Abi has become one of the standard 1st line treatments in mCRPC. Cross-talk signalling pathways such as PI3K/Akt/mTOR represent a possible resistance mechanism against Abi. The oral antidiabetic agent Met has been shown to have antiproliferative effects via inhibiting mTOR. We hypothesized that the addition of Met to pts with PSA progression on Abi could influence resistance to Abi and thus delaying start of second line therapy.
Men with mCRPC experiencing PSA progression on first line Abi were enrolled in this prospective single-arm open-label multicentre Phase II trial. Pts with visceral metastases were excluded. Abi (1000mg qd)/Prednisone (5mg bd) treatment was continued and pts received Met 1000mg bd in addition. Primary endpoint was progression-free survival (PFS) at 12 weeks according to RECIST 1.1 or PCWG2 criteria. Secondary endpoints included PFS, PSA response rate, OS, toxicity and safety. 25 pts were planned to consider the trial uninteresting (H0: PFS at 12 weeks ≤ 15%) or promising (H1: ≥ 35%) using a 5% significance level and a 80% power.
25 pts with a median age of 76 years (IQR 72-82), were included between November 2013-September 2016 in 3 Swiss cancer centres. Median time to development of castration resistance was 19.5 months (mts) (IQR 11-24), and median duration on Abi before study entry was 12.1 mts (IQR 8-19). PFS rate at 12 weeks was 12% (3 of 25 pts), median PFS was 9 weeks (IQR 7-11) and median OS 20.7 mts (IQR 14-23). One patient had PSA decline of 30% and another one of 26%, all other had PSA progression. 4 pts (16%) had radiographic progression at week 12. 11 pts (44%) had grade 1 and two pts each grade 2 (8%) or grade 3 (8%) gastrointestinal toxicity (nausea, diarrhoea).
The addition of Met to Abi in pts with mCRPC after PSA progression on Abi did not have a substantial impact on PFS or PSA response. Toxicity of Met in combination with Abi was higher than expected.
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S. Gillessen, R. Cathomas: Advisor for the Janssen on advisory boards. All other authors have declared no conflicts of interest.