Background: Olaparib is a PARP inhibitor that has shown high response rates and clinical activity in patients with advanced HER2-negative breast cancer (BC) and a germline BRCA1 and BRCA2 mutation. There is also evidence of cellular sensitivity to PARP inhibitors associated to defects in other genes involved in homologous recombination DNA repair (HRR) or mismatch repair pathway (microsatellite instability MSI). Moreover, about 15% of patients with ER+/HER2- metastatic BC have at least 100 mutations in their tumor, leading to genomic instability and potential sensitivity to PARP inhibitors. Several preclinical and clinical studies have suggested the benefit of an association of immune checkpoint blockade, like durvalumab, with PARP inhibitor. Indeed, tumors with BRCA1/2 mutations or other deficiency in HRR have high mutagenic burden and produce a larger number of neoantigens. Most BRCA-associated BC are ER+/HER2-. Although loss of the BRCA gene function is a key driver of oncogenesis in these patients, ER-pathway appears to remain a key target for their therapy. Preclinical data indicate that olaparib may enhance endocrine therapy efficacy and circumvent resistance. Therefore, the combination of durvalumab, olaparib and endocrine therapy could be a therapeutic option for patients with BRCA1/2 mutation or for patients with selected ER+/HER2- advanced BC.

Trial design: DOLAF is an open-label, international, multicentric, phase II trial assessing the combination of olaparib, fulvestrant, and durvalumab. Olaparib will be administered orally twice daily at 300 mg. Fulvestrant will be administered as two intramuscular injections of 250 mg (Cycle 1 Days 1 and 15, and Day 1 of each subsequent 28-day cycle). Durvalumab will be started 4 weeks after the first dose of olaparib at 1500 mg intravenous every 4 weeks.

Eligibility criteria include: ER+/HER2- metastatic or locally advanced BC with documented germline alteration in BRCA1 or BRCA2 or deleterious germline or somatic alterations implicated in the HRR pathway (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, FAND2, FANCL, MRE11A, NBN, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L) or in MSI status or other actionable genes (AKT1, ESR1, FGFR1, FGFR2, FGFR3, and PIK3CA) all based on central tumor next generation DNA sequencing. Patients could have received 1 line of endocrine therapy and/or 1 line of chemotherapy in the metastatic setting.Specific aims: To evaluate the efficacy of the combination in terms of progression-free survival rate at 24 weeks using RECIST v1.1. Secondary endpoints include: safety (according to the NCI-CTCAE v5.0), overall survival, progression-free survival, objective response rate, duration of response in the overall study population and in the germline BRCA mutated population.

Statistical methods: Given the lack of safety data from this association, a safety run-in of 6 patients was planned. With an optimum two-stage Simon design,α = 2.5%, β = 5%, p0 (the probability of inefficiency maximum) = 50%, p1 (the probability of minimum efficiency) = 65%, it would be necessary to include 149 evaluable patients. The strategy could be considered sufficiently effective if there are at least 87 successes. According to the established design (including a rate of 5% of patients lost to follow-up or non-evaluable), it will be necessary to include 158 patients. We hypothesized that about 20% of screened patients will have a molecular alteration to allow enrollment. Thus, we need to screen 790 patients.

The study is recruiting. The safety run-in is over. By July 1, 2020, 62 patients have been screened and 8 have been treated (NCT04053322). Contact information: DOLAF@unicancer.fr

Citation Format: Severine Guiu, Judith Balmana, Lise Roca, Anthony Goncalves, Audrey Mailliez, Frederic Bigot, Thomas Bachelot, Florence Dalenc, Nadine Dohollou, Dominique Genet, Isabelle Desmoulins, Camille Chakiba, Suzette Delaloge, Geraldine Martineau, Veronique Haddad, Philippe Follana. Dolaf- an international multicenter phase 2 trial of durvalumab (medi4736) plus olaparib plus fulvestrant in metastatic or locally advanced er-positive, her2-negative breast cancer patients selected using criteria that predict sensitivity to olaparib (UCBG308) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-13-05.