Efficacy of chemotherapy in BRCA1/2 mutation carrier ovarian cancer in the setting of PARP inhibitor resistance: a multi-institutional study.
OBJECTIVE
Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.


METHODS
We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.


RESULTS
Data were collected from 89 patients who received a median of 3 (range 1-11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13-21] and 34 weeks (95% CI, 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15-29) and OS of 45 weeks (95% CI, 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0-0.375)].


CONCLUSIONS
Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC.
Authors' Affiliations: The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton; Edinburgh Cancer Research UK Center, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh; The Cancer Research UK Gene Function Laboratory; Breakthrough Breast Cancer Research Center; Tumour Profiling Unit, The Institute of Cancer Research, London, United Kingdom; University of California San Francisco, San Francisco, California; Department of Medical Oncology, Prince of Wales Clinical School, Prince of Wales Hospital, Sydney, Australia; The Chaim Sheba Medical Center, Tel Hashomer, Israel; Princess Margaret Hospital, Toronto, Canada; Oncologisch Centrum Vrije Universiteit Brussel, Brussels, Belgium; and Dana Farber Cancer Center, Boston, Massachusetts.
Joo Ern
JE
Ang
Charlie
C
Gourley
C Bethan
CB
Powell
Hilda
H
High
Ronnie
R
Shapira-Frommer
Vincent
V
Castonguay
Jacques
J
De Greve
Tina
T
Atkinson
Timothy A
TA
Yap
Shahneen
S
Sandhu
Susana
S
Banerjee
Lee-May
LM
Chen
Michael L
ML
Friedlander
Bella
B
Kaufman
Amit M
AM
Oza
Ursula
U
Matulonis
Louise J
LJ
Barber
Iwanka
I
Kozarewa
Kerry
K
Fenwick
Ioannis
I
Assiotis
James
J
Campbell
Lina
L
Chen
Johann S
JS
de Bono
Martin E
ME
Gore
Christopher J
CJ
Lord
Alan
A
Ashworth
Stan B
SB
Kaye
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors