Lynparza combined with neoadjuvant chemotherapy can improve survival rate of patients with gBRCAm triple-negative breast cancer

Combining neoadjuvant chemotherapy with olaparib improved overall survival in patients with early-stage germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) triple-negative breast cancer (TNBC) in the Phase 2/3 PARTNER trial (NCT03150576).

According to the American Cancer Society, BC is the most common cancer among women in the United States, accounting for 30% of all new cancer diagnoses in women. Women who carry germline BRCA1 or BRCA2 mutations have a 70% higher lifetime risk of BC and other cancers, most of which occur before the age of 50. Mutations in these genes not only increase the chance of developing BC, but can also lead to a more aggressive form of the disease.

PolyThe development of inhibitors of ADP-ribose polymerase has greatly improved the prognosis of BC patients with BCRA1 and BCRA2 mutations. These drugs have demonstrated meaningful ability to selectively kill BRCA1- and BRCA2-deficient cancer cells and are therefore approved for the treatment of gBRCAm-associated cancers such as breast, ovarian, pancreatic, and prostate cancers.

Although PARP inhibitors show promise as monotherapy in gBRCAm TNBC, their pathological complete response (pCR) rates remain lower than standard combination chemotherapy. In addition, combining PARP inhibitors with platinum drugs such as carboplatin (Paraplatin; Bristol-Myers Squibb) can improve efficacy due to increased DNA damage. However, this strategy is limited by overlapping bone marrow toxicities. Trial investigators aimed to identify a feasible and effective way to combine these drugs in a novel adjuvant setting to improve patient outcomes without undue toxicity.

In an open-label, randomized, 3 phase 2/3 trial, they found that combining olaparibwith carboplatin avoided enhanced toxicity but maintained antitumor activity. EarlygBRCAm TNBC patients were divided into two groups. The study group received 4 cycles of carboplatin (AUC 5, every 3 weeks), paclitaxel (80 mg/m² weekly, day 1), and olaparib (150 mg twice daily, days 3 to 14), and the control group received standard chemotherapy (carboplatin plus paclitaxel, then an anthracycline) but without olaparib. The primary endpoint of the study was pCR, along with event-free survival (EFS), OS, BC-specific survival (BCSS), recurrence-free survival (RFS), distant disease-free survival (DFS) and time to second cancer.

The test results show that althoughThe pCR rate improved slightly, but the interstitial combination of olaparib and chemotherapy was safe and tolerable. The pCR of patients in the study group was 64%, while that of patients in the control group was 69.8%. However, the benefit of this regimen was mainly seen in other survival outcomes measured.

At36 months, compared with the control group, the study group had significantly improved EFS (96.4% vs. 80.1%; P=0.04), OS (100% vs. 88.2%; P=0.04), and BCSS (100% vs. 89.2%; P=0.04]). However, there were no statistically significant differences in RFS (96.4% vs. 87.9%; P = .20), distant DFS (same as RFS), or local recurrence-free survival and time to second cancer (96.4% vs. 87.8%; P = .202).

Grade ≥3 adverse events (AEs) occurred more frequently in the study group, such as thrombocytopenia and nonfebrile neutropenia (76.9% vs. 60%). More serious adverse events related to paclitaxel and carboplatin occurred in the control group. Discontinuation of treatment due to adverse events was similar in the study group (7.7%) and the control group (8.9%).

The PARTNER trial highlights a promising strategy to improve survival outcomes in patients with early-stage BRCAm TNBC by incorporating olaparib into neoadjuvant chemotherapy. These findings support further investigation of PARP inhibitor-based schedule optimization regimens in this high-risk population and may help refine personalized treatment approaches.

References:https://www.pharmacytimes.com/view/gap-scheduled-olaparib-plus-neoadjuvant-chemotherapy-improved-survival-in-patients-with-gbrcam-tbnc