Drug Pathways, Potential Mechanisms of Resistance in PARP Inhibition

One of the hallmarks of cancer is genomic instability, which is caused by defects in certain processes that control the way cells divide.¹ These defects include mutations in genes involved in the repair of damaged DNA or mistakes that are not corrected when DNA is copied in a cell.¹

PARP is a type of nuclear enzyme involved in many cellular functions, including facilitating the repair of DNA damage and participating in the regulation of cytokine expression that mediates inflammation.^2,3 When extensive DNA damage occurs, overactivation of PARP decreases cellular energy level and leads to cell death.³ Blocking PARP has been studied as a mechanism to manage cancer by preventing cancer cells from repairing their damaged DNA, forcing them to die.^2,4

Therapeutic Pathways and Potential Mechanisms of Resistance

PARP enzymes take part in various DNA damage response (DDR) pathways that detect and determine cellular fate following DNA damage, recruitment of cofactors, and regulation of biochemical activities.⁴ The most significant DDR pathways involving PARP include nucleotide excision repair, base excision repair, mismatch repair, homologous recombination (HR), and nonhomologous end joining recombination.⁴

One of the most dynamic developing targeted therapies is the use of PARP inhibitors (PARPi). PARPi are currently approved for the management of a range of tumor types and represent a class of cancer treatment that primarily inhibits the catalytic activity of specific enzymes called PARP1 and PARP2.^4-6 These are active in the DDR pathway through involvement in base excision repair of single-strand breaks (SSBs) in DNA.^4,6

PARP inhibition results in an accumulation of SSBs and entrapment of the PARP-DNA complex on SSBs, leading to double-strand breaks (DSBs).⁵ This PARP trapping is considered the major mechanism of antitumor activity.⁵

PARP inhibition is not effective in healthy cells because they can utilize the functional HR repair mechanism to repair DSBs, but it is very effective in cells that harbor HR deficiencies (HRDs), including the cells of specific types of breast and ovarian cancers with mutations in BRCA1 and BRCA2.^5,6 This concept, termed synthetic lethality, is the simultaneous loss of function of 2 ormore key molecules resulting in cell death; however, a deficiency in 1 key molecule is not lethal.^4-6 Recent clinical evidence has shown that PARPi can still be effective regardless of BRCA1/2, HRD status, or other DDR gene alterations, suggesting that a wider population of patients may benefit from PARPi therapy.^4,6

Although PARPi have been shown to improve progression-free survival (PFS), some cancers may inevitably develop resistance to them. Potential mechanisms of resistance to PARPi include restoration of HR capacity, stabilization of replication forks, diminished trapping of PARP1, P-glycoprotein–mediated drug efflux, alterations in cell cycle control, microRNA expression patterns, and other dysregulated signaling pathways.^5,6 Ongoing research is underway to improve understanding of how PARPi might help guide broader use, optimize efficacy, evaluate novel combinations with other types of targeted therapies, overcome resistance, and sensitize tumors.^5,6

Updates in Current Clinical Use and Future Perspectives

Since 2014, 4 PARPi have been approved by the FDA for clinical use: olaparib (Lynparza; AstraZeneca), rucaparib (Rubraca; Clovis Oncology), niraparib (Zejula; GSK), and talazoparib (Talzenna; Pfizer).^3,4,7 These 4 PARPi share similarities in their chemical structures and an aromatic system that mimics nicotinamide, part of nicotinamide adenine dinucleotide (NAD), allowing them to compete with NAD for PARP binding.⁵

Olaparib holds indications for select patients with advanced ovarian cancer, early or metastatic breast cancer, metastatic pancreatic cancer, and metastatic prostate cancer.⁸ Rucaparib is indicated for patients with BRCA-positive, metastatic castration-resistant prostate cancer and for the maintenance management of ovarian cancer, fallopian tube cancer, or primary peritoneal cancer in patients whose cancer has recurred and who achieve complete or partial response to a platinum-based chemotherapy.⁹

Niraparib is approved for use in the maintenance management of advanced ovarian cancer, fallopian tube cancer, or primary peritoneal cancer when the patient has achieved complete or partial response to treatment with platinum-based chemotherapy.¹⁰ Talazoparib manages germline BRCA-mutated, HER2-negative breast cancer that is locally advanced or metastatic.¹¹

However, as of October 2022, manufacturers of rucaparib, olaparib, and niraparib (the 3 PARPi approved by the FDA for third- and fourth-line management of ovarian cancer) had voluntarily withdrawn their approvals because of safety concerns.⁷ Finalized results of studies evaluating the use of PARPi have shown potential negative effects on overall survival (OS) for these indications, which were initially approved via the accelerated approval pathway based on objective response rate, PFS, and duration of response. The results from the most recent studies have shown that these outcomes ultimately did not correlate with OS.⁷

