ESMO E-Learning: PARP Inhibitors in Management of Breast Cancers in Patients with Pathogenic Variants in BRCA1/2

In this E-Learning module, the author profounds on PARP inhibition as an effective therapeutic target for breast cancer in patients with pathogenic variants in germline BRCA1/2 through process of synthetic lethality, PARP trapping as the primary mechanism of action for the benefit as well as for the toxicity of PARP inhibitors, and clinical benefit demonstrated in the trials.

In the first part of the E-Learning module, the author elaborates on the basics in double- and single-strand break repair, the function of PARP inhibitors and mechanism of action of PARP inhibition, relative PARP trapping potency of PARP inhibitors, mechanisms of action of PARP inhibition in homologous recombination repair deficient cells and principles of synthetic lethality.

This is followed by a clinical part elaborating olaparib in patients with metastatic breast cancer and germline BRCA1/2 pathogenic variants, olaparib in metastatic breast and ovarian cancers with or without germline BRCA1/2 mutations, detailed results from the OlympiAD study and subsequent evolution of PARP inhibitors in breast cancer, including the results from the EMBRACA, TBCRC 048 studies and featuring the recommendations from the clinical practice guidelines regarding the use of PARP inhibitors.

In the following section, the author provides an overview of the results from the (neo)adjuvant studies with PARP inhibitors in early breast cancer, including NEOTALA, BRIGHTNESS, GeparOLA, OlympiA. Besides the efficacy, the author analyses in depth also the adverse events of special interest, as well as reporting on-study pregnancies and outcomes.

The author also elaborates on the eligibility criteria in terms of adjuvant therapy alternatives in patients with germline BRCA1/2 pathogenic variants, particularly for triple-negative breast cancer with non-pathological complete response and for patients with ER-positive, HER2-negative disease with CPS+EG score more than 3 following neoadjuvant chemotherapy or at least 4 positive axillary lymph nodes at initial surgery.

The author is also questioning about potential candidates for PARP inhibitors among patients with germline BRCA pathogenic variants with moderate risk ER-positive early breast cancer, as well as among patients with germline BRCA pathogenic variants with borderline ER-positive early breast cancer.  At the end of the module, the author provides an overview of ongoing clinical trials of PARP inhibitors for patients with germline BRCA pathogenic variants.