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Medline ® Abstracts for References 58,59,61

of '复发性上皮性卵巢癌、输卵管癌或腹膜癌的药物治疗:铂类敏感型疾病'

58
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Olaparib maintenance therapy in patients with platinum-sensitive, relapsed serous ovarian cancer and a BRCA mutation: Overall survival adjusted for postprogression poly(adenosine diphosphate ribose) polymerase inhibitor therapy.
AU
Matulonis UA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Parry D, Grinsted L, Ledermann JA
SO
Cancer. 2016 Jun;122(12):1844-52. Epub 2016 Apr 8.
 
BACKGROUND: Maintenance treatment with the oral poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor olaparib (Lynparza) in Study 19 (study number, D0810C00019; ClinicalTrials.gov identifier, NCT00753545) significantly improved progression-free survival in comparison with a placebo for patients with platinum-sensitive, relapsed serous ovarian cancer with a BRCA1/2 mutation (BRCAm), but an interim analysis revealed no statistically significant overall survival (OS) benefit. However, 23% of the patients receiving the placebo switched to a PARP inhibitor after progression. To investigate whether this had a confounding effect on OS, this article reports an exploratory post hoc analysis that excluded all patients from sites where 1 or more placebo patients received postprogression PARP inhibitor treatment.
METHODS: In Study 19, 136 of the 265 patients receiving olaparib or a placebo had a BRCAm. Sixteen patients treated at 11 of the 82 investigational sites received a PARP inhibitor after progression; these sites were excluded from this analysis, and 97 BRCAm patients at 50 sites were included. OS was assessed with a Cox proportional hazards model analogous to the primary study analysis. A supporting rank-preserving structural failure time (RPSFT) model analysis was undertaken for all 136 BRCAm patients.
RESULTS: The OS hazard ratio (HR) was 0.52 (95% confidence interval [CI], 0.28-0.97) for the 97 BRCAm patients, whereas for the interim OS analysis with all 136 BRCAm patients, it was 0.73 (95% CI, 0.45-1.17). The supportive RPSFT analysis HR was approximately 0.66.
CONCLUSIONS: The numerical improvement in the OS HR suggests that in Study 19, postprogression PARP inhibitor treatment had a confounding influence on the interim OS analysis for BRCAm patients. There is a degree of uncertainty due to the small sample size and the lack of data maturity. Cancer 2016;122:1844-52.©2016 American Cancer Society.
AD
Dana-Farber Cancer Institute, Boston, Massachusetts.
PMID
59
TI
Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.
AU
Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM
SO
J Clin Oncol. 2015;33(3):244. Epub 2014 Nov 3.
 
PURPOSE: Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers.
PATIENTS AND METHODS: This multicenter phase II study enrolled individuals with a germline BRCA1/2 mutation and recurrent cancer. Eligibility included ovarian cancer resistant to prior platinum; breast cancer with≥three chemotherapy regimens for metastatic disease; pancreatic cancer with prior gemcitabine treatment; or prostate cancer with progression on hormonal and one systemic therapy. Olaparib was administered at 400 mg twice per day. The primary efficacy end point was tumor response rate.
RESULTS: A total of 298 patients received treatment and were evaluable. The tumor response rate was 26.2% (78 of 298; 95% CI, 21.3 to 31.6) overall and 31.1% (60 of 193; 95% CI, 24.6 to 38.1), 12.9% (eight of 62; 95% CI, 5.7 to 23.9), 21.7% (five of 23; 95% CI, 7.5 to 43.7), and 50.0% (four of eight; 95% CI, 15.7 to 84.3) in ovarian, breast, pancreatic, and prostate cancers, respectively. Stable disease≥8 weeks was observed in 42% of patients (95% CI, 36.0 to 47.4), including 40% (95% CI, 33.4 to 47.7), 47% (95% CI, 34.0 to 59.9), 35% (95% CI, 16.4 to 57.3), and 25% (95% CI, 3.2 to 65.1) of those with ovarian, breast, pancreatic, or prostate cancer, respectively. The most common adverse events (AEs) were fatigue, nausea, and vomiting. Grade≥3 AEs were reported for 54% of patients; anemia was the most common (17%).
CONCLUSION: Responses to olaparib were observed across different tumor types associated with germline BRCA1/2 mutations. Olaparib warrants further investigation in confirmatory studies.
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Bella Kaufman and Ronnie Shapira-Frommer, Sheba Medical Center, Tel Hashomer; Georgeta Fried, Institute of Oncology, Rambam Health Care Campus; Mariana Steiner, Linn Medical Centre, Haifa; Salomon M. Stemmer, Rabin Medical Center, Petah Tikva; Ayala Hubert, Hadassah-Hebrew University Hospital, Sharett Institute of Oncology; Ora Rosengarten, Shaare Zedek Medical Centre, Jerusalem, Israel; Rita K. Schmutzler, Center for Familial Breast and Ovarian Cancer and Center of Integrated Oncology, Cologne, Germany; M. William Audeh, Samuel Oschin Cancer Institute, Los Angeles, CA; Michael Friedlander, Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales; Gillian Mitchell, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia; Judith Balmaña, Vall d'Hebron Institute of Oncology, Barcelona, Spain; Niklas Loman, Skånes Universitetssjuk Lund, Lund, Sweden; Karin Bowen and Anitra Fielding, AstraZeneca, Macclesfield, United Kingdom; an
PMID
61
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A phase II evaluation of the potent, highly selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 mutation - An NRG Oncology/Gynecologic Oncology Group study.
AU
Coleman RL, Sill MW, Bell-McGuinn K, Aghajanian C, Gray HJ, Tewari KS, Rubin SC, Rutherford TJ, Chan JK, Chen A, Swisher EM
SO
Gynecol Oncol. 2015;137(3):386. Epub 2015 Mar 24.
 
BACKGROUND: Veliparib is a potent small molecule inhibitor of PARP-1/2, which is cytotoxic in tumor cells with deficiencies in BRCA1 or BRCA2. We studied the clinical activity and toxicity of veliparib in ovarian cancer patients carrying a germline BRCA1 or BRCA2 mutation (gBRCA).
METHODS: Eligibility included three or fewer prior chemotherapy regimens, measurable disease and no prior use of a PARP inhibitor. Veliparib was administered at 400mg orally BID with one cycle being 28days. The two-stage Simon design was capable of detecting a 25% response probability with 90% power while controlling alpha=10% (at a 10% assumed null response probability).
RESULTS: The median age of the 50 eligible patients was 57years (range 37-94) and 14, 18, and 18 patients had 1,2, and 3 prior therapies respectively. Thirty patients (60%) were platinum-resistant. The median number of cycles administered was 6 (1-27). There was one grade 4 thrombocytopenia. Grade 3 adverse events were: fatigue (n=3), nausea (2), leukopenia (1), neutropenia (1), dehydration (1), and ALT (1). Grade 2 events>10% were: nausea (46%), fatigue (26%), vomiting (18%), and anemia (14%). The proportion responding was 26% (90% CI: 16%-38%, CR: 2, PR: 11); for platinum-resistant and platinum-sensitive patients the proportion responding was 20% and 35%, respectively. The most common reason for treatment discontinuation was progression (62%). Twenty-nine patients are alive; two with SD remain on veliparib. The median PFS is 8.18months.
CONCLUSIONS: The single agent efficacy and tolerability of veliparib for BRCA mutation-associated recurrent ovarian cancer warrants further investigation.
AD
Dept. of Gynecologic Oncology&Reproductive Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rcoleman@mdanderson.org.
PMID