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December 27, 2018 N Engl J Med 2018; 379:2495-2505
DOI: 10.1056/NEJMoa1810858 Chinese Translation 中文翻译
Most women with newly diagnosed advanced ovarian cancer have a relapse within 3 years after standard treatment with surgery and platinum-based chemotherapy. The benefit of the oral poly(adenosine diphosphate–ribose) polymerase inhibitor olaparib in relapsed disease has been well established, but the benefit of olaparib as maintenance therapy in newly diagnosed disease is uncertain.
We conducted an international, randomized, double-blind, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients with newly diagnosed advanced (International Federation of Gynecology and Obstetrics stage III or IV) high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer (or a combination thereof) with a mutation in BRCA1 , BRCA2 , or both ( BRCA1/2 ) who had a complete or partial clinical response after platinum-based chemotherapy. The patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival.
Of the 391 patients who underwent randomization, 260 were assigned to receive olaparib and 131 to receive placebo. A total of 388 patients had a centrally confirmed germline BRCA1/2 mutation, and 2 patients had a centrally confirmed somatic BRCA1/2 mutation. After a median follow-up of 41 months, the risk of disease progression or death was 70% lower with olaparib than with placebo (Kaplan–Meier estimate of the rate of freedom from disease progression and from death at 3 years, 60% vs. 27%; hazard ratio for disease progression or death, 0.30; 95% confidence interval, 0.23 to 0.41; P<0.001). Adverse events were consistent with the known toxic effects of olaparib.
The use of maintenance therapy with olaparib provided a substantial benefit with regard to progression-free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olaparib than with placebo. (Funded by AstraZeneca and Merck; SOLO1 ClinicalTrials.gov number, NCT01844986 . opens in new tab .)
Standard therapy for patients with newly diagnosed advanced ovarian cancer consists of cytoreductive surgery and platinum-based chemotherapy. 1,2 Although the majority of such patients have no evidence of disease after treatment, approximately 70% have a relapse within the subsequent 3 years. 2 Recurrent ovarian cancer is typically incurable, with most patients receiving multiple additional lines of treatment before ultimately dying from the disease.
In primary analyses of phase 3 trials, the addition of intravenous bevacizumab to carboplatin plus paclitaxel (followed by bevacizumab alone) led to prolonged progression-free survival among patients with newly diagnosed advanced ovarian cancer, with hazard ratios for disease progression or death of 0.72 (Burger et al. 3 ) and 0.81 (Perren et al. 4 ). However, there was no improvement in overall survival. 5
Poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitors, such as olaparib, trap PARP on DNA at sites of single-strand breaks, thereby preventing the repair of the single-strand breaks and generating double-strand breaks that cannot be repaired accurately in tumors that have defects in homologous recombination repair, such as tumors with a mutation in BRCA1 or BRCA2 . The use of PARP inhibitors leads to an accumulation of DNA damage and tumor-cell death. 6
Olaparib has been approved in the United States and Europe as maintenance treatment for women with platinum-sensitive relapsed ovarian cancer who have a response to their most recent platinum-based regimen, regardless of BRCA mutation status. 7,8 It has also been approved in the United States for the treatment of women with advanced ovarian cancer and a deleterious or suspected deleterious germline BRCA mutation who have been treated with three or more lines of chemotherapy, regardless of sensitivity to platinum-based therapy. 7 National Comprehensive Cancer Network guidelines state that maintenance therapy with a PARP inhibitor should be considered in patients with relapsed ovarian cancer with sensitivity to platinum-based therapy, regardless of BRCA mutation status. 1 We conducted the phase 3 SOLO1 trial to evaluate the efficacy of maintenance therapy with a PARP inhibitor (olaparib) in patients with newly diagnosed advanced ovarian cancer with a germline or somatic mutation in BRCA1 , BRCA2 , or both ( BRCA1/2 ) who had a complete or partial clinical response after platinum-based chemotherapy.
Patients were eligible if they were 18 years of age or older and had newly diagnosed, histologically confirmed advanced (International Federation of Gynecology and Obstetrics stage III or IV) high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer (or a combination thereof). Those with stage III disease had undergone an attempt at cytoreductive surgery before the start chemotherapy (up front) or after the start but before the end of chemotherapy (interval). Those with stage IV disease had undergone either biopsy or up-front or interval cytoreductive surgery. Eligible patients had a deleterious or suspected deleterious germline or somatic BRCA1/2 mutation, as determined by local or central testing, with the use of the BRACAnalysis test (Myriad) or, in China, with the use of a BRCA1/2 genetic testing assay (BGI). Germline BRCA1/2 mutation status that was determined locally was confirmed centrally at Myriad or BGI, and tumor BRCA1/2 mutation status was assessed retrospectively at Foundation Medicine. Eligible patients also had received platinum-based chemotherapy without bevacizumab and were having a complete clinical response (no evidence of disease on imaging after chemotherapy and a normal CA-125 level) or a partial clinical response (a ≥30% decrease in tumor volume from the start to the end of chemotherapy or no evidence of disease on imaging after chemotherapy but a CA-125 level above the upper limit of the normal range). Further details and a complete list of eligibility criteria are provided in the Methods section in the Supplementary Appendix , available with the full text of this article at NEJM.org. All the patients provided written informed consent.
This randomized, double-blind, placebo-controlled, phase 3 trial was conducted in 15 countries. Randomization was performed centrally with a block design, with stratification according to clinical response after platinum-based chemotherapy (complete or partial). Patients were assigned to a trial group through an interactive Web-based or voice-response system.
After completion of platinum-based chemotherapy, patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or placebo. The trial intervention was continued until investigator-assessed objective disease progression on imaging (according to modified Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1), provided that the patient was having a benefit and did not meet any discontinuation criteria. Patients who had no evidence of disease
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