scholarly journals ATHENA (GOG-3020/ENGOT-ov45): a randomized, phase III trial to evaluate rucaparib as monotherapy (ATHENA–MONO) and rucaparib in combination with nivolumab (ATHENA–COMBO) as maintenance treatment following frontline platinum-based chemotherapy in ovarian cancer

2021 ◽  
pp. ijgc-2021-002933
Author(s):  
Bradley J Monk ◽  
Robert L Coleman ◽  
Keiichi Fujiwara ◽  
Michelle K Wilson ◽  
Amit M Oza ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Treatment ◽  
Standard Treatment ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Platinum Based Chemotherapy

BackgroundThe optimal treatment strategy for women with newly diagnosed ovarian cancer has yet to be determined. Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated substantial improvement in progression-free survival as monotherapy maintenance treatment in the frontline setting versus active surveillance. Furthermore, preclinical and early clinical studies have shown that PARP inhibitors and immune checkpoint inhibitors have synergistic antitumor activity and may provide an additional therapeutic option for patients in this population.Primary ObjectivesIn women with newly diagnosed ovarian, fallopian tube, or peritoneal cancer, we wish to assess the efficacy of frontline maintenance treatment with the PARP inhibitor rucaparib versus placebo following response to platinum-based chemotherapy (ATHENA–MONO), and to assess the combination of rucaparib plus nivolumab (a programmed death receptor 1 (PD-1)–blocking monoclonal antibody) versus rucaparib alone (ATHENA–COMBO).Study Hypothesis(1) Maintenance therapy with rucaparib monotherapy may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting. (2) The combination of nivolumab plus rucaparib may extend progression-free survival following standard treatment for ovarian cancer in the frontline setting compared with rucaparib alone.Trial DesignATHENA is an international, randomized, double-blind, phase III trial consisting of two independent comparisons (ATHENA–MONO and ATHENA–COMBO) in patients with newly diagnosed platinum-sensitive ovarian cancer. Patients are randomized 4:4:1:1 to the following: oral rucaparib+ intravenous nivolumab (arm A); oral rucaparib + intravenous placebo (arm B); oral placebo+ intravenous nivolumab (arm C); and oral placebo + intravenous placebo (arm D). The starting dose of rucaparib is 600 mg orally twice a day and nivolumab 480 mg intravenously every 4 weeks. ATHENA–MONO compares arm B with arm D to evaluate rucaparib monotherapy versus placebo, and ATHENA–COMBO evaluates arm A versus arm B to investigate the effects of rucaparib and nivolumab in combination versus rucaparib monotherapy. ATHENA–MONO and ATHENA–COMBO share a common treatment arm (arm B) but each comparison is independently powered.Major Inclusion/Exclusion CriteriaPatients ≥18 years of age with newly diagnosed advanced, high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancer who have achieved a response after completion of cytoreductive surgery and initial platinum-based chemotherapy are enrolled. No other prior treatment for ovarian cancer, other than the frontline platinum regimen, is permitted.Primary EndpointThe primary endpoint is investigator-assessed progression-free survival by Response Evaluation Criteria in Solid Tumors v1.1.Sample SizeApproximately 1000 patients have been enrolled and randomized.Estimated Dates for Completing Accrual and Presenting ResultsThe trial completed accrual in 2020. While dependent on event rates, primary results of ATHENA–MONO are anticipated in early 2022 and results of ATHENA–COMBO are anticipated to mature at a later date.Trial RegistrationThis trial is registered at clinicaltrials.gov (NCT03522246).

scholarly journals Atezolizumab, Bevacizumab, and Chemotherapy for Newly Diagnosed Stage III or IV Ovarian Cancer: Placebo-Controlled Randomized Phase III Trial (IMagyn050/GOG 3015/ENGOT-OV39)

