Elsevier

The Lancet

Volume 376, Issue 9737, 24–30 July 2010, Pages 235-244
The Lancet

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Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial

https://doi.org/10.1016/S0140-6736(10)60892-6Get rights and content

Summary

Background

Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer.

Methods

Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234.

Findings

Patients had been given a median of three previous chemotherapy regimens (range 1–5 in cohort 1, and 2–4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25–59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11–41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]).

Interpretation

The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations.

Funding

AstraZeneca.

Introduction

Breast cancer is one of the main causes of cancer-associated deaths in women. For most women, breast cancer arises after menopause, and the cause is probably related to a complex association of environmental1, 2 and polygenic genetic factors.3 For less than 5% of women, the disease arises in association with mutations in two highly penetrant breast and ovarian cancer predisposition genes—BRCA14 and BRCA2.5 The indicators include an early onset and a family history of several close relatives who are affected with breast, ovarian, prostate, or pancreatic cancer. Inheritance of one mutated BRCA1 or BRCA2 allele leads to a lifetime risk of breast cancer that is as high as 80%.6 Genetic counselling and testing programmes have been established that enable women to assess their risk and consider surveillance and risk-reducing surgical strategies.6 There has been great interest in the conversion of the rapid increase in elucidation of the function of the BRCA1 and BRCA2 genes into improved clinical management of breast cancer associated with mutations in these genes. The products of the BRCA1 and BRCA2 genes have roles in a highly specialised form of DNA repair—ie, homologous recombination.7, 8, 9 When the remaining wild-type allele is lost in a tumour precursor cell, this repair mechanism does not work, and the consequent rapid onset of genome instability10, 11, 12 is sufficient to enable tumour development.13, 14, 15, 16 Studies of invasive primary breast tumours in individuals with BRCA1 and BRCA2 mutations confirm loss of the remaining wild-type allele.17, 18, 19

The homologous recombination DNA repair defect might be a target for therapy.20 Indeed, the idea of synthetic lethality has been revisited21 and investigated in preclinical model systems with constitutive defects in BRCA1-dependent or BRCA2-dependent homologous recombination in combination with drug-induced inhibition of DNA repair mechanisms for single-strand breaks that were dependent on poly(ADP-ribose) polymerase (PARP)-1, resulting in highly selective cell killing.22, 23 We therefore postulated that inhibitors of PARP-1 would have significant antitumour efficacy and low toxicity when used in individuals with BRCA1 and BRCA2 mutations and advanced malignant disease. Olaparib (AZD2281) is a novel, small-molecule, orally active PARP inhibitor with up to 1000-fold selective potency in isogenic preclinical models.22 In the first-in-human phase 1 study of this drug in patients with advanced solid tumours, olaparib 400 mg twice daily was identified as the maximum tolerated dose.24 Pharmacodynamic activity in tumour biopsy samples, peripheral blood mononuclear cells, and hair follicles seemed to be maximum at doses greater than 60 mg twice daily.24 An expansion cohort of 22 patients with BRCA1 or BRCA2 mutations, and advanced treatment-refractory malignant disease from various primary tumour sites were recruited in this study, and an initial indication of antitumour efficacy was noted at doses of olaparib greater than 100 mg twice daily.24 We now report the results of a multicentre proof-of-concept phase 2 study designed to assess the efficacy and safety of oral olaparib at the maximum tolerated dose and at a lower dose that was pharmacodynamically active at phase 1 assessment,24 in women with BRCA1 and BRCA2 mutations and advanced breast cancer.

Section snippets

Study design

The study had a non-randomised, sequential cohort design, and was undertaken prospectively in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort was enrolled from June 15, 2007, to March 11, 2008; and the second cohort was enrolled from Feb 27 to Sept 5, 2008. The first cohort of patients (cohort 1) was treated at the phase 1 maximum tolerated dose (400 mg twice daily).24 A second sequential cohort (cohort 2) was given the lower PARP inhibitory dose (100 mg

Results

Figure 1 shows the trial profile. The enrolled patients were given at least one dose of olaparib. 25 (46%) of 54 patients discontinued treatment before being given the planned six cycles. The remaining 29 patients (54%) completed the full study schedule.

At the time the study database was locked, five patients were still taking olaparib with more patients still on study drug in cohort 2 as a result of the sequential nature of enrolment to the two cohorts. Four patients had protocol

Discussion

This trial was designed to test the safety and efficacy of a monotherapy PARP inhibitor strategy in women with BRCA1 and BRCA2 mutations with advanced metastatic breast cancer. The results of this phase 2 study show that the oral PARP inhibitor olaparib at 400 mg twice daily was active even in women with BRCA1 or BRCA2 mutations and advanced breast cancer that was resistant to conventional chemotherapy. These findings provide proof of concept for the clinical usefulness of tumour-specific

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