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Gap-Scheduled Olaparib Plus Neoadjuvant Chemotherapy Improved Survival in Patients With gBRCAm TBNC
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Key Takeaways
- Combining olaparib with chemotherapy improved event-free, overall, and breast cancer-specific survival in early-stage gBRCAm TNBC patients.
- The combination regimen was safe and tolerable, despite higher grade 3 adverse events like thrombocytopenia and non-febrile neutropenia.
Combining olaparib with neoadjuvant chemotherapy enhances survival rates for early-stage gBRCAm triple-negative breast cancer, offering new hope for patients.
Combining neoadjuvant chemotherapy with olaparib (Lynparza; AstraZeneca, Merck) improved overall survival benefit for patients with early-stage germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) triple-negative breast cancer (TNBC) in the phase 2/3 PARTNER trial (NCT03150576). The study data were published in Nature Communications.1,2
Olaparib box | Image Credit: © luchschenF - stock.adobe.com
BC is the most common cancer in women in the United States, accounting for 30% of all new female cancer diagnoses, according to the American Cancer Society. Women with germline BRCA1 or BRCA2 mutations have a 70% higher lifetime risk of developing BC, as well as other cancers, of which most occur before 50 years of age. Mutations in these genes not only lead to increased chances of developing BC but also more aggressive disease.3,4
The development of poly(ADP-ribose) polymerase inhibitors has greatly improved outcomes for patients with BC with BCRA1 and BCRA2 mutations. These agents have demonstrated meaningful capabilities in selectively killing BRCA1- and BRCA2-deficient cancer cells, leading to their approval for treatment of gBRCAm-related cancers such as breast, ovary, pancreas, and prostate.2
Although PARP inhibitors show promise as monotherapy in gBRCAm TNBC, their pathological complete response (pCR) rates remain lower than standard combination chemotherapy. Additionally, combining PARP inhibitors with platinum agents such as carboplatin (Paraplatin; Bristol-Myers Squibb) could enhance efficacy due to increased DNA damage. However, this strategy is limited by overlapping bone marrow toxicity. The trial investigators aimed to identify a feasible and effective way to combine these agents in the neoadjuvant setting to improve patient outcomes without excessive toxicity.2
In the open-label, randomized, 3-stage phase 2/3 trial, they found that combining olaparib and carboplatin avoids enhanced toxicity but maintains anti-tumor activity. Patients with early-stage gBRCAm TNBC were assigned to 2 separate arms. The research arm 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 arm was treated with standard chemotherapy (carboplatin plus paclitaxel followed by anthracyclines) without olaparib. The primary end point of the study was pCR, with additional end points of event-free survival (EFS), OS, BC-specific survival (BCSS), relapse-free survival (RFS), distant disease-free survival (DFS), and time to second cancer.2
The trial results demonstrated that a gap-scheduled combination of olaparib with chemotherapy was safe and tolerable, despite minimal improvement in pCR rates. Patients in the research arm achieved a pCR of 64% compared with 69.8% of patients in the control arm. However, the benefits of this regimen were primarily seen in the other survival outcomes measured.2
At 36 months, the research arm demonstrated significantly improved EFS (96.4% vs 80.1%; P = .04), OS (100% vs 88.2%; P= .04), and BCSS (100% vs 88.2%; P = .04) compared with the control arm. However, there were no statistically significant differences in RFS (96.4% vs 87.9%; P = .20), distant DFS (identical to RFS), or local recurrence-free survival and time to second cancer (96.4% vs 87.8%; P = .20).2
The research arm experienced a higher frequency of greater than or equal to grade 3 adverse events (AEs), such as thrombocytopenia and non-febrile neutropenia (76.9% vs 60%). The control group experienced more severe AEs associated with paclitaxel and carboplatin. A comparable percentage of the research (7.7%) and control arms (8.9%) had treatment discontinuation due to AEs.2
The PARTNER trial highlights a promising strategy for improving survival outcomes in patients with early-stage gBRCAm TNBC by integrating olaparib into neoadjuvant chemotherapy. These findings support further investigation of schedule-optimized PARP inhibitor–based regimens in this high-risk population and may help refine personalized treatment approaches.
