Description: <h2>Olaparib</h2>
<p>
Olaparib (brand name <em>Lynparza</em>; developmental name AZD2281) is an orally active
poly(ADP-ribose) polymerase (PARP) inhibitor used as an anticancer pharmaceutical.
It inhibits PARP-mediated DNA repair and produces the greatest cytotoxicity in tumour
cells with deficient homologous recombination repair, particularly cells carrying
deleterious <em>BRCA1</em> or <em>BRCA2</em> alterations.
</p>
<h3>Classification</h3>
<table>
<tr>
<th>Field</th>
<th>Information</th>
</tr>
<tr>
<td>Product type</td>
<td>Pharmaceutical; targeted anticancer agent</td>
</tr>
<tr>
<td>Drug class</td>
<td>PARP inhibitor</td>
</tr>
<tr>
<td>Primary targets</td>
<td>PARP1, PARP2 and PARP3</td>
</tr>
<tr>
<td>Mechanistic category</td>
<td>DNA-damage response inhibitor; synthetic-lethality agent</td>
</tr>
<tr>
<td>Common brand name</td>
<td>Lynparza</td>
</tr>
<tr>
<td>Developmental name</td>
<td>AZD2281</td>
</tr>
</table>
<h3>Major Mechanisms and Targets</h3>
<table>
<tr>
<th>Target or Process</th>
<th>Direction</th>
<th>Effect</th>
</tr>
<tr>
<td>PARP1</td>
<td>Down</td>
<td>Inhibits catalytic activity and promotes PARP1 trapping on damaged DNA.</td>
</tr>
<tr>
<td>PARP2</td>
<td>Down</td>
<td>Inhibits PARP2-dependent detection and repair of DNA strand breaks.</td>
</tr>
<tr>
<td>PARP3</td>
<td>Down</td>
<td>Inhibits an additional PARP-family enzyme involved in the DNA-damage response.</td>
</tr>
<tr>
<td>Poly(ADP-ribosyl)ation / PARylation</td>
<td>Down</td>
<td>Reduces PARP-dependent modification and recruitment of DNA-repair proteins.</td>
</tr>
<tr>
<td>PARP–DNA complexes / PARP trapping</td>
<td>Up</td>
<td>Stabilizes cytotoxic PARP–DNA complexes that obstruct replication-fork progression.</td>
</tr>
<tr>
<td>Single-strand DNA-break repair</td>
<td>Down</td>
<td>Prevents efficient repair of DNA single-strand lesions.</td>
</tr>
<tr>
<td>Replication-fork stalling and collapse</td>
<td>Up</td>
<td>Unrepaired lesions and trapped PARP complexes impede DNA replication.</td>
</tr>
<tr>
<td>DNA double-strand breaks</td>
<td>Up</td>
<td>Replication of unrepaired DNA lesions produces potentially lethal double-strand breaks.</td>
</tr>
<tr>
<td>DNA damage</td>
<td>Up</td>
<td>Causes progressive accumulation of genomic lesions in susceptible tumour cells.</td>
</tr>
<tr>
<td>γH2AX</td>
<td>Up</td>
<td>Increases a marker of DNA double-strand-break signalling.</td>
</tr>
<tr>
<td>Homologous recombination repair dependence</td>
<td>Up</td>
<td>Forces damaged cells to depend more strongly on BRCA-mediated homologous recombination.</td>
</tr>
<tr>
<td>Synthetic lethality</td>
<td>Up</td>
<td>
Selectively kills cells that combine PARP inhibition with deficient homologous
recombination repair.
</td>
</tr>
<tr>
<td>BRCA1/BRCA2-deficient cell survival</td>
<td>Down</td>
<td>
HR-deficient cells cannot adequately repair olaparib-induced double-strand DNA breaks.
</td>
</tr>
<tr>
<td>Genomic instability</td>
<td>Up</td>
<td>Increases chromosome and replication-associated damage beyond tolerable levels.</td>
</tr>
<tr>
<td>Cell-cycle arrest</td>
<td>Up</td>
<td>Activates DNA-damage checkpoints and inhibits progression through the cell cycle.</td>
</tr>
<tr>
<td>Apoptosis</td>
<td>Up</td>
<td>Induces programmed cell death following irreparable DNA damage.</td>
</tr>
<tr>
<td>Tumour-cell proliferation</td>
<td>Down</td>
<td>Suppresses proliferation, particularly in BRCA-mutated or HR-deficient tumour cells.</td>
</tr>
<tr>
<td>Tumour growth</td>
<td>Down</td>
<td>Reduces tumour growth in responsive preclinical and clinical settings.</td>
</tr>
<tr>
<td>Platinum sensitivity</td>
<td>Up / predictive association</td>
<td>
Tumours with homologous-recombination defects may be sensitive to both platinum agents
and PARP inhibition.
