Editor's Note: In recent years, PARP inhibitors like Olaparib have been continually exploring the optimal treatment timing and modalities for breast cancer patients carrying HRR mutations. DOLAF is an international phase II study aimed at evaluating the efficacy of a triple therapy combination of Olaparib, Durvalumab, and Fulvestrant in ER+/HER2- mBC patients. At the 2024 ESMO BC conference, the results of this study were presented. Oncology Outlook invited Professor Man Li from The Second Affiliated Hospital of Dalian Medical University to introduce and comment on this study.

Study Overview

179O – International Phase II DOLAF Trial: Triple Therapy with Olaparib, Durvalumab, and Fulvestrant in ER+/HER2- mBC

Study Background:

The DOLAF study aims to evaluate the efficacy and safety of Olaparib (a PARP inhibitor), Durvalumab (an immune checkpoint inhibitor), and Fulvestrant (a selective estrogen receptor degrader) in ER+/HER2- metastatic breast cancer (mBC) patients.

Study Methods:

Enrollment Criteria: Patients must have received at least one line of endocrine therapy (including CDK4/6 inhibitors) and no more than one line of chemotherapy for ER+/HER2- mBC. They must also carry pathogenic variants (PV) in homologous recombination repair (HRR) genes or be in a microsatellite instability (MSI) state.

The study employed a Simon two-stage design to determine if the 24-week progression-free survival rate (24w PFSR) exceeds 50%. The primary endpoint was 24w PFSR, with secondary endpoints including safety, progression-free survival (PFS), overall survival (OS), and objective response rate (ORR).

Study Results:

The study included 172 breast cancer patients, with gBRCA1/2 mutations being the most common HRR gene variant (39%), followed by ATM/ATR (16%), FANCA (12%), PALB2 (9%), and CHEK2 (6%).

With a median overall follow-up of 24.6 months (95% CI, 19.3-28), the 24w PFSR was 66%, the median PFS was 9.3 months (95% CI: 7.5-12.7 months), the median OS was 30 months (95% CI: 26.6-NR), and the ORR was 41% (95% CI: 33.5%-49.3%).

Subgroup Analysis:

• Patients with Germline gBRCA Mutations: 24w PFSR: 76.3% (95% CI: 63.4%-86.4%) Median PFS: 12.6 months (95% CI: 8.2-16.7) Median OS: 29.3 months (95% CI: 22.2-NR) ORR: 57.1% (95% CI: 44%-69.5%)
• Patients with Other HRR Mutations or MSI-H: 24w PFSR: 67.3% (95% CI: 52.9%-79.7%) Median PFS: 9.2 months (95% CI: 7.2-16.4) Median OS: 29.5 months (95% CI: 26.6-NR) ORR: 37.7% (95% CI: 24.8%-52.1%)
• Patients with Non-HRR and Non-MSI Mutations: 24w PFSR: 51.2% (95% CI: 35.1%-67.1%) Median PFS: 7.3 months (95% CI: 5.3-10.8) Median OS: 30.0 months (95% CI: 18.7-NR) ORR: 23.3% (95% CI: 11.8%-38.6%)

Safety: The most common treatment-related adverse events (TRAEs) were nausea (64%) and fatigue (53%). No toxicity warnings were observed during the study.

Conclusions:

For endocrine-resistant ER+/HER2- mBC patients with molecular phenotypes sensitive to PARP inhibitors, the combination of Durvalumab, Olaparib, and Fulvestrant demonstrated favorable clinical outcomes with acceptable toxicity profiles.

Expert Commentary

Hormone receptor-positive (HR) breast cancer accounts for approximately 65%-70% of advanced breast cancer cases. While most patients benefit from endocrine therapy, nearly all HR+ breast cancer patients eventually experience disease progression. About 12% of metastatic breast cancer patients have homologous recombination repair deficiency (HRD), mainly due to germline mutations in HRR-related genes, which are crucial for repairing DNA double-strand breaks.

HRR-related genes include BRCA1/2, PALB2, CHEK2, ATM, and FANCA. The 2021 consensus on the clinical detection and application of homologous recombination repair deficiency states that the mutation frequency of HRR-related genes in breast cancer patients ranges from 12%-24%. Studies have found that 5%-10% of breast cancer patients carry BRCA1/2 mutations, with a high frequency of PALB2 mutations in women aged ≤30 years (1.85%, P<0.0001).

Olaparib, the world’s first approved PARP inhibitor, blocks the DNA damage repair pathway in HRR-deficient cells/tumors through the “synthetic lethality” mechanism, inhibiting tumor cell growth. The NCCN guidelines recommend Olaparib and Talazoparib as first-line treatments for recurrent, unresectable, or stage IV HR+/HER2- breast cancer patients with BRCA1/2 germline mutations. The TBCRC 048 study found that Olaparib achieved an ORR of 82% in metastatic breast cancer patients with PALB2 germline mutations.

However, not all tumors with homologous recombination deficiency respond to PARP inhibitors. The benefit of PARP inhibitors for other HRR gene mutations remains unclear, and effective treatment strategies for these patients are still being explored. In recent years, PARP inhibitors like Olaparib have been used to explore the best treatment timing and modalities for breast cancer patients with HRR mutations, including combination therapies with immunotherapy and anti-angiogenic inhibitors.

Patients with HER2-negative and/or HRD tumors often have high microsatellite instability (MSI-H). Studies show that metastatic breast cancer patients are more likely to have MSI-H (1.9% vs. 0.4%) and high tumor mutational burden (TMB-H) (16.2% vs. 5.4%) compared to non-metastatic primary patients, indicating the potential benefit of immunotherapy.

Small-sample clinical trials have explored the efficacy of PARP inhibitors combined with immunotherapy in triple-negative breast cancer. The I-SPY2 study showed that a neoadjuvant regimen of Olaparib combined with Durvalumab and chemotherapy significantly improved the pathological complete response (pCR) rate in HER2-negative patients (37% vs. 20%). The MEDIOLA study included 34 patients with BRCA1/2-mutated HER2-negative metastatic breast cancer, showing a 12-week disease control rate of 80% for the combination of Olaparib and Durvalumab. These studies suggest potential clinical benefits of combining PARP inhibitors with immunotherapy in triple-negative breast cancer.

The DOLAF study brings a new perspective and hope for selecting patients who may benefit from PARP inhibitor combined with immunotherapy, particularly in HR-positive advanced breast cancer patients with HRD and/or MSI-H. With more evidence, triple therapy combining PARP inhibitors, immunotherapy, and endocrine therapy may effectively identify and benefit these patients. The DOLAF study results give us confidence and highlight the need for further exploration in precision treatment to benefit breast cancer patients.

In terms of safety, the most common AEs were nausea and fatigue, which were manageable. However, identifying which breast cancer patient subgroups benefit the most remains an area for further research, with the DOLAF study and future studies providing more evidence to guide clinical treatment.