What is the least effective dose of Olaparib (Poly (ADP-ribose) polymerase inhibitor) for a patient with metastatic prostate cancer and a potential BRCA1 or BRCA2 mutation?

Olaparib Dosing for Metastatic Prostate Cancer with BRCA1/2 Mutations

The standard and only recommended dose of olaparib for metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 mutations is 300 mg orally twice daily (total 600 mg/day), as established by the PROfound trial and approved by the FDA. 1

Standard Dosing Protocol

• Olaparib 300 mg twice daily is the FDA-approved dose for patients with mCRPC harboring deleterious or suspected deleterious germline or somatic mutations in BRCA1, BRCA2, or other homologous recombination repair (HRR) genes who have progressed on prior enzalutamide or abiraterone. 1

• This dosing regimen demonstrated significant survival benefit in the PROfound trial, with an overall survival hazard ratio of 0.69 (95% CI 0.50-0.97, P=0.02) in patients with BRCA1/2 or ATM mutations (Cohort A). 1

• There is no "least effective dose" recommended in guidelines—the 300 mg twice daily dose is the established therapeutic dose, and dose reductions are only made for toxicity management, not as an intentional lower-efficacy strategy. 1

Critical Patient Selection Criteria

Before initiating olaparib at the standard dose, confirm:

• Prior treatment requirement: Patient must have received at least one prior androgen receptor-directed therapy (enzalutamide or abiraterone). 1

• Confirmed HRR mutation: Use commercially available analytically and clinically validated somatic tumor, ctDNA, or germline assays to identify mutations in BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L. 1

• Greatest benefit in BRCA2 mutations: Patients with BRCA2 mutations experienced the most robust overall survival benefit (HR 0.59,95% CI 0.37-0.95), followed by BRCA1 mutations, while ATM mutations showed minimal OS benefit (HR 0.93,95% CI 0.53-1.75). 1

Dose Modifications for Toxicity Only

Dose reductions from the standard 300 mg twice daily are made only for managing adverse events, not as a planned lower-dose strategy:

• Anemia is the most common dose-limiting toxicity, occurring in 39-63% of patients (grade ≥3 in 17-31%), often requiring transfusion support. 2

• Approximately 56-75% of patients require dose reductions when olaparib is used in combination therapy. 2

• 12-20% of patients discontinue olaparib entirely due to adverse events. 2

Mandatory Monitoring Requirements

Implement intensive monitoring from treatment initiation:

• Complete blood counts must be monitored carefully throughout therapy, with type and screen availability maintained at all times for potential transfusion support. 1, 2

• Monitor hepatic and renal function regularly, as creatinine elevation occurs in a subset of patients. 1, 2

• Intensify CBC monitoring to at least every 2 weeks when combining olaparib with skeletal radiation therapy due to substantially elevated hematologic toxicity risk. 2

Common Pitfalls to Avoid

Do not attempt to use lower doses as initial therapy—there is no evidence supporting sub-therapeutic dosing, and the 300 mg twice daily dose is the only regimen validated for efficacy in clinical trials. 1

Do not overestimate efficacy in non-BRCA mutations—while olaparib is FDA-approved for 14 HRR genes, the clinical benefit is predominantly driven by BRCA1/2 mutations, with substantially lower response rates in other HRR gene alterations like CHEK2 or ATM. 1, 3

Prior taxane therapy is not required—the PROfound study did not mandate prior docetaxel, so olaparib can be used before or after taxane-based chemotherapy. 1