The mechanism and efficacy of PARP inhibitors have been well studied in some cancers, especially homologous recombination (HR)-deficient ovarian cancer and breast cancer, yet such studies are still relatively fewer in lung cancer.
The use of PARP inhibitors in other cancers with homologous recombination repair deficiencies, such as breast cancer and prostate cancer, is gradually evolving as well, including their use in the neoadjuvant and adjuvant settings.
The data provide insight into the mechanism of action of PARP inhibitors in <i>BRCA</i>-associated breast cancer.<i>This article is highlighted in the In This Issue feature, p. 681</i>.
The exposure of breast cancer cells to the lactone was associated with a depolarization in mitochondrial membrane potential, and cleavage of caspase and PARP.
PARP inhibitors have recently been approved as monotherapies for the treatment of recurrent ovarian cancer and metastatic <i>BRCA</i>-associated breast cancer, and ongoing studies are exploring additional indications and combinations with other agents.
PARP inhibitors have been proven clinically efficacious in platinum-responsive ovarian cancer regardless of BRCA1/2 status and in breast cancers with germline BRCA1/2 mutation.
Overall, biological rationale, preclinical, and clinical data support the prominent role of CDK 4/6 inhibitors plus endocrine therapy, even in combination with PARP inhibitors, in the treatment of BRCA-mutated, ER-positive breast cancers.
PARP inhibitors represent one of the successful models of translational research in this area and clinical data showed high efficacy and reasonable toxicity with these agents in patients with breast cancer and BRCA mutation.
In the following paragraphs, we will set out the major targeted drug that have received indications in breast cancer, both in the localized and in advanced disease, referring to the specific target (hormonal receptors, HER2, VEGF, m-TOR, PARP etc ...).
For example, the FDA-approved use of the PARP inhibitor olaparib is for ovarian or breast cancers in patients harboring a <i>BRCA</i> germline mutation [N Engl J Med 2012;366:1382-1392, N Eng J Med 2017;377:523-533].
PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful.
Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit - for example, the PARP inhibitor olaparib has shown benefit in <i>BRCA</i>-mutant ovarian and breast cancer.
Inhibition of mTOR downregulates expression of DNA repair proteins and is highly efficient against BRCA2-mutated breast cancer in combination to PARP inhibition.
The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer.
The consistent observation that brain metastases of breast cancer tend to have higher HRD measures may raise the possibility that brain metastases may be more sensitive to PARP inhibitor treatment.