2021 ◽  
pp. JCO.21.00306
Author(s):  
Kathleen N. Moore ◽  
Michael Bookman ◽  
Jalid Sehouli ◽  
Austin Miller ◽  
Charles Anderson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Progression Free Survival ◽  
Figo Stage ◽  
Phase Iii ◽  
Stage Iii ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Intention To Treat ◽  
To Receive

PURPOSE To evaluate the addition of the humanized monoclonal antiprogrammed death ligand-1 (PD-L1) antibody, atezolizumab, to platinum-based chemotherapy and bevacizumab in newly diagnosed stage III or IV ovarian cancer (OC). METHODS This multicenter placebo-controlled double-blind randomized phase III trial (ClinicalTrials.gov identifier: NCT03038100 ) enrolled patients with newly diagnosed untreated International Federation of Gynecology and Obstetrics (FIGO) stage III or IV OC who either had undergone primary cytoreductive surgery with macroscopic residual disease or were planned to receive neoadjuvant chemotherapy and interval surgery. Patients were stratified by FIGO stage, Eastern Cooperative Oncology Group performance status, tumor immune cell PD-L1 staining, and treatment strategy and randomly assigned 1:1 to receive 3-weekly cycles of atezolizumab 1,200 mg or placebo (day 1, cycles 1-22), with paclitaxel plus carboplatin (day 1, cycles 1-6) plus bevacizumab 15 mg/kg (day 1, cycles 2-22), omitting perioperative bevacizumab in neoadjuvant patients. The co-primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat and PD-L1–positive populations. RESULTS Between March 8, 2017, and March 26, 2019, 1,301 patients were enrolled. The median progression-free survival was 19.5 versus 18.4 months with atezolizumab versus placebo, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.07; stratified log-rank P = .28), in the intention-to-treat population and 20.8 versus 18.5 months, respectively (hazard ratio, 0.80; 95% CI, 0.65 to 0.99; P = .038), in the PD-L1–positive population. The interim (immature) overall survival results showed no significant benefit from atezolizumab. The most common grade 3 or 4 adverse events were neutropenia (21% with atezolizumab v 21% with placebo), hypertension (18% v 20%, respectively), and anemia (12% v 12%). CONCLUSION Current evidence does not support the use of immune checkpoint inhibitors in newly diagnosed OC. Insight from this trial should inform further evaluation of immunotherapy in OC.

ENGOT-ov54/Swiss-GO-2/MATAO including LOGOS (Low-Grade Ovarian cancer Sub-study): MAintenance Therapy with Aromatase inhibitor in epithelial Ovarian cancer—A randomized, double-blinded, placebo-controlled, multicenter phase III Trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5598-TPS5598
Author(s):  
Viola A. Heinzelmann-Schwarz ◽  
Christian Kurzeder ◽  
Seraina Schmid ◽  
Natalie Gabriel ◽  
Andreas Mueller ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Phase Iii ◽  
Low Grade ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Double Blinded

TPS5598 Background: The prognosis of advanced epithelial ovarian cancer (OC) is poor with a relapse rate of 75% at 5 years. Some 80% of OC express estrogen receptor (ER). This is the first trial that wants to capitalize on this and prospectively evaluates letrozole, a potent aromatase inhibitor, as initial maintenance treatment for high and low grade OC. Methods: Eligible pts have primary OC, FIGO Stage II-IV with low or high grade serous or endometrioid histology, with (interval) debulking surgery, ECOG-status 0-2, Positivity (≥ 1%) for ER expression, and at least 4 cycles of platinum-based chemotherapy (neoadjuvant allowed). Pts are allowed to undergo concurrent maintenance treatment with bevacizumab and PARP inhibitors. Extensive quality of life (QoL) questionnaires via an App and physical activity measurements by a tracking device as well as G8 geriatric score, ESGO surgery questionnaire, and Charleson Comorbidity Index are routinely assessed. Primary objective is to evaluate the efficacy of letrozole maintenance therapy after standard surgical and chemotherapy treatment as measured by Progression Free Survival (PFS) compared to no maintenance therapy (placebo). Primary outcome is PFS, defined as time from date of first letrozole/placebo administration until date of progression or death by any cause. Stratification for high and low grade histologies and ER measurement is performed via a digital centralized pathology review process. Final analysis will be performed for the whole cohort and for the subgroup of low grade ovarian cancers (LOGOS subprotocol). Secondary objectives and outcomes are overall survival (OS), quality adjusted progression free survival (QAPFS), time to first subsequent treatment (TFST), quality adjusted time without symptoms (TWiST), and health related QoL. Study is designed as international, randomized (1:1 ratio), two-arm, multi-centric, double-blinded, placebo-controlled superiority phase III trial. In total, 528 pts will be randomly assigned to letrozole or placebo for 5 yrs or until unacceptable toxicity, progression of underlying disease, or study discontinuation. Final analysis is planned after 5 years without interval analysis and follow-up is collected for up to 10yr and for the low-grade cohort for up to 12yr. Clinical trial information: NCT04111978.

