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Update on PARP Inhibitors in Breast Cancer
Alexandra S Zimmer1, Mitchell Gillard2, Stanley Lipkowitz3
1Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, 10 Center Dr. MSC1906 Building 10, Room 4B54, Bethesda, MD, 20892-1906, USA. alexandra.zimmer@nih.gov.
Opinion Statement:
The single agent activity of PARP inhibitors (PARPi) in germline BRCA mutated (gBRCAm) breast and ovarian cancer suggests untapped potential for this new class of drug in breast cancer. The US Food and Drug Administration has approved three PARPi (olaparib, rucaparib, and niraparib) so far to treat certain ovarian cancers, including those with gBRCAm and olaparib for treatment of gBRCAm breast cancers. Several PARPi are now under clinical development for breast cancer in the various treatment settings. Recently, two phase III trials of olaparib (OlympiaD) and talazoparib (EMBRACA) demonstrated 3-month progression-free survival improvement with PARPi compared to physician's choice single agent chemotherapy in metastatic gBRCAm breast cancer. To date, PARPi seems less efficacious in metastatic breast cancer patients than those with BRCA mutated platinum-sensitive recurrent ovarian cancer, perhaps reflecting the biologic heterogeneity and low somatic BRCA mutation rate in breast cancer. The use of PARPi is gradually evolving, including combination strategies with chemotherapy, targeted agents, radiotherapy, or immunotherapy in women with and without gBRCAm. The role of predictive biomarkers, including molecular signatures and homologous recombination repair deficiency scores based on loss of heterozygosity and other structural genomic aberrations, will be crucial to identify a subgroup of patients who may have benefit from PARPi. An improved understanding of the mechanisms underlying PARPi clinical resistance will also be important to enable the development of new approaches to increase efficacy. This is a field rich in opportunity, and the coming years should see a better understanding of which breast cancer patients we should treat with PARPi and where these agents should come in over the course of treatment.
Insights
Poly (ADP-ribose) polymerase inhibitors (PARPi) show promise for breast cancer, particularly in patients with germline BRCA mutations (gBRCAm). Further research is needed to optimize their use and identify responsive patient subgroups.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- PARP inhibitors (PARPi) demonstrate single-agent activity in germline BRCA-mutated (gBRCAm) breast and ovarian cancers.
- FDA-approved PARPi include olaparib, rucaparib, and niraparib for ovarian cancers, with olaparib also approved for gBRCAm breast cancer.
- Multiple PARPi are in clinical development for various breast cancer treatment settings.
Purpose of the Study:
- To review the current status and future potential of PARPi in breast cancer treatment.
- To discuss the efficacy of PARPi in metastatic gBRCAm breast cancer compared to ovarian cancer.
- To explore evolving combination strategies and the role of predictive biomarkers for PARPi therapy.
Main Methods:
- Review of recent phase III clinical trials (OlympiAD and EMBRACA) evaluating PARPi in metastatic gBRCAm breast cancer.
- Analysis of comparative efficacy between PARPi in breast and ovarian cancers.
- Discussion of emerging combination therapies and biomarker strategies.
Main Results:
- Phase III trials showed a 3-month progression-free survival benefit with PARPi (olaparib, talazoparib) versus chemotherapy in metastatic gBRCAm breast cancer.
- PARPi appear less efficacious in metastatic breast cancer than in BRCA-mutated ovarian cancer, potentially due to biologic heterogeneity and lower somatic BRCA mutation rates.
- PARPi use is expanding to include combination strategies with chemotherapy, targeted agents, radiotherapy, or immunotherapy.
Conclusions:
- PARPi represent a significant advancement in treating gBRCAm breast cancer, with ongoing research exploring broader applications.
- Predictive biomarkers, such as molecular signatures and homologous recombination deficiency scores, are crucial for identifying patients who will benefit from PARPi.
- Understanding PARPi resistance mechanisms is essential for developing novel therapeutic approaches to enhance efficacy in breast cancer.
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