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 .).
Summary Background The poly(ADP-ribose) polymerase inhibitor olaparib has shown antitumour activity in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer with or without ...BRCA1 or BRCA2 mutations. The aim of this study was to assess the efficacy and tolerability of olaparib in combination with chemotherapy, followed by olaparib maintenance monotherapy, versus chemotherapy alone in patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer. Methods In this randomised, open-label, phase 2 study, adult patients with platinum-sensitive, recurrent, high-grade serous ovarian cancer who had received up to three previous courses of platinum-based chemotherapy and who were progression free for at least 6 months before randomisation received either olaparib (200 mg capsules twice daily, administered orally on days 1–10 of each 21-day cycle) plus paclitaxel (175 mg/m2 , administered intravenously on day 1) and carboplatin (area under the curve AUC 4 mg/mL per min, according to the Calvert formula, administered intravenously on day 1), then olaparib monotherapy (400 mg capsules twice daily, given continuously) until progression (the olaparib plus chemotherapy group), or paclitaxel (175 mg/m2 on day 1) and carboplatin (AUC 6 mg/mL per min on day 1) then no further treatment (the chemotherapy alone group). Randomisation was done by an interactive voice response system, stratified by number of previous platinum-containing regimens received and time to disease progression after the previous platinum regimen. The primary endpoint was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1, analysed by intention to treat. Prespecified exploratory analyses included efficacy by BRCA mutation status, assessed retrospectively. This study is registered with ClinicalTrials.gov , number NCT01081951 , and has been completed. Findings Between Feb 12 and July 30, 2010, 173 patients at 43 investigational sites in 12 countries were enrolled into the study, of whom 162 were eligible and were randomly assigned to the two treatment groups (81 to the olaparib plus chemotherapy group and 81 to the chemotherapy alone group). Of these randomised patients, 156 were treated in the combination phase (81 in the olaparib plus chemotherapy group and 75 in the chemotherapy alone group) and 121 continued to the maintenance or no further treatment phase (66 in the olaparib plus chemotherapy group and 55 in the chemotherapy alone group). BRCA mutation status was known for 107 patients (either at baseline or determined retrospectively): 41 (38%) of 107 had a BRCA mutation (20 in the olaparib plus chemotherapy group and 21 in the chemotherapy alone group). Progression-free survival was significantly longer in the olaparib plus chemotherapy group (median 12·2 months 95% CI 9·7–15·0) than in the chemotherapy alone group (median 9·6 months 95% CI 9·1–9·7) (HR 0·51 95% CI 0·34–0·77; p=0·0012), especially in patients with BRCA mutations (HR 0·21 0·08–0·55; p=0·0015). In the combination phase, adverse events that were reported at least 10% more frequently with olaparib plus chemotherapy than with chemotherapy alone were alopecia (60 74% of 81 vs 44 59% of 75), nausea (56 69% vs 43 57%), neutropenia (40 49% vs 29 39%), diarrhoea (34 42% vs 20 27%), headache (27 33% vs seven 9%), peripheral neuropathy (25 31% vs 14 19%), and dyspepsia (21 26% vs 9 12%); most were of mild-to-moderate intensity. The most common grade 3 or higher adverse events during the combination phase were neutropenia (in 35 43% of 81 patients in the olaparib plus chemotherapy group vs 26 35% of 75 in the chemotherapy alone group) and anaemia (seven 9% vs five 7%). Serious adverse events were reported in 12 (15%) of 81 patients in the olaparib plus chemotherapy group and 16 of 75 (21%) patients in the chemotherapy alone group. Interpretation Olaparib plus paclitaxel and carboplatin followed by maintenance monotherapy significantly improved progression-free survival versus paclitaxel plus carboplatin alone, with the greatest clinical benefit in BRCA -mutated patients, and had an acceptable and manageable tolerability profile. Funding AstraZeneca.
