Cancer treatment has come a long way with the development of newer targeted therapies. One such class of targeted drugs that has shown promising results is PARP inhibitors. PARP inhibitors work by blocking an enzyme called poly ADP ribose polymerase or PARP that helps repair DNA damage in cancer cells.

How PARP Inhibitors Work

PARP is an important enzyme involved in the process of DNA repair. It helps cancer cells repair single-strand DNA breaks that commonly occur due to various causes like environmental exposure, smoking etc. PARP inhibitors prevent the action of this enzyme by binding to it and blocking its function. When DNA breaks are not repaired, they eventually lead to double-strand DNA breaks during cell division. Double strand breaks are much harder for cancer cells to repair. This results in cell death, especially in cancers that already have deficiencies in homologous recombination repair (HRR) pathways. Cancers like ovarian and breast cancers often have HRR gene mutations like BRCA1/2 which make them particularly sensitive to PARP inhibition.

Current FDA approved PARP inhibitors

Currently, three PARP Inhibitors have been approved by the US FDA for use in specific cancer settings:

– Olaparib (Lynparza): Approved for advanced ovarian cancer with BRCA mutations and HER2-negative metastatic breast cancer with BRCA mutations.

– Rucaparib (Rubraca): Approved for advanced ovarian cancer, including those with BRCA mutations who have been treated with two or more prior chemotherapy types.

– Niraparib (Zejula): Approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Effectiveness against breast and ovarian cancers

Given the rationale of targeting HRR deficient cancers, PARP inhibitors have shown greatest promise in breast and ovarian cancers:

– BRCA mutated ovarian cancer: Studies have shown olaparib and rucaparib increase progression-free survival by more than 10 months compared to placebo in patients with platinum sensitive recurrent ovarian cancer and BRCA mutations.

– BRCA mutated breast cancer: Olaparib has been approved based on the OlympiAD trial that reported a significant increase in progression-free survival versus standard therapy in HER2-negative breast cancer patients with germline BRCA mutations.

– Beyond BRCA mutations: Recent studies also suggest that some ovarian and breast cancers may have deficiencies in HRR even without BRCA mutations. PARP inhibitors could help these “BRCAness” phenotypes as well.

Expanding role in other cancers

Encouraged by success in breast and ovarian cancers, ongoing research is evaluating PARP inhibitors in other cancers too:

– Prostate cancer: Studies indicate 10-15% of prostate cancers have HRR defects making PARP inhibition an attractive option. Olaparib showed early promise for CRPC with BRCA1/2 mutations.

– Pancreatic cancer: Combining PARP inhibition with chemotherapy showed improved outcomes in pancreatic cancer patients with germline BRCA mutations in early studies.

– Myeloid malignancies: Targeting DNA damage response in leukemias and myelodysplastic syndromes is an area of interest. Early trials reported responses to PARP inhibitors alone or in combination.

– Other solid tumors: Evaluation of PARP inhibitors continues in lung, gastric and other cancers to determine predictive biomarkers of response beyond BRCA status.

Combination strategies and next generation PARP inhibitors

To improve responses, several combination strategies are being explored:

– PARP inhibitors with chemotherapy: Data suggests potential synergistic cytotoxic effects when combined with DNA damaging drugs.

– PARP inhibitors with immunotherapy: Preclinical studies show PARP inhibition may enhance anti-tumor immune responses. Combination trials ongoing.

– PARP inhibitors with CDK4/6 inhibitors: May offer improved progression-free survival benefits compared to either agent alone in metastatic breast cancer.

Next generation PARP inhibitors under development aim to overcome resistance, improve pharmacokinetics and achieve greater PARP trapping for increased potency. Oral options like talazoparib and niraparib offer convenience.

PARP inhibition represents a major breakthrough in targeted cancer therapies. Robust evidence confirms their efficacy against BRCA deficient cancers. Ongoing research evaluates expanding applications across tumor types and translating molecularly driven approaches into systematic clinical benefit through rational combinations. PARP inhibitors are certainly poised to revolutionize cancer care.

*Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it