Phase II, open-label, randomized, multicenter study comparing the efficacy and safety of olaparib, a poly (ADP-ribose) polymerase inhibitor, and pegylated liposomal doxorubicin in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer.
OBJECTIVE
Olaparib (AZD2281), an orally active poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in BRCA1- or BRCA2-deficient cells, has shown promising clinical efficacy in nonrandomized phase II trials in patients with ovarian cancer with BRCA1 or BRCA2 deficiency. We assessed the comparative efficacy and safety of olaparib and pegylated liposomal doxorubicin (PLD) in this patient population.


METHODS
In this multicenter, open-label, randomized, phase II study, patients with ovarian cancer that recurred within 12 months of prior platinum therapy and with confirmed germline BRCA1 or BRCA2 mutations were enrolled. Patients were assigned in a 1:1:1 ratio to olaparib 200 mg twice per day or 400 mg twice per day continuously or PLD 50 mg/m(2) intravenously every 28 days. The primary efficacy end point was Response Evaluation Criteria in Solid Tumors (RECIST) -assessed progression-free survival (PFS). Secondary end points included objective response rate (ORR) and safety.


RESULTS
Ninety-seven patients were randomly assigned. Median PFS was 6.5 months (95% CI, 5.5 to 10.1 months), 8.8 months (95% CI, 5.4 to 9.2 months), and 7.1 months (95% CI, 3.7 to 10.7 months) for the olaparib 200 mg, olaparib 400 mg, and PLD groups, respectively. There was no statistically significant difference in PFS (hazard ratio, 0.88; 95% CI, 0.51 to 1.56; P = .66) for combined olaparib doses versus PLD. RECIST-assessed ORRs were 25%, 31%, and 18% for olaparib 200 mg, olaparib 400 mg, and PLD, respectively; differences were not statistically significant. Tolerability of both treatments was as expected based on previous trials.


CONCLUSIONS
The efficacy of olaparib was consistent with previous studies. However, the efficacy of PLD was greater than expected. Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population.
The Royal Marsden National Health Service Foundation Trust and The Institute of Cancer Research, Sycamore House, Downs Rd, Sutton, Surrey SM2 5PT, UK. stan.kaye@rmh.nhs.uk
Stan B
SB
Kaye
Jan
J
Lubinski
Ursula
U
Matulonis
Joo Ern
JE
Ang
Charlie
C
Gourley
Beth Y
BY
Karlan
Amit
A
Amnon
Katherine M
KM
Bell-McGuinn
Lee-May
LM
Chen
Michael
M
Friedlander
Tamar
T
Safra
Ignace
I
Vergote
Mark
M
Wickens
Elizabeth S
ES
Lowe
James
J
Carmichael
Bella
B
Kaufman
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D011446:Prospective Studies; D016019:Survival Analysis
D010793:Phthalazines; D010879:Piperazines; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; C531550:olaparib