There is a high unmet need for treatment regimens that increase the chance of long-term remission and possibly cure for women with newly diagnosed advanced ovarian cancer. In the primary analysis of ...SOLO1/GOG 3004, the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib significantly improved progression-free survival versus placebo in patients with a BRCA mutation; median progression-free survival was not reached. Here, we report an updated, post-hoc analysis of progression-free survival from SOLO1, after 5 years of follow-up.
SOLO1 was a randomised, double-blind, placebo-controlled, phase 3 trial, done across 118 centres in 15 countries, that enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0–1 and with BRCA-mutated, newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer with a complete or partial clinical response after platinum-based chemotherapy. Patients were randomly assigned (2:1) via a web-based or interactive voice-response system to receive olaparib (300 mg twice daily) or placebo tablets orally as maintenance monotherapy for up to 2 years; randomisation was by blocks and was stratified according to clinical response after platinum-based chemotherapy. Patients, treatment providers, and data assessors were masked to group assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy is reported in the intention-to-treat population and safety in patients who received at least one dose of treatment. The data cutoff for this updated, post-hoc analysis was March 5, 2020. This trial is registered with ClinicalTrials.gov (NCT01844986) and is ongoing but closed to new participants.
Between Sept 3, 2013, and March 6, 2015, 260 patients were randomly assigned to olaparib and 131 to placebo. The median treatment duration was 24·6 months (IQR 11·2–24·9) in the olaparib group and 13·9 months (8·0–24·8) in the placebo group; median follow-up was 4·8 years (2·8–5·3) in the olaparib group and 5·0 years (2·6–5·3) in the placebo group. In this post-hoc analysis, median progression-free survival was 56·0 months (95% CI 41·9–not reached) with olaparib versus 13·8 months (11·1–18·2) with placebo (hazard ratio 0·33 95% CI 0·25–0·43). The most common grade 3–4 adverse events were anaemia (57 22% of 260 patients receiving olaparib vs two 2% of 130 receiving placebo) and neutropenia (22 8% vs six 5%), and serious adverse events occurred in 55 (21%) of 260 patients in the olaparib group and 17 (13%) of 130 in the placebo group. No treatment-related adverse events that occurred during study treatment or up to 30 days after discontinuation were reported as leading to death. No additional cases of myelodysplastic syndrome or acute myeloid leukaemia were reported since the primary data cutoff, including after the 30-day safety follow-up period.
For patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, after, to our knowledge, the longest follow-up for any randomised controlled trial of a PARP inhibitor in this setting, the benefit derived from 2 years' maintenance therapy with olaparib was sustained beyond the end of treatment, extending median progression-free survival past 4·5 years. These results support the use of maintenance olaparib as a standard of care in this setting.
AstraZeneca; Merck Sharpe & Dohme, a subsidiary of Merck & Co, Kenilworth, NJ, USA.
We evaluated the effectiveness of a low-intensity, home-based physical activity program (Onco-Move) and a moderate- to high-intensity, combined supervised resistance and aerobic exercise program ...(OnTrack) versus usual care (UC) in maintaining or enhancing physical fitness, minimizing fatigue, enhancing health-related quality of life, and optimizing chemotherapy completion rates in patients undergoing adjuvant chemotherapy for breast cancer.
We randomly assigned patients who were scheduled to undergo adjuvant chemotherapy (N = 230) to Onco-Move, OnTrack, or UC. Performance-based and self-reported outcomes were assessed before random assignment, at the end of chemotherapy, and at the 6-month follow-up. We used generalized estimating equations to compare the groups over time.
Onco-Move and OnTrack resulted in less decline in cardiorespiratory fitness (P < .001), better physical functioning (P ≤ .001), less nausea and vomiting (P = .029 and .031, respectively) and less pain (P = .003 and .011, respectively) compared with UC. OnTrack also resulted in better outcomes for muscle strength (P = .002) and physical fatigue (P < .001). At the 6-month follow-up, most outcomes returned to baseline levels for all three groups. A smaller percentage of participants in OnTrack required chemotherapy dose adjustments than those in the UC or Onco-Move groups (P = .002). Both intervention groups returned earlier (P = .012), as well as for more hours per week (P = .014), to work than the control group.