A randomized, double-blind phase III trial of niraparib maintenance treatment in patients with HRD+ advanced ovarian cancer after response to front-line platinum-based chemotherapy.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. TPS5606-TPS5606 ◽  
Author(s):  
Antonio Gonzalez-Martin ◽  
Floor Jennishens Backes ◽  
Klaus H. Baumann ◽  
Dana Meredith Chase ◽  
Mathias Konrad Fehr ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Treatment ◽  
Advanced Ovarian Cancer ◽  
Phase Iii ◽  
Front Line ◽  
Double Blind ◽  
Phase Iii Trial ◽  
Platinum Based Chemotherapy

Benefit in progression-free survival (PFS) to expect based on CA125 reduction at week 6 in recurrent ovarian cancer (ROC) patients: CALYPSO phase III trial data (a GINECO-GCIG study).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5547-5547 ◽  
Author(s):  
Melanie Wilbaux ◽  
Emilie Henin ◽  
Olivier Colomban ◽  
Amit M. Oza ◽  
Eric Pujade-Lauraine ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Progression Free Survival ◽  
Predictive Performance ◽  
Recurrent Ovarian Cancer ◽  
Phase Iii ◽  
Validation Dataset ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Parametric Survival Model ◽  
Parametric Survival

5547 Background: Prediction of the expected survival benefit based on CA125 change in treated recurrent ovarian cancer (ROC) patients would be very useful. It may help for early selection of the best drug candidates during drug development, and for clinical trials. We used mathematical modeling to: 1) quantify the links between CA125 kinetics and progression-free survival (PFS) benefit, and 2) to estimate the CA125 decline required to observe a 50% PFS improvement. Methods: CALYPSO randomized phase III trial database, comparing 2 platinum-based regimens in ROC patients was used. The cohort was randomly split into a “learning dataset” (N=356) to estimate model parameters and a “validation dataset” (N=178) to validate model performances. A full parametric survival model was developed to quantify the links between tumor size changes; CA125 kinetics; prognostic factors and PFS. The predictive performance of the model was evaluated with simulations on the validation dataset. Results: PFS from 534 ROC patients was properly described by a parametric model with log-logistic distribution. The factors significantly linked to PFS were fractional changes in CA125 (ΔCA125) and in tumor size (ΔTS) from baseline at week 6; baseline CA125 (CA125BL); and patient therapy free interval. By reducing this model, ΔCA125 was a better predictor of PFS than ΔTS. Simulations verified the predictive performance of this model. Patients should achieve at least 49% ΔCA125 decline induced by treatment to observe 50% PFS improvement. This effect was independent on treatment arm. Conclusions: This is the first drug-independent parametric survival model quantifying links between PFS and CA125 kinetics in ROC. The CA125 modeled decline required to observe a 50% improvement in PFS in treated ROC patients was defined. It may be a surrogate marker of PFS gain, and may embody an early predictive tool for go/no go drug development decisions and for clinical trials. Validation in other datasets is warranted.