</td>
</tr>
</table>
<h3>Biomarkers Associated with Response</h3>
<table>
<tr>
<th>Biomarker</th>
<th>Association</th>
</tr>
<tr>
<td>BRCA1 mutation or loss</td>
<td>Generally associated with increased olaparib sensitivity.</td>
</tr>
<tr>
<td>BRCA2 mutation or loss</td>
<td>Generally associated with increased olaparib sensitivity.</td>
</tr>
<tr>
<td>Homologous recombination deficiency (HRD)</td>
<td>May identify tumours with impaired double-strand-break repair and greater benefit.</td>
</tr>
<tr>
<td>Genomic instability</td>
<td>Can serve as an indirect measure of historical homologous-recombination deficiency.</td>
</tr>
<tr>
<td>Platinum sensitivity</td>
<td>Often correlates with PARP-inhibitor responsiveness but is not a definitive biomarker.</td>
</tr>
</table>
<h3>Resistance Mechanisms</h3>
<table>
<tr>
<th>Resistance Mechanism</th>
<th>Effect</th>
</tr>
<tr>
<td>BRCA1/BRCA2 reversion mutations</td>
<td>Restore the reading frame and homologous-recombination repair capacity.</td>
</tr>
<tr>
<td>Restoration of homologous recombination</td>
<td>Allows repair of olaparib-induced double-strand DNA breaks.</td>
</tr>
<tr>
<td>Replication-fork stabilization</td>
<td>Protects stalled replication forks from degradation and collapse.</td>
</tr>
<tr>
<td>Reduced PARP1 expression or altered PARP1</td>
<td>Can reduce formation of cytotoxic trapped PARP–DNA complexes.</td>
</tr>
<tr>
<td>Drug-efflux transporters</td>
<td>Increased ABC transporter activity may lower intracellular olaparib exposure.</td>
</tr>
<tr>
<td>Loss of 53BP1 pathway activity</td>
<td>May partially restore DNA-end resection and homologous recombination in BRCA1-deficient cells.</td>
</tr>
</table>
<h3>Clinical Cancer Applications</h3>
<p>
Depending on jurisdiction, tumour biomarkers, disease stage and prior therapy,
olaparib is used in selected ovarian, fallopian-tube, primary peritoneal, breast,
pancreatic and prostate cancers. Some indications require a germline or somatic
<em>BRCA1/2</em> alteration, homologous-recombination deficiency, or another qualifying
homologous-recombination-repair alteration.
</p>
<h3>Typical Pharmaceutical Dose</h3>
<p>
A commonly used adult tablet regimen is 300 mg orally twice daily. Dose reduction,
temporary interruption or discontinuation may be required for toxicity, renal
impairment or clinically significant drug interactions. Olaparib capsules and tablets
are not milligram-for-milligram interchangeable.
</p>
<h3>Major Adverse Effects and Precautions</h3>
<ul>
<li>Anaemia, neutropenia, leukopenia and thrombocytopenia</li>
<li>Nausea, vomiting, diarrhoea, dyspepsia and reduced appetite</li>
<li>Fatigue or asthenia</li>
<li>Headache and dizziness</li>
<li>Elevated serum creatinine related partly to transporter inhibition</li>
<li>Rare but serious myelodysplastic syndrome or acute myeloid leukaemia</li>
<li>Rare pneumonitis</li>
<li>Embryo-fetal toxicity</li>
<li>Potential clinically significant CYP3A-mediated drug interactions</li>
</ul>
<h3>Summary</h3>
<p>
Olaparib inhibits PARP catalytic activity and traps PARP proteins on damaged DNA.
This suppresses DNA strand-break repair, obstructs replication forks and increases
double-strand DNA breaks. Tumour cells with defective BRCA-dependent homologous
recombination cannot adequately repair this damage, producing synthetic lethality,
cell-cycle arrest and apoptosis. Olaparib should therefore be classified primarily
as a PARP1/PARP2 inhibitor, PARP-trapping agent, DNA-repair inhibitor and
synthetic-lethality pharmaceutical.
</p>