An Adaptive Study to Determine the Optimal Dose of the Tablet Formulation of the PARP Inhibitor Olaparib

Area of Science:

• Pharmacology and Drug Development
• Oncology
• Clinical Trials

Background:

• Olaparib's poor solubility necessitates advanced drug delivery for bioavailability.
• Current 400 mg twice-daily dosing requires 16 capsules, leading to a high pill burden.
• A tablet formulation was developed to improve patient compliance and reduce pill burden.

Purpose of the Study:

• To evaluate the optimal dose and administration schedule of a new olaparib tablet formulation.
• To compare the pharmacokinetic properties of olaparib tablet and capsule formulations.
• To determine the maximum tolerated dose and recommended dose for future trials.

Main Methods:

• Two-stage clinical trial design with sequentially enrolled cohorts.
• Stage 1: Pharmacokinetic comparison of tablet vs. capsule formulations in advanced solid tumors.
• Stage 2: Dose escalation and expansion cohorts in solid tumors and BRCA-mutated breast/ovarian cancers.

Main Results:

• Olaparib 200 mg tablets showed similar Cmax,ss but lower AUCss and Cmin,ss than 400 mg capsules.
• Steady-state exposure with olaparib tablets ≥300 mg matched or exceeded 400 mg capsules.
• Maximum tolerated dose was 400 mg twice daily, but 65% required reduction to 300 mg due to toxicity; intermittent dosing showed no benefit. Tumor shrinkage was comparable across relevant doses/formulations.

Conclusions:

• The recommended monotherapy dose for olaparib tablets in Phase III trials is 300 mg twice daily.
• This dose simplifies administration from 16 capsules to four tablets daily.
• The new tablet formulation improves patient convenience while maintaining therapeutic exposure and efficacy.