Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.
OBJECTIVE
Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel.


METHODS
In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS).


RESULTS
One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings.


CONCLUSIONS
Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China. bangyj@snu.ac.kr.
Yung-Jue
YJ
Bang
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Seock-Ah
SA
Im
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Keun-Wook
KW
Lee
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Jae Yong
JY
Cho
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Eun-Kee
EK
Song
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Kyung Hee
KH
Lee
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Yeul Hong
YH
Kim
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Joon Oh
JO
Park
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Hoo Geun
HG
Chun
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Dae Young
DY
Zang
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Anitra
A
Fielding
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Jacqui
J
Rowbottom
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Darren
D
Hodgson
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Mark J
MJ
O'Connor
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Xiaolu
X
Yin
Yung-Jue Bang, Seock-Ah Im, and Woo Ho Kim, Seoul National University College of Medicine; Jae Yong Cho, Yonsei University College of Medicine, Gangnam Severance Hospital; Yeul Hong Kim, Anam Hospital, Korea University College of Medicine; Joon Oh Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Hoo Geun Chun, Seoul St Mary's Hospital, Catholic University of Korea, Seoul; Keun-Wook Lee, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam; Eun-Kee Song, Chonbuk National University Medical School, Jeonju; Kyung Hee Lee, Yeungnam University Hospital, Daegu; Dae Young Zang, Hallym University Sacred Heart Hospital, Anyang, Korea; Anitra Fielding, Jacqui Rowbottom, Darren Hodgson, and Mark J. O'Connor, AstraZeneca, Macclesfield, United Kingdom; and Xiaolu Yin, Innovation Centre, AstraZeneca, Shanghai, China.
Woo Ho
WH
Kim
D000230:Adenocarcinoma / Q000145:classification / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood; D001707:Biopsy, Needle; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000145:classification / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D010793:Phthalazines / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D016016:Proportional Hazards Models; D011446:Prospective Studies; D013274:Stomach Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D010793:Phthalazines; D010879:Piperazines; D064007:Ataxia Telangiectasia Mutated Proteins; D017239:Paclitaxel; C531550:olaparib