Efficacy of maintenance olaparib for newly diagnosed, advanced ovarian cancer patients (pts) by BRCA1 or BRCA2 mutation in the phase III SOLO1 trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5551-5551
Author(s):  
Michael Friedlander ◽  
Kathleen N. Moore ◽  
Nicoletta Colombo ◽  
Giovanni Scambia ◽  
Byoung-Gie Kim ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Statistical Tests ◽  
Brca2 Mutation ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Primary Data ◽  
Newly Diagnosed ◽  
Brca1 And Brca2 ◽  
Platinum Based Chemotherapy

5551 Background: In SOLO1 (NCT01844986), maintenance olaparib resulted in a significant improvement in progression-free survival (PFS) for newly diagnosed, BRCA1- and/or BRCA2-mutated, advanced ovarian cancer pts compared with placebo (HR 0.30, 95% CI 0.23–0.41; median not reached vs 13.8 months; Moore et al. N Engl J Med 2018). We investigated PFS in SOLO1 for the subgroups of pts with BRCA1 mutations ( BRCA1m) or BRCA2 mutations ( BRCA2m). Methods: All pts were in clinical complete or partial response to platinum-based chemotherapy and were randomized to maintenance olaparib (300 mg twice daily; tablets) or placebo. After 2 years, pts with no evidence of disease discontinued study treatment, but pts with evidence of disease could continue study treatment. PFS by BRCAm was a predefined analysis. BRCAm were identified by central germline (Myriad or BGI) or local testing; Foundation Medicine testing confirmed tumor BRCAm. Results: Median follow-up for PFS was ~41 months in the olaparib and placebo arms. Of 391 randomized pts, 282 had BRCA1m (72%), 106 had BRCA2m (27%) and three (1%) had both (Table). Two pts in the olaparib arm had somatic BRCAm (one BRCA1m, one BRCA2m); all others had germline BRCAm. At the primary data cut-off, 155 pts in the BRCA1-mutated group (55%), 43 in the BRCA2-mutated group (41%) and none in the BRCA1/2 -mutated group had disease progression. The percentage of BRCA1-mutated pts who received olaparib and were progression-free at 1, 2 and 3 years was 86%, 69% and 53% (vs 52%, 36% and 26% receiving placebo) and for BRCA2-mutated pts was 92%, 85% and 80% (vs 50%, 32% and 29%, respectively). Conclusions: Significant PFS benefit with olaparib versus placebo was demonstrated for all pts, regardless of whether they had BRCA1m or BRCA2m. Statistical tests were not used to compare BRCA1- and BRCA2-mutated pts, but those with BRCA2m appeared to receive greater benefit from maintenance olaparib than those with BRCA1m. Clinical trial information: NCT01844986. [Table: see text]

scholarly journals The role of subgroup analyses: results from the NOVA trial

2017 ◽  
Vol 5 (1) ◽  
pp. 40-42
Author(s):  
Massimo Di Maio ◽  
Alice Bergamini
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Wild Type ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Subgroup Analyses

The clinical efficacy of poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors in BRCA-mutated ovarian cancer patients has been widely reported. However, novel challenges are currently aimed at broadening the benefit of PARP inhibitors to patients with wild-type BRCA and homologous recombination deficiency (HRD) and identifying a test able to select those patients who might benefit most from this therapy. The recently published ENGOT-OV16/NOVA trial reported an advantage in progression-free survival (PFS) for patients receiving the PARP1/2 inhibitor niraparib, as maintenance treatment for platinum-sensitive ovarian cancer compared to placebo, regardless of their germline BRCA or HRD status. This suggests that niraparib could potentially represent a valuable maintenance option for virtually all patients with platinum-sensitive relapsed ovarian cancer and that the HRD assay used in this trial is not able to reliably identify those patients who benefit the most from niraparib maintenance. These provocative considerations are the result of subgroup analyses that should be interpreted with caution but are useful to show the consistency of the effect of niraparib across the whole population.

