• Preliminary safety data from stage 1 and 2 of the phase II/III PARTNER trial: Addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

      Alba, KP; McMurtry, E; Vallier, AL; Grybowicz, L; Copson, E; Armstrong, Anne C; Roylance, R; Qian, WD; Demiris, N; Thomas, S; et al. (2020)
      Background: Triple negative breast cancers (TNBCs) are an aggressive and diverse subgroup with no specific targeted therapies currently available. Basal TNBCs show some phenotypic and molecular similarities with germline BRCA mutated BC (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow PARP inhibitors (olaparib) to work more effectively. PARTNER was designed to establish if the addition of olaparib to neoadjuvant platinum-based chemotherapy for gBRCA and/or basal TNBC is safe and improves efficacy (pathological complete response (pCR)). This is the first time a clinical trial provides safety data of the combination of olaparib with platinum and taxane chemotherapy in an early breast cancer setting. Methods: PARTNER is a 3-stage open label randomised Phase II/III trial of neoadjuvant Carboplatin AUC5 with weekly Paclitaxel 80mg/m2 (CP) +/- olaparib (O) 150mgBD for 12 days x 4 cycles, followed by clinicians' choice of anthracycline regimen x 3 cycles. Basal-TNBC and/or gBRCA patients are eligible for inclusion. Primary endpoints are defined by stage: Stage 1 - Safety, Stage2 - Schedule selection, and Stage 3 - Efficacy (pCR rate). The trial is now powered for efficacy analysis in the BRCA and non-BRCA population independently. Stage 1 and 2 randomization was(1:1:1) to CP: CP + O from day (D) -2: or CP + O from D 3. G-CSF was mandatory during the first 4 cycles of treatment. We present a pooled-safety analysis from Stage 1 and 2 of the two research arms only. Recruitment continues into Stage 3. Results: Between June 2016 and April 2018, 159 patients were recruited among the three arms. Overall, median age was 48.2 [range 22.3- 70.9]; 12% had Tumours >5cm, 34% had Axillary involvement; 17% were gBRCA. Adverse events (AE) that were reported as common (in at least 10% of patients) were Anaemia 23%, Neutropenia 18% and Infection 10%. Fatigue and Diarrhoea were next most prevalent with 9% and 6% respectively. The most common AE Grade >=3 were haematological events. These include Neutropenia 19%, Anaemia 15%, and Thrombocytopenia 5%. Febrile Neutropenia and Haemorrhage were reported in only 2% and 1% of cases. Grade 3 Non- haematological events were Fatigue 7%, Hypertension 3%, Headache 3% and Diarrhoea 2%. Grade 3 Sensory neuropathy was present in 2% of patients. No grade 4 sensory or motor neuropathy events were described. Serious adverse reactions related to investigational regimen were reported in 17% of patients and include fever and infection with 8 and 4 events respectively. No toxicity related deaths were reported. As per July 8th 2019, 373 patients have been recruited from which 58 were gBRCA. Conclusions: Combinations of olaparib with neoadjuvant CP chemotherapy showed an acceptable and manageable toxicity profile. Although haematological events were the most common, they did not exceed historical frequencies reported for standard chemotherapy regimens. Final safety analysis will be performed once recruitment is complete and will include detailed long-term neuropathy data.