Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer
Andrew Tutt
Breakthrough Breast Cancer Research Unit, Kings College London School of Medicine, Guy's Hospital, London, UK
Background
Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces
synthetic lethality in homozygous BRCA-deficient cells. A phase I trial
identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal
of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510). The
primary aim of this study was to test the efficacy of olaparib in confirmed
BRCA1/BRCA2 carriers with advanced refractory breast cancer. The secondary aim
was to assess safety and tolerability in this population.
Methods
In
an international, multicenter, proof-of-concept, single-arm, phase II study,
two sequential patient (pt) cohorts received continuous oral olaparib in 28-day
cycles initially at the MTD, 400 mg bd (27 pts), and subsequently at 100 mg bd,
a previously identified PARP inhibitory dose (27 pts). Eligibility criteria
included confirmed BRCA1/BRCA2 mutation and recurrent, measurable
chemotherapy-refractory breast cancer. The primary efficacy endpoint was best
objective response rate (ORR; RECIST) post baseline. Progression-free survival
(PFS) and clinical benefit rate were secondary endpoints. All adverse events
were reported using CTCAE v3.
Results
On November 20, 2008, 54 pts exposed to a median of three prior lines of
chemotherapy had been enrolled. 27 pts were dosed at 400 mg bd (18 BRCA1
deficient and 9 BRCA2 deficient), and 24 of these had databased RECIST
assessments. The ORR (currently based on unconfirmed responses) was 38% (9/24)
(400 mg bd). Causally-related toxicity was mainly mild (grade 1-2) in severity;
9/27 pts (33%) had fatigue; 7/27 (26%) had nausea; 4/27 (15%) had vomiting; and
1/27 (4%) had anemia. Causally-related grade 3 or higher toxicities were seen
in 5 pts (19%) with fatigue (3 pts), nausea (2 pts), and anemia (1 pt). 27 pts
were treated in the subsequent 100 mg bd cohort where no data are currently
available.
Conclusions
Olaparib at 400 mg bd is well tolerated and highly active in advanced
chemotherapy-refractory BRCA-deficient breast cancer. Toxicity in BRCA1/BRCA2
carriers was similar to that reported previously in non-carriers. This first
study with olaparib in BRCA-deficient breast cancers provides positive proof of
concept for high activity and tolerability of a genetically defined targeted
therapy.
