Neoadjuvant olaparib extends survival in gBRCA-mutated breast cancer

The intermittent 48-h “gap” schedule of olaparib in combination with carboplatin/paclitaxel and anthracycline chemotherapy provides substantial survival benefits in patients with germline BRCA-mutated breast cancer (gBRCA) regardless of their pathological complete response (pCR) status, results of the PARTNER trial have shown.

Olaparib is a small-molecule inhibitor of Poly (ADP-ribose) polymerase (PARP) that can selectively destroy BRCA1/2-deficient cancer cells, according to the authors.

“The PARTNER trial tested olaparib in combination with neoadjuvant carboplatin and paclitaxel in patients with gBRCA in three stages: 1, safety; 2, schedule; and 3, efficacy,” said lead author Dr JE Abraham from the Department of Oncology, University of Cambridge, Cambridge, UK.

In stages 1 and 2, Abraham and colleagues recruited 108 patients between June 2016 and May 2023. Participants received either neoadjuvant carboplatin and paclitaxel then anthracycline or chemotherapy alone (control arm). Two research arms were formed to receive intermittent olaparib 150 mg with carboplatin and paclitaxel: R1 schedule (olaparib day 2 to 10) and R2 (olaparib day 3 to day 14).

The authors applied a “pick the winner design” using a prespecified criteria, which allowed a 1:1 randomization in stage 3 between the control arm and the “winner” of the two research arms. The primary endpoint was pCR, while event-free (EFS) and overall survival (OS) were secondary. Response was assessed based on a preplanned interim analysis at ~50-percent gBRCA recruitment.

Gap schedule

The intermittent, 48-h gap schedule R2 emerged as the “winner” between research arms. Of the patients, 86 were randomized to R2 (n=39) or control (n=47) at 23 UK centres. Data cutoff was 30 November 2023, with a median follow-up of 40.7 months. The two groups had similar patient and tumour characteristics. [AACR 2024, abstract CT011]

Majority (89.7 percent) of the patients in R2 received at least 80 percent of the planned olaparib dose. Likewise, most patients in R2 and the control arm received at least 80 percent of the planned carboplatin (R2: 97 percent; control: 91 percent) and paclitaxel dose (100 percent for both arms).

No safety concerns arose in any of the treatment groups. Moreover, 25 patients (64.1 percent) in R2 and 30 (69.8 percent) in the control arm met the primary endpoint, with a difference of ‒5.7 percent (95 percent confidence interval, ‒25.8 to 14.6; p=0.586).

Regardless of pCR status, patients in R2 showed significant improvements in all survival outcomes relative to those in the control arm. Only one event (ie, local and distant relapse) occurred in R2, whereas nine events occurred in controls (p=0.04). No deaths occurred in R2, whereas six patients in the control arm died (OS, 100 percent vs 82.8 percent; p=0.042).

In the dropped arm R1 (n=22), nine events including six deaths occurred. Compared with R2, R1 had significantly worse survival outcomes.

“The stark contrast in survival outcomes between the two research arms (R1 and R2) suggests a different mechanistic interplay between the PARPi and chemotherapy,” Abraham said. “In gBRCA, the PARTNER R2 arm is a potentially curative regimen requiring validation in a larger trial.”

Wild type

On the other hand, further analysis in the PARTNER trial revealed that neoadjuvant olaparib plus carboplatin/paclitaxel and anthracycline chemotherapy fell short of improving pCR rates, EFS, or OS in triple negative breast cancer patients with gBRCA wild type. [AACR 2024, abstract CT012]

“These results are in marked contrast to the significant benefit of olaparib in those with gBRCA mutations reported in parallel,” Abraham said.