The New England journal of medicine 2018-12-27
Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer.
Abstract
Background
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.
Methods
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.
Results
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.
Conclusions
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 .).
Related Questions
For a BRCA1+ patient with a history of stage IVB endometrioid ovarian carcinoma s/p upfront surgery and adjuvant chemotherapy who has now completed 3 years of maintenance niraparib and is NED, how would you counsel about discontinuing vs continuing PARPi therapy?
Recommendation: I recommend that this patient with Stage IVB ovarian cancer, with a complete response to surgery, chemotherapy, and 3 years of maintenance PARPi, be counseled to discontinue niraparib.Background:The duration of therapy for primary maintenance PARPi should be tailored based on the ass...
How long would you continue second line maintenance PARP inhibitor in a patient with recurrent stage IV BRCA+ ovarian cancer who had CR and remains NED?
For patients with platinum-sensitive relapsed ovarian cancer with a partial or complete response to platinum-based chemotherapy, niraparib, olaparib, and rucaparib are approved by the FDA for maintenance therapy. While PFS outcomes are improved with these agents regardless of BRCA mutation status, t...
What factors impact your decision to include bevacizumab with primary chemotherapy for patients with BRCA+ or HRD+ ovarian cancer?
The decision for bev isn’t based on HRD or BRCA biomarkers – it is based on clinical factors and provider preference. Bev is approved for all epithelial ovarian cancer, advanced stage with and to follow platinum based chemotherapy based on a clinically and statistically significant improvement in PF...
How do you advise patients on duration of first line maintenance PARPi and the potential risk of MDS or AML?
For patients, who could derive significant survival benefit from first line maintenance PARP-inhibition (BRCA+ and HRD tumors), we advise them to take PARP-inhibitors up to 2 years (olaparib) or up to 3 years (niraparib) if no disease progression or unacceptable toxicity. I counsel patients that dev...
What is your current practice for obtaining mutation status for a patient with newly diagnosed ovarian cancer?
My current practice is to test all newly diagnosed epithelial ovarian cancer patients (includes fallopian tube and peritoneal) with both germline multigene and somatic multigene/NGS panels. Only recently have I adopted the practice of concurrent testing at diagnosis rather than basing the decision t...
How are you counseling HR-proficient ovarian cancer patients about front line PARP inhibitor maintenance?
I think this is a tough decision, but I recommend observation for patients with HR proficient disease. In brief, I don't find a PFS advantage, without a proven OS advantage, enough to justify this long-term, expensive, and not non-toxic treatment.For BRCA carriers the answer is easier—with SOLO2 (20...
Would you consider IP chemotherapy in a BRCA positive advanced ovarian cancer patient after upfront ovarian debulking surgery to no gross residual?
There are at least two literature sources (Naumann et al 2018 Gynecol Oncol most recently) suggesting improved survival in patients with BRCA mutations undergoing IP therapy, consistent with observations that mutated patients are more platinum sensitive. Dose intensification of platinum should there...
Do you recommend frontline bevacizumab with carbo/taxol in patients with advanced epithelial ovarian and BRCA mutation who will be receiving olaparib maintenance?
As shown in GOG-218, there is no apparent benefit to using concurrent bevacizumab with paclitaxel and carboplatin in the first-line setting, if this drug is not then continued during maintenance therapy. Our approach is to obtain genetic testing in patients with epithelial ovarian cancer as soon as ...
Should olaparib maintenance therapy be recommended in patients with BRCA-positive, advanced ovarian cancer after first line platinum-based chemotherapy?
While the results of the SOLO-1 trial are initially impressive, we need to wait for the survival data and the results of the other 2 European trials (Paola-1 and ENGOT). Definitively a field of research to keep an eye on. Today, probably premature. On a case by case basis, might be acceptable, but n...