Pharmacokinetic Effects and Safety of Olaparib Administered with Endocrine Therapy: A Phase I Study in Patients with Advanced Solid Tumours

Adv Ther. 2018 Nov;35(11):1945-1964. doi: 10.1007/s12325-018-0804-z. Epub 2018 Oct 15.

Abstract

Introduction: The PARP inhibitor olaparib is efficacious as monotherapy and has potential application in combination with endocrine therapy for the treatment of breast cancer. This phase I study assessed the safety and pharmacokinetic (PK) profiles of olaparib combined with tamoxifen, anastrozole or letrozole in patients with advanced solid tumours.

Methods: During part A, PK profiles were assessed in three consecutive treatment periods: (1) olaparib (tablet) 300 mg bid, days 1-5 followed by a 4-day washout; (2) cohort 1, tamoxifen 60 mg loading dose qd days 10-13, 20 mg qd days 14-26; cohort 2, anastrozole 1 mg qd days 10-19; cohort 3, letrozole 2.5 mg qd days 10-38; (3) as for period 2, with concomitant olaparib 300 mg bid for 5 days. Patients could then enter part B and receive olaparib monotherapy (300 mg bid continuously). Safety was assessed in parts A and B until 12 months after the last patient entered part B.

Results: Seventy-nine patients (20.3% with breast cancer) received treatment in part A; 72 completed part A and 69 entered part B. Anastrozole and letrozole had no effect on the PK profile of olaparib and vice versa. Co-administration with tamoxifen produced a modest decrease in exposure to olaparib [geometric least-squares mean (GLSmean) Cmax,ss and AUC0-τ decreased by 20% (90% CI 0.71-0.90) and 27% (0.63-0.84), respectively]. Exposure to tamoxifen was slightly increased when combined with olaparib [GLSmean Cmax,ss and AUC0-τ increased by 13% (1.06-1.22) and 16% (1.11-1.21), respectively]; however, the 90% CI fell within the 0.7-1.43 boundary and there were no changes in exposure to tamoxifen metabolites. The safety profile for olaparib alone and in combination with the antihormonal therapies was acceptable.

Conclusions: The combination of olaparib and either anastrozole, letrozole or tamoxifen was generally well tolerated, with no clinically relevant PK interactions identified.

Funding: AstraZeneca.

Clinical trial registration: NCT02093351.

Keywords: Anastrozole; Antihormonal therapy; Endocrine therapy; Letrozole; Lynparza; Olaparib; PARP inhibitor; Pharmacokinetics; Safety; Tamoxifen.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anastrozole / administration & dosage
  • Anastrozole / pharmacokinetics
  • Antineoplastic Agents, Hormonal / administration & dosage
  • Antineoplastic Agents, Hormonal / pharmacokinetics
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / pathology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Monitoring / methods
  • Drug Therapy, Combination* / adverse effects
  • Drug Therapy, Combination* / methods
  • Female
  • Humans
  • Letrozole / administration & dosage
  • Letrozole / pharmacokinetics
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Neoplasms / classification
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Phthalazines / administration & dosage
  • Phthalazines / pharmacokinetics*
  • Piperazines / administration & dosage
  • Piperazines / pharmacokinetics*
  • Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacokinetics
  • Tamoxifen / administration & dosage
  • Tamoxifen / pharmacokinetics
  • Treatment Outcome

Substances

  • Antineoplastic Agents, Hormonal
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Tamoxifen
  • Anastrozole
  • Letrozole
  • olaparib

Associated data

  • ClinicalTrials.gov/NCT02093351
  • figshare/10.6084/m9.figshare.7146524