PARP inhibitors

Definition
PARP inhibitors are a class of targeted anticancer therapies that interfere with the DNA damage repair mechanism in cancer cells. Specifically, they inhibit the enzyme poly(ADP-ribose) polymerase (PARP), which is essential for repairing single-strand DNA breaks via the base excision repair (BER) pathway. By blocking PARP activity, these agents induce accumulation of DNA damage, particularly in cells already deficient in other DNA repair pathways—such as those with mutations in BRCA1 or BRCA2 genes—leading to synthetic lethality and cancer cell death.

Approved PARP inhibitors include:

• Olaparib (Lynparza)

• Rucaparib (Rubraca)

• Niraparib (Zejula)

• Talazoparib (Talzenna)

• Pamiparib (Partruvix – approved in China)

They are most commonly used in:

• Ovarian cancer

• Breast cancer

• Pancreatic cancer

• Prostate cancer

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1. Mechanism of Action

PARP enzymes (primarily PARP1 and PARP2) detect single-strand breaks (SSBs) in DNA and facilitate repair by recruiting other DNA repair proteins. PARP inhibitors work via:

• Catalytic inhibition: Preventing PARP from repairing SSBs.

• PARP trapping: Stabilizing PARP-DNA complexes and preventing release, which leads to replication fork collapse and double-strand breaks (DSBs).

• In BRCA-deficient cells, homologous recombination repair (HRR) is impaired, so DSBs cannot be repaired, leading to genomic instability and cell death.

This dual mechanism (enzyme inhibition + PARP trapping) underpins their effectiveness, especially in tumors with HRR deficiencies such as BRCA mutations.

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2. Approved PARP Inhibitors

Generic Name	Brand Name	Approval Year (FDA)	Developer	Main Indications
Olaparib	Lynparza	2014	AstraZeneca	Ovarian, breast, pancreatic, prostate cancers
Rucaparib	Rubraca	2016	Clovis Oncology	Ovarian, prostate cancers
Niraparib	Zejula	2017	GSK	Ovarian, endometrial cancers
Talazoparib	Talzenna	2018	Pfizer	Breast cancer
Pamiparib	Partruvix	2020 (China)	BeiGene	Ovarian cancer

3. Indications and FDA-Approved Uses

Drug	Cancer Type	Approved Use
Olaparib	Ovarian	Maintenance after platinum response; BRCA-mutant advanced cases
Olaparib	Breast	HER2-negative BRCA-mutant metastatic breast cancer
Olaparib	Pancreatic	Germline BRCA-mutant, metastatic, maintenance therapy
Olaparib	Prostate	BRCA1/2 or HRR-mutated metastatic castration-resistant
Niraparib	Ovarian	Maintenance regardless of BRCA status
Niraparib	Endometrial	Under trial, limited approval in some jurisdictions
Rucaparib	Ovarian	Maintenance & BRCA-mutant advanced disease
Rucaparib	Prostate	BRCA1/2-mutant metastatic prostate cancer
Talazoparib	Breast	Germline BRCA-mutant HER2-negative metastatic breast cancer

4. Pharmacokinetics

Parameter	Olaparib	Niraparib	Rucaparib	Talazoparib
Bioavailability	~30–50%	~73%	~36%	~55%
Half-life	~12 hours	~36 hours	~17 hours	~90 hours
Metabolism	CYP3A4 (main)	Carboxylesterases	CYP1A2, CYP3A4	Minimal (not CYP)
Excretion	Renal + hepatic	Hepatic	Hepatic + renal	Fecal + renal
Dosing	BID (olaparib)	QD (niraparib)	BID (rucaparib)	QD (talazoparib)

5. Dosing and Administration

• Olaparib: 300 mg orally twice daily (tablet), with or without food.

• Niraparib: 200–300 mg once daily (adjusted based on weight/platelets).

• Rucaparib: 600 mg orally twice daily.

• Talazoparib: 1 mg orally once daily.

All agents are oral, and treatment is continued until disease progression or unacceptable toxicity.

