Generic Name

Olaparib

Mechanism

Olaparib is an oral PARP (poly‑ADP ribose polymerase) inhibitor.
• SYNTHESIS BLOCKAGE: It blocks the repair of single‑strand DNA breaks by inhibiting PARP‑1/2, leading to accumulation of DNA damage.
• PARP TRAPPING: In cells harboring pathogenic BRCA1/2 or other homologous recombination repair (HRR) deficiencies, trapped PARP–DNA complexes convert single‑strand lesions into lethal double‑strand breaks.
• Synthetic Lethality: Tumor cells lacking functional HRR cannot repair these breaks, resulting in apoptosis, while normal cells recover via intact HRR pathways.

Pharmacokinetics

• Formulation: Oral tablets.
• Absorption: Peak plasma concentration (Tmax) ≈ 1–4 h; 80 % oral bioavailability.
• Distribution: Volume of distribution ~ 4 L kg⁻¹; protein binding ~ 73 %.
• Metabolism: Primarily hepatic CYP3A4 and CYP3A5; minor contribution of CYP1A2.
• Elimination: 60 % excreted renally (urine), 30 % fecal; half‑life ≈ 18 h.
• Drug interactions: Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) increase AUC by ~ 2‑fold; strong CYP3A4 inducers (e.g., rifampin, carbamazepine) reduce AUC by > 60 %. Avoid concomitant CYP3A4 modulators unless dose adjusted.

Indications

• Maintenance Therapy
• Ovarian cancer: Advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer with germline or somatic BRCA mutation (≥ 6 mo after platinum‑based chemotherapy).
• Treatment of Recurrent Disease
• Ovarian cancer: Recurrent germline/somatic BRCA‑mutated disease.
• Breast cancer: HER2‑negative, BRCA‑mutated metastatic breast cancer post‑chemotherapy.
• Pancreatic adenocarcinoma: Germline or somatic BRCA‑mutated disease after 1–2 chemotherapy lines.
• Prostate cancer: Metastatic castration‑resistant prostate cancer with BRCA‑mutated disease (or other HRR defects) after platinum‑based therapy.

*Note*: Approval status may vary by region; dosing and indication should follow national regulatory guidance.*

Contraindications

• Contraindications
• Severe hypersensitivity to olaparib or excipients.
• Known active myelodysplastic syndrome or aplastic anemia.
• Warnings
• Myelosuppression: Grade ≥ 3 neutropenia, anemia, thrombocytopenia.
• Gastrointestinal toxicity: Nausea, vomiting, diarrhea.
• Pulmonary: Rare instances of interstitial lung disease.
• Cancer‑related: Secondary malignancies reported (e.g., acute myeloid leukemia).
• Precautions
• Pregnancy: Teratogenic potential – contraindicated. Use effective contraception in both sexes.
• Breastfeeding: No data; advise avoidance.
• Renal/hepatic impairment: Dose may need adjustment for creatinine clearance < 30 mL min⁻¹ or grade 3/4 liver dysfunction.

Dosing

• Standard adult dose: 300 mg orally, twice daily (BID) (900 mg total/day) with or without food.
• Body‑surface‑area adjustments: Not routinely required; monitor toxicity.
• Re‑dose: If Grade ≥ 3 neutropenia or thrombocytopenia, hold for recovery; resume at 200 mg BID after hematologic recovery.
• Peri‑operative: Discontinue ≥ 7 days before surgery; resume ≥ 48 h post‑procedure once hemostasis achieved.

Adverse Effects

• Common (≥ 10 %)
• Nausea, vomiting, fatigue, anorexia, malaise.
• Hematologic: anemia, neutropenia, thrombocytopenia.
• Skin: rash, alopecia.
• Serious (≥ 1 %)
• Grade ≥ 3 neutropenia/ANC < 1 × 10⁹ L⁻¹.
• Severe anemia (Hb < 8 g/dL).
• Severe thrombocytopenia (platelets < 25 × 10⁹ L⁻¹).
• Acute graft‑vs‑host disease (in post‑HCT settings).
• Pulmonary toxicity.
• Secondary acute myeloid leukemia or MDS.

Monitoring

Clinical Pearls

• Dual‑pathway protection: In BRCA‑deficient tumors, *Olaparib* both inhibits single‑strand repair and physically traps PARP, creating “double‑strand” lethal lesions that normal cells rarely generate.
• Biomarker‑driven therapy: Tumors with HRR deficiencies other than BRCA (e.g., PALB2, RAD51, ATM) may also respond; emerging companion diagnostics expand eligibility.
• Dose adjustments in combination: When paired with platinum agents or PI3K inhibitors, consider a temporary dose reduction (200 mg BID) to mitigate overlapping myelotoxicity.
• P‑gp and CYP3A4 interactions: Co‑administration of strong inhibitors (ketoconazole) should prompt a 50 % dose reduction; inducers (rifampin) require increasing the dose or switching to an alternative therapy.
• Adjuvant setting: In ovarian cancer, maintenance *Olaparib* post‑chemotherapy prolongs progression‑free survival up to 18 months; discuss cost‑effectiveness and patient preference.
• Patient education: Emphasize that GI symptoms peak within the first 2–3 cycles; antiemetics and dietary changes (small, frequent meals) mitigate intolerance.
• Re‑challenge strategy: Patients who had dose‑reducing discontinuation due to neutropenia can often resume therapy at the reduced 200 mg BID dose once hematology stabilizes.

*These pearls are derived from pivotal trials (ARIEL, EMBRACA, OlympiAD, POLO, PROfound) and current prescribing information.*