Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses.
BACKGROUND
Olaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.


METHODS
Eligible patients had measurable or evaluable disease, gBRCAm, and good end-organ function. A 3 + 3 dose escalation tested daily oral capsule olaparib (100 or 200mg every 12 hours; dose level1 or 2) with carboplatin area under the curve (AUC) on day 8 (AUC3 day 8), then every 21 days. For dose levels 3 to 6, patients were given olaparib days 1 to 7 at 200 and 400 mg every 12 hours, with carboplatin AUC3 to 5 on day 1 or 2 every 21 days; a maximum of eight combination cycles were permitted, after which daily maintenance of olaparib 400mg every12 hours continued until progression. Dose-limiting toxicity was defined in the first two cycles. Peripheral blood mononuclear cells were collected for polymorphism analysis and polyADP-ribose incorporation. Paired tumor biopsies (before/after cycle 1) were obtained for biomarker proteomics and apoptosis endpoints.


RESULTS
Forty-five women (37 OvCa/8 BrCa) were treated. Dose-limiting toxicity was not reached on the intermittent schedule. Expansion proceeded with olaparib 400mg every 12 hours on days 1 to 7/carboplatin AUC5. Grade 3/4 adverse events included neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%). Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). Proteomic analysis suggests high pretreatment pS209-eIF4E and FOXO3a correlated with duration of response (two-sided P < .001; Pearson's R (2) = 0.94).


CONCLUSIONS
Olaparib capsules 400mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD. leej6@mail.nih.gov.
Jung-Min
JM
Lee
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
John L
JL
Hays
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Christina M
CM
Annunziata
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Anne M
AM
Noonan
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Lori
L
Minasian
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Jo Anne
JA
Zujewski
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Minshu
M
Yu
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Nicolas
N
Gordon
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Jiuping
J
Ji
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Tristan M
TM
Sissung
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
William D
WD
Figg
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Nilofer
N
Azad
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Bradford J
BJ
Wood
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
James
J
Doroshow
Affiliations of authors: Medical Oncology Branch, Center for Cancer Research (J-ML, JLH, CMA, AMN, LM, JAZ, MY, NG, TMS, WDF, NA, ECK), National Clinical Target Validation Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research (JJ), Center for Interventional Oncology, Radiology, and Imaging Sciences, Clinical Center and National Cancer Institute (BJW), and Division of Cancer Treatment and Diagnosis, National Cancer Institute (JD), National Institutes of Health, Bethesda, MD.
Elise C
EC
Kohn
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011237:Predictive Value of Tests
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010793:Phthalazines; D010879:Piperazines; D011064:Poly Adenosine Diphosphate Ribose; D016190:Carboplatin; C531550:olaparib