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Olaparib (brand name Lynparza) is a pioneering targeted anticancer therapy known as a PARP inhibitor (poly [ADP-ribose] polymerase inhibitor). It is available in oral tablet form, with 150 mg being one of the standard strengths used in various dosing regimens. Olaparib represents a significant advancement in precision oncology, specifically for patients with cancers associated with BRCA1/2 and other homologous recombination repair (HRR) gene mutations.
Approved by the U.S. Food and Drug Administration (FDA) in 2014, olaparib 150 mg has transformed the management of several malignancies, including ovarian, breast, pancreatic, and prostate cancers, by exploiting the concept of synthetic lethality—a mechanism that selectively kills cancer cells while sparing most normal tissues.
1. The Biological Foundation: DNA Damage and Repair
To understand how olaparib works, it’s important to first consider how cells repair DNA damage.
DNA in every cell is constantly exposed to damage from internal metabolic processes and external agents such as radiation or chemicals. To maintain stability, cells rely on several DNA repair mechanisms:
Base excision repair (BER): Fixes small, single-strand DNA breaks.
Homologous recombination repair (HRR): Repairs more severe, double-strand DNA breaks using a sister chromatid as a template.
The PARP enzyme family, particularly PARP-1 and PARP-2, plays a critical role in single-strand break repair. When a single-strand break occurs, PARP detects the damage, binds to the site, and recruits repair proteins to restore the DNA.
However, in certain individuals, particularly those with BRCA1 or BRCA2 mutations, the HRR pathway is defective. This deficiency leaves cancer cells highly dependent on the PARP-mediated repair pathway for survival. Olaparib’s therapeutic strategy is based precisely on exploiting this vulnerability.
2. Mechanism of Action: The Role of PARP Inhibition
Olaparib acts by inhibiting the PARP enzymes, particularly PARP-1 and PARP-2, which are responsible for detecting and repairing single-strand breaks in DNA. The mechanism unfolds through several interconnected steps:
PARP Enzyme Inhibition:
Olaparib binds to the catalytic domain of the PARP enzyme, preventing it from synthesizing poly(ADP-ribose) chains needed for recruiting DNA repair proteins.
“PARP Trapping” on DNA:
Beyond simply blocking the enzyme’s activity, olaparib causes PARP to become “trapped” on DNA strands at the site of damage. These trapped PARP–DNA complexes obstruct the progression of replication forks during cell division.
Accumulation of Double-Strand Breaks:
The unrepaired single-strand breaks eventually lead to double-strand breaks (DSBs) when cells attempt to replicate their DNA.
Synthetic Lethality in BRCA-Mutant Cells:
In normal cells, DSBs can be accurately repaired by the HRR pathway. However, in BRCA1/2-mutated cancer cells where HRR is defective, these DSBs remain unrepaired, leading to genomic instability, mitotic catastrophe, and ultimately cell death.
This selective killing of HRR-deficient cells while sparing healthy cells with intact repair mechanisms is the hallmark of synthetic lethality.
Through this mechanism, olaparib effectively targets cancer cells that rely heavily on PARP for survival while minimizing toxicity to normal cells.
3. Pharmacology and Dosing Context
The 150 mg tablet is a commonly used strength in olaparib therapy. Standard dosing regimens vary by indication but typically involve 300 mg twice daily (two 150 mg tablets per dose).
Pharmacokinetic Profile:
Absorption: Olaparib is well absorbed orally, reaching peak plasma concentrations within 1.5 to 3 hours after ingestion.
Metabolism: It is metabolized mainly by CYP3A4, meaning strong inhibitors or inducers of this enzyme can affect drug levels.
Half-life: The terminal elimination half-life is approximately 12 hours, supporting twice-daily dosing.
Steady-State: Achieved within 3–4 days of continuous use.
The tablet formulation (150 mg and 100 mg) provides improved bioavailability and patient convenience compared to earlier capsule forms.
4. Clinical Indications
Olaparib 150 mg is approved for several cancers associated with DNA repair deficiencies, either as monotherapy or combination therapy.
A. Ovarian and Fallopian Tube Cancer
Maintenance Therapy: For patients with platinum-sensitive, relapsed ovarian cancer, especially those with BRCA mutations, olaparib maintenance therapy significantly prolongs progression-free survival (PFS).
Front-Line Use: In combination with bevacizumab, olaparib is used as first-line maintenance therapy for advanced ovarian cancer with HRD-positive status.
B. Breast Cancer
Indicated for germline BRCA-mutated, HER2-negative metastatic breast cancer after prior chemotherapy.
Clinical trials (e.g., OlympiAD) demonstrated improved PFS compared to standard chemotherapy.
C. Pancreatic Cancer
Approved as maintenance therapy for metastatic pancreatic cancer with germline BRCA mutations following at least 16 weeks of platinum-based chemotherapy.
The POLO trial showed significant improvement in PFS in this patient population.
D. Prostate Cancer
Used in metastatic castration-resistant prostate cancer (mCRPC) with HRR gene mutations (including BRCA1/2 and ATM).
The PROfound trial demonstrated superior clinical outcomes with olaparib compared to enzalutamide or abiraterone.
5. Safety Profile and Tolerability
While olaparib is generally well tolerated, it has some common side effects that result from its action on rapidly dividing cells:
Fatigue or asthenia
Nausea and vomiting
Anemia and cytopenias
Diarrhea or decreased appetite
Serious but less frequent adverse events include myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), particularly with prolonged use.
To minimize side effects, patients are advised to take olaparib after meals, maintain adequate hydration, and undergo regular blood monitoring for hematologic parameters.
6. Clinical Impact and Significance
Olaparib’s development marked a paradigm shift in oncology. By targeting cancer’s genetic vulnerabilities rather than relying on broad cytotoxic effects, it exemplifies the precision medicine approach. The concept of synthetic lethality that underlies olaparib’s mechanism has paved the way for the development of other PARP inhibitors and DNA repair–targeted therapies.
The ability of olaparib 150 mg to specifically kill BRCA-mutated and HRR-deficient cells without significantly affecting normal tissue provides:
Improved quality of life
Reduced toxicity
Durable remission periods, especially in maintenance settings
7. Summary Table
Aspect Details
Drug Name Olaparib (Lynparza)
Tablet Strength Discussed 150 mg
Drug Class PARP inhibitor
Mechanism Inhibits PARP-1 and PARP-2, causing DNA repair failure and synthetic lethality in BRCA-mutant cells
Key Indications Ovarian, breast, pancreatic, and prostate cancers with BRCA or HRR mutations
Typical Dose 300 mg twice daily (2 × 150 mg tablets)
Common Side Effects Fatigue, nausea, anemia, GI upset
Clinical Benefit Prolonged progression-free survival, targeted action, chemotherapy-free option
Conclusion
Olaparib 150 mg works by inhibiting PARP enzymes, disrupting cancer cells’ ability to repair DNA damage. In tumors deficient in BRCA1/2 or HRR pathways, this leads to an accumulation of lethal DNA damage—a process known as synthetic lethality. Through this precise mechanism, olaparib selectively kills cancer cells while preserving healthy tissue. Its success in multiple cancer types highlights the power of targeted therapy and represents a major advancement in personalized cancer treatment.
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