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6. Adverse Effects

System	Common Adverse Effects	Serious Toxicities
Hematologic	Anemia, thrombocytopenia, neutropenia	Myelodysplastic syndrome (MDS), AML (~1%)
GI	Nausea, vomiting, constipation, anorexia	GI perforation (rare)
Fatigue	Common across all agents	Dose-limiting fatigue
CNS	Headache, dizziness	Rare: confusion, seizures
Renal	Increased creatinine (especially olaparib)	Dose modification may be required
Hepatic	Transaminase elevation (mainly rucaparib)	Hepatotoxicity (monitor LFTs)
Other	Hypertension (niraparib), rash, dysgeusia	Pulmonary embolism, infection

Regular blood monitoring is necessary—especially CBC, renal function, and LFTs.

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7. Contraindications and Precautions

Condition	Consideration
Pregnancy/Breastfeeding	Teratogenic; contraindicated
Myelodysplastic syndrome	Contraindicated
Severe renal/hepatic disease	Dose reduction or avoidance
Bone marrow suppression	Contraindicated in baseline cytopenias

8. Drug Interactions

Interacting Drug/Class	Impact
CYP3A4 inhibitors (ketoconazole)	↑ Olaparib, Rucaparib exposure → risk of toxicity
CYP3A4 inducers (rifampin)	↓ Efficacy of PARP inhibitors
Anticoagulants (warfarin)	Risk of bleeding with hematologic suppression
QT-prolonging drugs	Additive risk (esp. with rucaparib)
P-gp/BCRP inhibitors	May alter PARP inhibitor absorption
Food	Improves absorption (especially for rucaparib)

9. Mechanisms of Resistance

Over time, some tumors develop resistance to PARP inhibitors through:

• Restoration of homologous recombination via BRCA reversion mutations

• Drug efflux pump activation (e.g., ABCB1 overexpression)

• PARP1 mutations preventing drug binding

• Reduced PARP trapping efficacy

• Altered DNA replication pathways

Ongoing research is focusing on combination therapies to overcome resistance, including immunotherapy and ATR inhibitors.

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10. Special Populations

Population	Notes
Elderly	Generally well tolerated; monitor for cytopenias
Pediatrics	Not widely approved; trials underway
Pregnancy	Contraindicated due to embryo-fetal toxicity
Renal impairment	Olaparib requires adjustment for CrCl < 30 mL/min
Hepatic impairment	Niraparib, rucaparib may need dose reduction

11. Genomic and Companion Diagnostics

Treatment with PARP inhibitors is often guided by genetic testing:

• BRCA1/2 mutations (germline or somatic)

• HRR deficiency (HRD) scores

• Loss of heterozygosity (LOH)

• RAD51C/D, PALB2 mutations

Commercial tests like Myriad BRACAnalysis CDx, FoundationOne CDx, and MSK-IMPACT are approved as companion diagnostics.

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12. Comparative Overview

Feature	Olaparib	Niraparib	Rucaparib	Talazoparib
BRCA required?	Not always	No (used broadly)	Initially yes	Yes (breast)
Dosing	BID	QD	BID	QD
Anemia	Moderate	High incidence	Moderate	Moderate
Nausea	Common	High incidence	Common	Moderate
MDS/AML risk	~1–2%	~1%	~1%	Rare

13. Clinical Trial Highlights

• SOLO1 (Olaparib): First-line maintenance in BRCA-mutated ovarian cancer, showing significant progression-free survival (PFS) benefit.

• PROfound (Olaparib): mCRPC with BRCA1/2 or ATM mutation showed survival advantage.

• NOVA (Niraparib): Maintenance therapy improved PFS in both BRCA-mutated and wild-type ovarian cancer.

• EMBRACA (Talazoparib): Improved PFS in BRCA-mutated advanced breast cancer compared to standard chemo.

• ARIEL3 (Rucaparib): Demonstrated PFS benefit in high-grade serous ovarian cancer.

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14. Emerging Directions

• Combination therapy with:

  • Immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors)

  • Angiogenesis inhibitors (e.g., bevacizumab + olaparib)

  • ATR/CHK1 inhibitors

• Biomarker refinement to guide PARP use beyond BRCA mutations

• Expanding indications to HRD-positive tumors regardless of cancer origin (pan-tumor strategy)

• Trials in early-stage cancers and maintenance settings post-chemotherapy