LBA14 - Intensified alkylating chemotherapy with autologous stem cell rescue (IACT) or conventional chemotherapy followed by olaparib (CCT-O) in stage III, HER2-negative, homologous recombination deficient (HRD) breast cancer (BC): Survival results of the randomized-controlled SUBITO trial

Background

HRD is an adverse prognostic feature of BC. HRD BCs are particularly sensitive to DNA double strand break-inducing regimens, such as (intensified) alkylating agents, platinum agents, or PARP inhibitors. Our ‘BRCA1-like’ HRD test identified patients (pts) with stage III BC who derived substantial benefit from IACT when compared to 2^nd generation chemotherapy (4-year overall survival (OS) 78% vs 35%; Vollebergh et al., 2011). It is unknown whether adding olaparib to 3^rd generation chemotherapy (long lasting regimen) can achieve similar OS as IACT (fast & forceful regimen) in pts with high-risk HRD BCs.

Methods

In this multicenter, open-label phase III trial pts with stage III, HER2-negative, BRCA1-like or germline BRCA1/2 mutated (gBRCAm) BC were randomized 1:1 to IACT (4x dose-dense doxorubicin-cyclophosphamide (ddAC), followed by 2 cycles of carboplatin 800 mg/m2, thiotepa 250 mg/m2, and cyclophosphamide 3,000 mg/m2 with autologous stem cell rescue), or CCT-O (4xddAC-4x carboplatin-paclitaxel, and 1 year of olaparib). Adjuvant capecitabine was offered to pts without a pathological complete response (pCR) in both arms after an amendment in 2019. Primary endpoint was OS. Secondary endpoints included safety and quality of life (QoL), and OS in pts with BRCA1-like BC without gBRCAm.

Results

Pts (n=174) were randomized to IACT (n=87) or CCT-O (n=87). Pts (median age 42 years) were characterized by 90% triple-negative BC, 49% clinical stage IIIc, and 27% gBRCAm. With a median follow-up of 41.0 months, 4-year OS rates for IACT vs CCT-O were 77% vs 76% (hazard ratio (HR): 1.11; p=NS), and 75% vs 72% in BRCA1-like BC (HR: 0.93; p=NS). 4-year recurrence-free survival rates for IACT vs CCT-O were 75 vs 74%. pCR rates were 40% (IACT) and 43% (CCT-O), with a 4-year OS rate of 97% in both pCR groups. No treatment-related deaths occurred. Overall, QoL was comparable between arms.

Conclusions

Both DNA double strand break-inducing regimens yield promising 4-year OS rates in pts with high-risk stage III, HER2-negative, HRD breast cancer, especially when reaching a pCR.

Clinical trial identification

NCT02810743.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

The Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, A Sister’s Hope, AstraZeneca (drug and institutional research grant), Eurocept Pharmaceuticals (institutional research grant).

Disclosure

S. Linn: Financial Interests, Institutional, Research Funding, Institutional research funding and study drug supply: AstraZeneca; Financial Interests, Institutional, Research Funding: Eurocept Pharmaceuticals, Genentech/Roche, Tesaro (now GSK), Merck, Immunomedics (now Gilead), Agendia, Novartis; Financial Interests, Institutional, Advisory Role: Daiichi Sankyo, AstraZeneca, IBM; Non-Financial Interests, Institutional, Advisory Role: Cergentis; Financial Interests, Institutional, Other, Travel, Accommodations, Expenses: Daiichi Sankyo Europe GmbH. A. Gonçalves: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, MSD, Innate Pharma, Parexel, Gilead; Financial Interests, Institutional, Local PI: Novartis, AstraZeneca, Daiichi Sanko; Financial Interests, Institutional, Coordinating PI: Roche, MSD; Other, Travel Accomadation Meeting Regsitration: Mylan; Other, Travel Accomodation Meeting Registration: Novartis; Other, Travel, Accomodation, Meeting Registration: Roche, Menarini. I.R. Konings: Financial Interests, Research Grant: Novartis, Gilead; Financial Interests, Other, Travel grant: Daiichi Sankyo, AstraZeneca. V. Tjan-Heijnen: Financial Interests, Personal, Advisory Board: E Lilly, AstraZeneca, Novartis; Financial Interests, Institutional, Research Grant: E Lilly, Novartis, Pfizer, AstraZeneca, Roche, Gilead. A. Jager: Financial Interests, Institutional, Research Funding, Institutional research funding and study drug supply: AstraZeneca; Financial Interests, Institutional, Research Funding: Eurocept Pharmaceuticals, Daiichi Sankyo, Pfizer, Immunomedics (now Gilead), AstraZeneca, Agendia, Genentech/Roche; Financial Interests, Institutional, Advisory Role: AstraZeneca. All other authors have declared no conflicts of interest.