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This article summarizes the scientific review of the application leading to regulatory approval of carfilzomib in combination with lenalidomide and dexamethasone in the European Union.

Background: Preclinical data (de la Haba J, AACR 2011) and retrospective clinical data (Mander P, Cancer 2003; Linderhol B, JCO 2000) suggest that high vascular endothelial growth factor (VEGF) levels in breast tumors are associated with a decreased response to endocrine therapy. We designed the randomized phase III LEA study of first-line bevacizumab in combination with hormone therapy in endocrine responsive advanced breast cancer patients to address the hypothesis that anti-VEGF treatment can prevent resistance to hormone therapy in these patients. Methods: A multicenter, bi-national, randomized, open label, phase III study investigated the addition of Bevacizumab (B) 15mg/kg every 3 weeks to an endocrine therapy (ET) with letrozole (2.5 mg/day) or fulvestrant (250mg/4 weeks) as first-line therapy in advanced breast cancer. Postmenopausal patients with HER2-negative and hormone-receptor-positive breast cancer were eligible and randomized in a 1:1 ratio after being stratified for prior adjuvant therapy with an aromatase inhibitor (AI); number of involved sites (one/multiple); measurable lesions (yes/no) and participating country (Spain/Germany). The primary objective was to compare progression-free survival (PFS) between treatment arms. Secondary objectives were overall survival, time to treatment failure, overall response rate, response duration, clinical benefit rate, and safety. In total, 344 patients (172 in each treatment arm) were needed to detect a hazard ratio of 0.69 (corresponding to a median PFS of 9 months in the ET arm and 13 months in the ET+B arm) with α=0.05 and β=0.2. With an expected drop-out rate of 10%, 378 patients were to be included. The efficacy analysis is pre-planned after 270 events. Results: From 11/2007 to 8/2011, 380 patients were randomized in Spain and Germany to ET (n = 189) or ET+B (n = 191), 342 patients received letrozole and 38 fulvestrant. Baseline characteristics were well balanced. Median age was 65 years (38–86) and 72% of patients had ECOG PS 0. Twelve patients (4%) entered the trial with locally advanced disease, 65% had measurable lesions, 63% had bone and 45% visceral metastasis. 76% of patients had both hormone receptor positive. 44% had adjuvant chemotherapy and 51% adjuvant endocrine therapy from which 36% of patients received adjuvant AI. Full safety data will be presented at ESMO this year. The main side effects (any grade, per patient, ET+B vs ET) were anemia 76% vs 44%, p < 0.001; fatigue 50% vs 31%, p = 0.001; hemorrhage 19% vs 2%, p < 0.001; hypertension 55% vs 12%, p < 0.001; proteinuria 21%vs 3%, p < 0.001; and thrombosis grade 3–4, 2.3% vs 0%, p = 0.057. Until June 2012, 226 PFS events have been observed. The current event rate holds out the expectation to have the 270 necessary events by August-2012. Conclusions: LEA is the first phase III study to explore the use of an anti-angiogenic drug in combination with endocrine therapy. The efficacy results will be presented at the meeting. First and second authors have contributed equally to this study Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S1-7.

5004 Background: Docetaxel (DOCE) is a standard of care in metastatic castration-resistant prostate cancer (mCRPC). Several retrospective cohort studies suggest a decrease in PC incidence and mortality with metformin (MET). MET has also demonstrated anti-tumor activity in PC preclinical models, with increase apoptosis when added to DOCE. The addition of MET could enhance DOCE efficacy in mCRPC patients (pts). Methods: TAXOMET is a phase II prospective multicentric randomized controlled trial. Non-diabetic mCRPC pts were assigned 1:1 to receive DOCE 75mg/m2 every 21 days + prednisone (P) 5 mg twice a day and either MET 850mg twice a day (arm A) or placebo (arm B), up to 10 cycles. The primary end point was PSA response rate (≥50% decrease). Main secondary endpoints included objective response rate (ORR, according to RECIST v1.1), clinical and biological progression-free survival (PFS), overall survival (OS), toxicity and quality of life (QoL). Comparisons between arm A and B were performed using Chi² test for qualitative data and Log-rank test for survival data. Results: From January 2013 to December 2015, 99 pts were randomized (50 pts in arm A and 49 pts in arm B) in 10 french centers, and 95 pts were evaluable. No difference was observed between arm A and arm B in PSA-response rate (72% in both arms), ORR (28% in both arms), clinical or biological mPFS (7.3 months vs 5.8 months p = 0.848) and mOS (24.2 months (95CI: 17.2 – 33.7) vs 19.7 months (95CI: 14.8 – 36.8), p = 0.53), respectively. There was no difference between arms in adverse events, except a trend for diarrhea to be more common with MET (70% in arm A vs 50% in arm B, p = 0.072), but few grade 3-4 events. There was no difference in QoL according to QLQ-C30 score between the two arms during the treatment period. Conclusions: This is the first prospective randomized controlled trial to evaluate the combination of MET with DOCE+P in mCRPC. The addition of MET has no meaningful clinical benefit in this setting. Clinical trial information: NCT01796028.

INTRODUCTION: PREDICT is an online tool that estimates the 10-year breast cancer overall survival (10OS) with different adjuvant treatment combination. EndoPredict® is a genetic biomarker to guide decision on adjuvant systemic therapy in hormone-positive early-stage breast cancer. No study had ever correlated the estimated outcomes of PREDICT and EndoPredict® results. MATERIAL AND METHODS: We collected data of 249 patients with a 12-gene molecular test (EndoPredict®). EndoPredict® risk-score (EPclin) categorized patients in low (EPclin < 3.3) or high-risk (EPclin ≥ 3.3) of recurrence. The benefit of chemotherapy and the overall survival at 10 years (10OS) with endocrine therapy alone or with chemoendocrine therapy was estimated with PREDICT. RESULTS: From March 2017 to May 2022, 249 EndoPredict® tests (39% low-risk EPClin and 61% high-risk EPClin) were evaluated. In high-risk EPclin population compared with low-risk EPclin, 15% vs 6% (p=0.047) had a previous breast cancer event, 31% vs 14% a total mastectomy (p=0.006), 23% vs 10% do not express the progesterone receptor (p=0.011), 11% vs 5% had a SBR grade III (p=0.004) and 84% vs 63% had a Ki67 higher than 10% (p<0.001). The median estimated 10OS was prolonged by chemoendocrine therapy (85%) compared with endocrine therapy alone (83%) in high-risk EPclin (p=0.02), without difference in low-risk EPclin. The median chemotherapy benefit at 10OS was 2% [0.5-5.9] for low-risk and 2,6% [0.7-7.5] for high-risk EPclin (p = 0.0001). CONCLUSION: EPclin seemed to be a predictive factor of adjuvant chemotherapy at 10OS. Results of prospective trials UNIRAD and RESCUE are pending.