Dataset Information

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial.

ABSTRACT:

Objectives

In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1.

Methods

Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130).

Results

Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was <3 months in olaparib-treated patients. The first event of anemia, neutropenia, thrombocytopenia, nausea and vomiting lasted a median of <2 months and the first event of fatigue/asthenia lasted a median of 3.48 months in the olaparib group. These adverse events were manageable with supportive treatment and/or olaparib dose modification in most patients, with few patients requiring discontinuation of olaparib. Of 162 patients still receiving olaparib at month 24, 64.2% were receiving the recommended starting dose of olaparib 300 mg twice daily.

Conclusions

Maintenance olaparib had a predictable and manageable adverse event profile in the newly diagnosed setting with no new safety signals identified. Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients.

SUBMITTER: Colombo N

PROVIDER: S-EPMC9555119 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Publications

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial.

Colombo Nicoletta N Moore Kathleen K Scambia Giovanni G Oaknin Ana A Friedlander Michael M Lisyanskaya Alla A Floquet Anne A Leary Alexandra A Sonke Gabe S GS Gourley Charlie C Banerjee Susana S Oza Amit A González-Martín Antonio A Aghajanian Carol C Bradley William H WH Kim Jae-Weon JW Mathews Cara C Liu Joyce J Lowe Elizabeth S ES Bloomfield Ralph R DiSilvestro Paul P

Gynecologic oncology 20210802 1

<h4>Objectives</h4>In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1.<h4>Methods</h4>Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or place ...[more]

PMID: 34353615

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Project description:ImportanceTesting for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing.ObjectiveTo investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile.Design, setting, and participantsThis cohort study was a secondary analysis of the PAOLA-1 randomized clinical trial that compared olaparib plus bevacizumab with placebo plus bevacizumab as maintenance treatment in patients with advanced high-grade ovarian cancer after a good response to first-line platinum with taxane chemotherapy plus bevacizumab, irrespective of germline or tumor BRCA1/2 mutation status. All patients with available tumor DNA were included in the analysis. The current analysis tested for an interaction between BRCA-like status and olaparib treatment on survival outcomes. The original trial was conducted between July 2015 and September 2017; at the time of data extraction for analysis in March 2022, a median follow-up of 54.1 months (IQR, 28.5-62.2 months) and a total follow-up time of 21 711 months was available, with 336 PFS and 245 OS events.ExposuresTumor homologous recombination deficiency was assessed using the BRCA-like copy number aberration profile classifier. Myriad MyChoice CDx was previously measured. The trial was randomized between the olaparib and bevacizumab and placebo plus bevacizumab groups.Main outcomes and measuresThis secondary analysis assessed hazard ratios (HRs) of olaparib vs placebo among biomarker strata and tested for interaction between BRCA-like status and olaparib treatment on PFS and OS, using Cox proportional hazards regression.ResultsA total of 469 patients (median age, 60 [range 26-80] years) were included in this study. The patient cohort consisted of women with International Federation of Gynaecology and Obstetrics stage III (76%) high-grade serous (95%) ovarian cancer who had no evaluable disease or complete remission at initial or interval debulking surgery (76%). Thirty-one percent of the tumor samples (n = 138) harbored a pathogenic BRCA mutation, and BRCA-like classification was performed for 442 patients. Patients with a BRCA-like tumor had a longer PFS after olaparib treatment than after placebo (36.4 vs 18.6 months; HR, 0.49; 95% CI, 0.37-0.65; P < .001). No association of olaparib with PFS was found in patients with a non-BRCA-like tumor (17.6 vs 16.6 months; HR, 1.02; 95% CI, 0.68-1.51; P = .93). The interaction was significant (P = .004), and HRs and P values (for interaction) were similar in the relevant subgroups, OS, and multivariable analyses.Conclusions and relevanceIn this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.

