Transcript Related Guidelines

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

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


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.


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