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Brief description/objective

Clinical Trial with an IMP, risk category B according to HRA. Abiraterone acetate (AA) is a standard treatment option both in chemotherapy naïve and docetaxel pre-treated men with metastatic castrate-resistant prostate cancer (CRPC). With the approval of AA before chemo-therapy an increasing proportion of patients (asymptomatic or minimally symptomatic and without visceral metastases) will be treated with AA before chemotherapy. Currently, there is no standard treatment option available for patients progressing after AA and docetaxel. The second-line chemotherapy cabazitaxel has not been tested in this set-ting and neither has enzalutamide been evaluated in a prospective trial post AA and postdocetaxel. A number of retrospective cohort studies have furthermore indicated limited activity of enzalutamide post AA and docetaxel (9, 10). Furthermore due to the risk of seizures associated with enzalutamide patients with predisposing factors should not be treated with this compound. While molecular subtyping has resulted in therapeutic benefit and improved patient survival namely in breast, melanoma, colorectal and lung cancer, no such advances have been made for prostate cancer patients. All patients with metastatic CRPC are treated identically, without any selection of appropriate therapeutic regimens based on tumour profiling. Abi-raterone acetate re-challenge has not been prospectively tested in CTU 14/020, Version 1.0, 02 July 2015 confiden-tial Page 9 of 69 CRPC patients. Recently a small retro-spective analysis of 12 CRPC patients re-treated with abi-raterone acetate has bene published (Leibowitz-Amit et al. 2014) (11). The rate of ≥50% PSA decline rates in patients that had previously experienced a significant PSA decline was 46% (3/7 patients). Recent results also showed the importance of expression of AR splice variants and re-sponse to AR targeting drugs. In 31 abiraterone-treated patients, a total of 19.4% had detectable AR-V7 from CTCs. For patients receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median 1.3 months vs not reached, P<0.001), and PFS (median 2.3 months vs not reached, P<0.001). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length AR expression levels (12). Based on the fact that patients progressing post AA and post docetaxel have significant levels of nuclear AR expression in tumour biopsies we hypothesize that a proportion of patients will have disease that is sensitive to further treatment with AA (re-challenge) despite initial progression during treatment with this drug. This trial is important because it: Offers a well-tolerated treatment op-tion to CRPC patients with a biological rationale (prior re-sponse to AA). Will include a detailed molecular character-ization at baseline and at progression on AA re-challenge using next generation sequencing techniques.