Effect of BRCA1 and XPG mutations on treatment response to trabectedin and pegylated liposomal doxorubicin in patients with advanced ovarian cancer: exploratory analysis of the phase 3 OVA-301 study.
BACKGROUND
We investigated the association of BRCA1 and XPG mutations with response rate (RR), progression-free survival (PFS) and overall survival (OS) in a subset of patients from a phase 3 clinical trial comparing the efficacy and safety of trabectedin + pegylated liposomal doxorubicin (PLD) versus PLD alone in patients with recurrent ovarian cancer.


METHODS
A candidate array was designed based on the Breast Cancer Information Core database for BRCA mutation analyses. An exploratory analysis of BRCA1/XPG mutation status was conducted using a two-sided log-rank test and 0.05 significance in germline DNA samples from 264 women with failed first-line platinum-based chemotherapy, randomized (1 : 1) to trabectedin + PLD or PLD alone.


RESULTS
Overall, 41 (16%) of the 264 women had BRCA1(mut) (trabectedin + PLD: n = 24/135, 18%; PLD: n = 17/129; 13%) and 17 (6%) had XPG(mut) (trabectedin + PLD: n = 8/135, 6%; PLD: n = 9/129, 7%). A higher RR was observed in BRCA1(mut) patients (20/41; 49%) versus BRCA1(wt) patients (62/223; 28%). Within the BRCA1(mut) group, trabectedin + PLD-treated patients had longer PFS and longer OS than PLD-treated patients (median PFS 13.5 versus 5.5 months, P = 0.0002; median OS 23.8 versus 12.5 months, P = 0.0086), whereas in BRCA1(wt) patients, OS was not significantly different (median OS: 19.1 versus 19.3 months; P = 0.9377). There were no differences in OS or PFS of patients with XPG(mut) between the two treatment arms. However, trabectedin + PLD-treated patients with XPG(mut) had a trend toward shorter PFS (median PFS: 1.9 versus 7.5 months; P = 0.1666) and OS (median OS: 14.5 versus 20.7 months; P = 0.1774) than those with XPG(wt).


CONCLUSIONS
In this exploratory analysis, patients with recurrent ovarian cancer carrying the BRCA1(mut) had improved outcomes with trabectedin + PLD treatment compared with PLD alone. Prospective evaluation of BRCA status is likely an important evaluation for DNA-damaging agents and may significantly impact interpretation of clinical studies. XPG may be a biomarker of poor outcome in these patients.
Division of Gynecologic Oncology, University of Arizona Cancer Center, Creighton University School of Medicine, at Dignity Health St. Joseph's Hospital and Medical Center, Phoenix, USA. Electronic address: bradley.monk@chw.edu.
B J
BJ
Monk
Department of Gynecologic Oncology, University of Calgary, Alberta, Canada.
P
P
Ghatage
Department of Gynecologic Oncology, Janssen Research & Development LLC, Raritan, USA.
T
T
Parekh
Department of Gynecologic Oncology, Janssen Research & Development LLC, Raritan, USA.
E
E
Henitz
Department of Gynecologic Oncology, Janssen Research & Development LLC, Raritan, USA.
R
R
Knoblauch
Department of Clinical R&D, PharmaMar SA, Madrid.
A S
AS
Matos-Pita
Department of Clinical R&D, PharmaMar SA, Madrid.
A
A
Nieto
Department of Gynecologic Oncology, Janssen Research & Development LLC, Raritan, USA.
Y C
YC
Park
Department of Gynecologic Oncology, Janssen Research & Development LLC, Raritan, USA.
P S
PS
Cheng
Department of Gynecologic Oncology, Janssen Research & Development LLC, Raritan, USA.
W
W
Li
Department of Gynecologic Oncology, Janssen Research & Development LLC, Raritan, USA.
R
R
Favis
Department of Gynecologic Oncology, Janssen Research & Development LLC, Raritan, USA.
D
D
Ricci
Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, València, Spain.
A
A
Poveda
D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use*; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004149:Dioxoles / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D010597:Pharmacogenetics; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use; D044005:Tetrahydroisoquinolines / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D000077606:Trabectedin; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D000099250:DNA Excision Repair Protein ERCC-5
D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D004149:Dioxoles; D004317:Doxorubicin; D004720:Endonucleases; D009687:Nuclear Proteins; D011092:Polyethylene Glycols; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D014157:Transcription Factors; D000099250:DNA Excision Repair Protein ERCC-5; C492913:BRCA1 protein, human; C506643:liposomal doxorubicin
BRCA1; XPG; pegylated liposomal doxorubicin; recurrent ovarian cancer; trabectedin