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    Transcript Related Guidelines

    The Role of PARP Inhibitors in Non-BRCA Mutated Breast Cancer

    Tarah J. Ballinger, MD · Indiana University School of Medicine

    Disclosures

    January 13, 2023

    Key Takeaways:

    • Progression-free and disease-free survival benefit was demonstrated in the OlympiA and OlympiAD trials for patients with germline BRCA mutations who were treated with PARP inhibitor monotherapy in both the metastatic and curative settings.

    • Results of the phase 2 TBCRC 048 trial showed PARP inhibitor response in patients with germline PALB2 mutations.

    • Further research is needed to determine optimal use of PARP inhibitor therapy in patients with and without germline BRCA mutations.

    This transcript has been edited for clarity.

    The OlympiA and BRCA and OlympiAD trials have established survival benefits for the use of single-agent PARP inhibitor therapy for patients who have germline BRCA mutations in both the metastatic and curative settings.[1,2] These medications take advantage of defective homologous recombination pathways in the BRCA-deficient tumors, so it makes sense to hypothesize that these medications may also work well in patients who have mutations in other genes within the homologous recombination pathway other than BRCA. 

    The best data that we have so far that investigates this question is the prospective phase 2 TBCRC 048 trial.[3] This trial enrolled patients with metastatic breast cancer who had either somatic BRCA mutations or had germline mutations in other genes in the HRD (homologous recombination deficiency) pathway besides BRCA. Most of the patients in that trial had PALB2, CHEK2, or ATM mutations. What we saw in that trial was an impressive 82% response rate and 100% clinical benefit rate for the use of olaparib in patients who had germline PALB2 mutations, but we did not see responses in patients who had CHEK2 or ATM mutations. This suggests that not all of these mutations are created equal in terms of PARP inhibitor response and that does make sense when you look at the role that each of those proteins play in the homologous recombination pathway.[4,5] Although it's not currently standard of care, I do think it's reasonable to consider off-label PARP inhibitor use for patients with metastatic disease who have germline PALB2 mutations. However, I think the priority is to get these patients to clinical trials that test combinations of PARP inhibitors with other targeted therapies.[4] 

    Ultimately, less than 5% of patients with breast cancer have germline BRCA mutations,[6] and even within those patients, these medicines don't work all the time. So, we really do have a lot of work to do to optimize use of these medicines and the number of patients that can benefit from them.

    National Comprehensive Cancer Network

    • Assess for germline BRCA1/2 mutations in all patients with recurrent or metastatic breast cancer to identify candidates for PARP inhibitor therapy. While olaparib and talazoparib are FDA indicated in HER2-negative disease, the panel supports use in any breast cancer subtype associated with a germline BRCA1 or BRCA2 mutation

    • The addition of 1 year of adjuvant olaparib is an option for select patients with germline BRCA1/2 mutation after completion of adjuvant chemotherapy

    • If cancer is hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative or HR-negative/HER2-negative, adjuvant endocrine therapy + adjuvant olaparib is recommended if germline BRCA1/2 mutation is present and combined positive score + estrogen-receptor status and grade (CPS+EG) score ≥3, and residual disease

    • When adjuvant olaparib is used, olaparib should be given after completion of radiotherapy

    • For patients with triple-negative recurrent/stage IV breast cancer and germline BRCA1/2 mutations, platinum agents (cisplatin and carboplatin) are preferred treatment options. It is unknown how PARP inhibitors compare with platinum agents in this setting

    Reviewed by Tarah J. Ballinger, MD

    View Full Guidelines

    American Society of Clinical Oncology

    Adjuvant PARP Inhibitors in Patients With High-Risk Early-Stage HER2-Negative Breast Cancer and Germline BRCA Mutations:

    • For patients with early-stage, HER2-negative breast cancer with high risk of recurrence and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, 1 year of adjuvant olaparib should be offered after completion of (neo)adjuvant chemotherapy and local treatment, including radiation

    • For those who had surgery first, 1 year of adjuvant olaparib should be offered for patients with triple-negative breast cancer and tumor size >2 cm or any involved axillary nodes

    • For those with hormone receptor–positive disease, 1 year of adjuvant olaparib should be offered to those with at least four involved axillary lymph nodes

    • For patients who had neoadjuvant chemotherapy, 1 year of adjuvant olaparib should be offered to patients with triple-negative breast cancer and any residual cancer; for patients with hormone receptor–positive disease, 1 year of adjuvant olaparib should be offered to patients with residual disease and a clinical stage, pathologic stage, estrogen receptor, and tumor grade score ≥3

    Reviewed by Tarah J. Ballinger, MD

    View Full Guidelines

    American Society of Clinical Oncology

    Management of Hereditary Breast Cancer:

    • For BRCA1/2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered as an alternative to chemotherapy in the first- to third-line settings. For BRCA1/2 mutation carriers with metastatic HER2-negative breast cancer, there are no data directly comparing the efficacy of PARP inhibitors with platinum chemotherapy

    • The addition of veliparib to platinum-based chemotherapy in early-stage breast cancer does not improve pathologic complete response rates among BRCA carriers

    • There are no data addressing the efficacy of PARP inhibitors in patients with breast cancer with a tumor-identified (ie, somatic) BRCA mutation in the absence of a germline mutation

    Reviewed by Tarah J. Ballinger, MD

    View Full Guidelines

    European Society for Medical Oncology

    • Germline BRCA1/2 mutation (gBRCAm) status should be assessed in HER2-negative metastatic breast cancer as part of routine clinical practice 

    • Patients with ER-positive, HER2-negative metastatic breast cancer: PARP inhibitor monotherapy (olaparib or talazoparib) should be considered in second-line treatment for patients with germline pathogenic BRCA1/2 mutations and as an option for those with somatic pathogenic or likely pathogenic BRCA1/2 or germline PALB2 mutations

    • Patients with metastatic triple-negative breast cancer: If gBRCAm and PD-L1 negative, the preferred options in first-line treatment are olaparib or talazoparib or chemotherapy with carboplatin

    • No robust, prospective randomized data exist on the use of platinum compounds in the adjuvant setting, either in unselected triple-negative tumors or in BRCA1/2 mutation carriers and they cannot therefore be recommended 

    • The addition of a platinum compound may be considered in triple-negative tumors and/or in patients with deleterious BRCA1/2 mutations

    • Patients with HER2-negative metastatic breast cancer and germline pathogenic or likely pathogenic variants in BRCA1 or BRCA2 should be offered treatment with a PARP inhibitor (olaparib or talazoparib), independent of HR status, as an alternative to chemotherapy

    • Prior treatment with anthracyclines-taxanes should not be required before offering patients with metastatic breast cancer and gBRCAm treatment with a PARP inhibitor; nor should HR-positive patients be required to demonstrate complete endocrine resistance

    • There is insufficient evidence to determine the optimal sequencing of PARP inhibitors with other active treatments such as chemotherapy-immune checkpoint inhibitor combinations in metastatic triple-negative breast cancer or endocrine therapy and targeted therapy combinations in HR-positive disease

    • Patients who may be considered for treatment with a PARP inhibitor should be offered genetic testing for pathogenic variants in BRCA1 and BRCA2 regardless of age, family history or breast cancer subtype

    Reviewed by Tarah J. Ballinger, MD

    View Full Guidelines

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