In November 2022, the FDA requested that indication for rucaparib be removed for use in patients with recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have achieved complete or partial response to platinumbased chemotherapy and be used only in the secondline maintenance setting for patients harboring BRCA mutations.⁷ In the same month, GSK restricted the use of niraparib following an FDA request that it be used only for patients with deleterious or suspected deleterious germline BRCA mutations.⁷

PARP enzymes play many roles at different cell cycle stages, so understanding the interaction network within the cell is important for investigators exploring new potential therapies. For example, current research shows PARPi might heighten sensitivity to immune checkpoint inhibitors (ICIs) because PARPi indirectly affect the tumor microenvironment by increasing genomic instability and immune pathway activation and inhibiting surface proteins including CTLA4, PD-1 expressed by activated T cells, and its ligand PD-L1.^4,6,7 The use of potential PARPi combinations with products interacting with PD1/PD-L1 pathways was based on research that DNA-damaging agents lead to the activation of interferon pathways due to DNA damage, that the level of interferon expression has an impact on levels of PD-L1, and that PARPi themselves cause upregulation of PD-L1.^4,6

Conclusion

PARPi monotherapy has been a milestone in the management of many BRCA1/2-mutated cancers, offering patients and prescribers the hope of effective therapy options. Alternate therapeutic pathways for PARPi and potential mechanisms of sensitivity and resistance remain major areas of current clinical research.^4,7 Numerous clinical trials are ongoing to develop nextgeneration PARPi and validate the use of combination therapies, particularly the potential synergistic effect of PARPi with ICIs.^5,7 Additional studies are necessary to investigate potential PARPi combinations in groups of patients who have clinically unmet anticancer needs, including patients who do not respond well to established PARPi/ICI monotherapies. Biomarkers are critical in identifying optimal patient populations, because although the effect is beneficial in tumors with BRCA1/2 mutations or HRD, HR-proficient markers have yet to be determined.⁴ Stakeholders including payers, prescribers, and specialty pharmacies will need to continue to track current market changes and update clinical criteria as necessary.

References

1. "Definition of genomic instability - NCI Dictionary of Cancer Terms." National Cancer Institute, The National Institutes of Health, www.cancer.gov/publications/dictionaries/cancer-terms/def/genomic-instability. Accessed 7 Dec. 2022.

2. "Definition of PARP inhibitor - NCI Dictionary of Cancer Terms." National Cancer Institute, The National Institutes of Health, www.cancer.gov/publications/dictionaries/cancer-terms/def/parp-inhibitor. Accessed 7 Dec. 2022.

3. "Target Report: Poly ADP-Ribose Polymerase (PARP)." Biomedtracker Pharma Intelligence, Pharma Intelligence UK Limited, Dec. 2022, www.biomedtracker.com/targetreport.cfm?targetid=665. Accessed 7 Dec. 2022.

4. Bruin, M.A.C., et al. "Pharmacokinetics and Pharmacodynamics of PARP Inhibitors in Oncology." Clinical Pharmacokinetics, 11 Oct. 2022, https://doi.org/10.1007/s40262-022-01167-6. Accessed 7 Dec. 2022.

5. Hunia, Jaromir, et al. "The potential of PARP inhibitors in targeted cancer therapy and immunotherapy." Front. Mol. Biosci., 01. Sec. Molecular Diagnostics and Therapeutics, Dec. 2022, https://doi.org/10.3389/fmolb.2022.1073797. Accessed 7 Dec. 2022.

6. Kim, Dae-Seok, et al. "Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance." Nature: Experimental & Molecular Medicine, vol. 53, no. 42-5, 25 Jan. 2021, https://doi.org/10.1038/s12276-021-00557-3. Accessed 7 Dec. 2022.

7. "PARP Inhibitor Update: Ovarian Cancer." IPD Analytics Payer & Provider Insights, IPD Analytics, LLC, 28 Oct. 2022, secure.ipdanalytics.com/User/Pharma/RxStrategy/Recent/Reports. Accessed 7 Dec. 2022.

8. Lynparza (olaparib), AstraZeneca, Nov. 2022, www.lynparza.com. Accessed 15 Dec. 2022.9. Rubraca (rucaparib), Clovis Oncology, Jun. 2022, www.rubraca.com. Accessed 15 Dec. 2022.

10. Zejula (niraparib), GSK, Sept. 2022. www.zejula.com. Accessed 15 Dec. 2022.11. Talzenna (talazoparib), Pfizer, Jan. 2021. www.talzenna.com. Accessed 15 Dec. 2022.

About the Author

Rachel K. Anderson, PharmD, CSP, is a clinical program manager at AllianceRx Walgreens Pharmacy in Pittsburgh, Pennsylvania.