Project description:ObjectiveIn the PAOLA-1/ENGOT-ov25 trial (NCT02477644), adding maintenance olaparib to bevacizumab provided a substantial progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and homologous recombination deficiency (HRD)-positive tumors, irrespective of clinical risk. Subsequently, a clinically meaningful improvement in overall survival was reported with olaparib plus bevacizumab in the HRD-positive subgroup. We report updated progression-free survival and overall survival by clinical risk and HRD status.MethodsPatients in clinical response after first-line platinum-based chemotherapy plus bevacizumab received maintenance olaparib (up to 24 months) plus bevacizumab (up to 15 months in total) or placebo plus bevacizumab. This post hoc analysis evaluated 5-year progression-free survival and mature overall survival in patients classified by clinical risk and HRD status.ResultsOf 806 randomized patients, 74% were higher-risk and 26% were lower-risk. In higher-risk HRD-positive patients, the hazard ratio (HR) for progression-free survival was 0.46 (95% confidence interval (95% CI) 0.34 to 0.61), with 5-year progression-free survival of 35% with olaparib plus bevacizumab versus 15% with bevacizumab alone; and the HR for overall survival was 0.70 (95% CI 0.50 to 1.00), with 5-year overall survival of 55% versus 42%, respectively. In lower-risk HRD-positive patients, the HR for progression-free survival was 0.26 (95% CI 0.15 to 0.45), with 5-year progression-free survival of 72% with olaparib plus bevacizumab versus 28% with bevacizumab alone; and the HR for overall survival was 0.31 (95% CI 0.14 to 0.66), with 5-year overall survival of 88% versus 61%, respectively. No benefit was seen in HRD-negative patients regardless of clinical risk.ConclusionThis post hoc analysis indicates that in patients with newly diagnosed advanced HRD-positive ovarian cancer, maintenance olaparib plus bevacizumab should not be limited to those considered at higher risk of disease progression. Five-year progression-free survival rates support long-term remission and suggest an increased potential for cure with particular benefit suggested in lower-risk HRD-positive patients.

Project description:The incidence and mortality rates of ovarian cancer are increasing globally. Ovarian cancer is diagnosed at an advanced stage in 80% of women. After standard, platinum-based, front-line chemotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors and antiangiogenic agents are successfully employed as maintenance strategies for newly diagnosed, advanced ovarian cancer patients. Landmark clinical studies, including SOLO-1, PAOLA-1, PRIMA, and VELIA, have provided crucial insights on optimizing first-line maintenance treatment using PARP inhibitors. A group of ovarian cancer experts, primarily from low- and middle-income countries, met in September 2019 to discuss new developments for the first-line treatment of ovarian cancer and its implications. Key implications of the evolving clinical data included: (1) olaparib or niraparib maintenance therapy appears to be the preferred choice for patients with BRCA1/2 mutations; hence, BRCA testing is beneficial in identifying these patients; (2) niraparib monotherapy and olaparib in combination with bevacizumab have demonstrated significant benefit in progression-free survival (PFS) in homologous recombination deficiency (HRD)-positive patients; (3) bevacizumab, niraparib alone, or observation can be an alternative for HRD-negative patients; (4) further data is warranted to explore the role of PARP inhibitors in treating HRD-negative, ovarian cancer patients to confirm findings of the exploratory analysis of PRIMA; (5) PARP inhibitors may be beneficial for stage IV ovarian cancer patients with inoperable disease and patients with prior neoadjuvant chemotherapy; and (6) there is an urgent need to increase awareness in both clinicians and patients on BRCA and HRD testing for optimizing treatment decision-making and improving clinical outcomes in newly diagnosed, advanced ovarian cancer patients. In clinical medicine, the limited availability of family history (FH) information and the complexity of FH criteria has hampered the implementation of BRCA testing. Moreover, many cancer patients with BRCA mutations are not tested because they do not meet the criteria for FH. Consequently, BRCA testing in many high income countries, including the US and Australia, is underused and used inappropriately, which has resulted in the loss of valuable opportunities for better cancer management and cancer prevention.

Dataset Information

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial.

Objectives

Methods

Results

Conclusions

Publications

Tolerability of maintenance olaparib in newly diagnosed patients with advanced ovarian cancer and a BRCA mutation in the randomized phase III SOLO1 trial.

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