A supervised, moderate- to high-intensity, combined resistance and aerobic exercise program is most effective for patients with breast cancer undergoing adjuvant chemotherapy. A home-based, low-intensity physical activity program represents a viable alternative for women who are unable or unwilling to follow the higher intensity program.
In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in ...patients with newly diagnosed advanced ovarian cancer and a
and/or
(BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting.
This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up.
The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76;
= .0004
< .0001 required to declare statistical significance). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups.
Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.
In an earlier analysis of this phase 3 trial, ribociclib plus fulvestrant showed a greater benefit with regard to progression-free survival than fulvestrant alone in postmenopausal patients with ...hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Here we report the results of a protocol-specified second interim analysis of overall survival.
Patients were randomly assigned in a 2:1 ratio to receive either ribociclib or placebo in addition to fulvestrant as first-line or second-line treatment. Survival was evaluated by means of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
This analysis was based on 275 deaths: 167 among 484 patients (34.5%) receiving ribociclib and 108 among 242 (44.6%) receiving placebo. Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant. The estimated overall survival at 42 months was 57.8% (95% confidence interval CI, 52.0 to 63.2) in the ribociclib group and 45.9% (95% CI, 36.9 to 54.5) in the placebo group, for a 28% difference in the relative risk of death (hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.00455). The benefit was consistent across most subgroups. In a descriptive update, median progression-free survival among patients receiving first-line treatment was 33.6 months (95% CI, 27.1 to 41.3) in the ribociclib group and 19.2 months (95% CI, 14.9 to 23.6) in the placebo group. No new safety signals were observed.
Ribociclib plus fulvestrant showed a significant overall survival benefit over placebo plus fulvestrant in patients with hormone-receptor-positive, HER2-negative advanced breast cancer. (Funded by Novartis; MONALEESA-3 ClinicalTrials.gov number, NCT02422615.).
In a previous analysis of this phase 3 trial, first-line ribociclib plus letrozole resulted in significantly longer progression-free survival than letrozole alone among postmenopausal patients with ...hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether overall survival would also be longer with ribociclib was not known.
Here we report the results of the protocol-specified final analysis of overall survival, a key secondary end point. Patients were randomly assigned in a 1:1 ratio to receive either ribociclib or placebo in combination with letrozole. Overall survival was assessed with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods after 400 deaths had occurred. A hierarchical testing strategy was used for the analysis of progression-free survival and overall survival to ensure the validity of the findings.
After a median follow-up of 6.6 years, 181 deaths had occurred among 334 patients (54.2%) in the ribociclib group and 219 among 334 (65.6%) in the placebo group. Ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole. Median overall survival was 63.9 months (95% confidence interval CI, 52.4 to 71.0) with ribociclib plus letrozole and 51.4 months (95% CI, 47.2 to 59.7) with placebo plus letrozole (hazard ratio for death, 0.76; 95% CI, 0.63 to 0.93; two-sided P = 0.008). No new safety signals were observed.
First-line therapy with ribociclib plus letrozole showed a significant overall survival benefit as compared with placebo plus letrozole in patients with HR-positive, HER2-negative advanced breast cancer. Median overall survival was more than 12 months longer with ribociclib than with placebo. (Funded by Novartis; MONALEESA-2 ClinicalTrials.gov number, NCT01958021.).
Summary Background The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding ...DPD ( DPYD ), including DPYD *2A and c.2846A>T. Three other variants— DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A—have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. Methods We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). Findings 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08–9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29–1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86–2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40–23·33, p=0·015; and 2·04, 1·49–2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03–31·48, p=0·00014; and 2·07, 1·17–3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD *2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75–4·62, p<0·0001; and 3·02, 2·22–4·10, p<0·0001, respectively). Interpretation DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD *2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. Funding None.
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