated patients. CONCLUSIONS: The clinical activity of enzalutamide appears to be blunted in patients who have previously received docetaxel chemotherapy. These results support the concept of cross-resistance between these two agents.
Authors: C Montagut; I Tusquets; B Ferrer; J M Corominas; B Bellosillo; C Campas; M Suarez; X Fabregat; E Campo; P Gascon; S Serrano; P L Fernandez; A Rovira; J Albanell Journal: Endocr Relat Cancer Date: 2006-06 Impact factor: 5.678
Authors: Chris Tran; Samedy Ouk; Nicola J Clegg; Yu Chen; Philip A Watson; Vivek Arora; John Wongvipat; Peter M Smith-Jones; Dongwon Yoo; Andrew Kwon; Teresa Wasielewska; Derek Welsbie; Charlie Degui Chen; Celestia S Higano; Tomasz M Beer; David T Hung; Howard I Scher; Michael E Jung; Charles L Sawyers Journal: Science Date: 2009-04-09 Impact factor: 47.728
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: Ian F Tannock; Ronald de Wit; William R Berry; Jozsef Horti; Anna Pluzanska; Kim N Chi; Stephane Oudard; Christine Théodore; Nicholas D James; Ingela Turesson; Mark A Rosenthal; Mario A Eisenberger Journal: N Engl J Med Date: 2004-10-07 Impact factor: 91.245
Authors: Michael T Schweizer; Xian C Zhou; Hao Wang; Sunakshi Bassi; Michael A Carducci; Mario A Eisenberger; Emmanuel S Antonarakis Journal: Eur Urol Date: 2014-01-24 Impact factor: 20.096
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Authors: T Visakorpi; E Hyytinen; P Koivisto; M Tanner; R Keinänen; C Palmberg; A Palotie; T Tammela; J Isola; O P Kallioniemi Journal: Nat Genet Date: 1995-04 Impact factor: 38.330
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