Real-world progression-free survival among patients with newly diagnosed advanced ovarian cancer: Does maintenance therapy work?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18707-e18707
Author(s):  
Jinan Liu ◽  
John Chan ◽  
Janvi Sah ◽  
Eric M. Maiese ◽  
Oscar Bee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Real World ◽  
Maintenance Treatment ◽  
Index Date ◽  
Progression Free Survival ◽  
Tumor Biomarker ◽  
Newly Diagnosed ◽  
Debulking Surgery ◽  
Free Survival

e18707 Background: Options for first-line (1L) maintenance therapy in ovarian cancer (OC) have evolved in the US in recent years, particularly with FDA approvals of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi). Olaparib was approved in 2018 for 1L maintenance treatment of patients (pts) with advanced OC with BRCA mutation and in 2020 as combination therapy with bevacizumab for 1L maintenance treatment of pts with homologous recombination deficient (HRd)–positive tumors. Additionally, the FDA approved niraparib in 2020 for maintenance treatment of pts with advanced OC regardless of tumor biomarker status. This study aimed to describe use and outcomes of 1L maintenance vs. active surveillance (AS) among PARPi-eligible pts with OC in a real-world setting prior to the most recent 2020 FDA approvals. Methods: This retrospective cohort study included pts with newly diagnosed stage III/IV OC who received 6–9 cycles of 1L platinum-based chemotherapy (PBC) and either primary debulking surgery or interval debulking surgery following neoadjuvant chemotherapy between January 1, 2016, and February 29, 2020, regardless of biomarker status, from the Flatiron Health database, a longitudinal electronic health record-derived database consisting of de-identified patient-level data that are curated via technology-enabled abstraction. The end of the last cycle of 1L PBC was defined as the index date. Pts who started second-line (2L) treatment within 2 months of the index date were excluded. Primary endpoint was time to initiation of 2L systemic therapy (as a surrogate for progression) or death. Inverse probability of treatment weighting and Cox proportional hazard model were used to adjust for baseline differences among pts on maintenance therapy and pts on AS. Results: A total of 463 pts were included in the study, 87.7% from community practices and 12.3% from academic institutions. Of the pts included, 21.0% received maintenance therapy, while 79.0% did not. Of those who received maintenance therapy, 48.5% received bevacizumab, 40.2% received PARPi (olaparib, rucaparib), and 11.3% received paclitaxel. Median progression-free survival (PFS) for pts who received 1L maintenance therapy was 16.1 months, compared with 12.2 months in pts who did not receive 1L maintenance therapy. After adjusting for baseline differences in characteristics and demographics, including age, race, stage of cancer, and BRCA status, pts on maintenance therapy had a statistically significant, 29% lower risk of progression or death than those receiving AS (hazard ratio: 0.71; 95% CI, 0.52–0.99; P= 0.04). Conclusions: In this real-world analysis, the majority of pts did not receive maintenance therapy; however, a PFS benefit was found in those receiving maintenance therapy. Further studies are needed to understand how biomarker status drives practice patterns.

Phase III Study of the Value of Thalidomide Added to Melphalan Plus Prednisone in Elderly Patients With Newly Diagnosed Multiple Myeloma: The HOVON 49 Study

2010 ◽  
Vol 28 (19) ◽  
pp. 3160-3166 ◽  
Author(s):  
Pierre Wijermans ◽  
Martijn Schaafsma ◽  
Fabian Termorshuizen ◽  
Rianne Ammerlaan ◽  
Shulamiet Wittebol ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Elderly Patients ◽  
Response Rate ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Intent To Treat

Purpose For several decades, the treatment of elderly patients with multiple myeloma (MM) has consisted of melphalan and prednisone (MP). The Dutch-Belgium Hemato-Oncology Cooperative Group (HOVON) investigated the efficacy of thalidomide added to MP (MP-T) in a randomized phase III trial. The objective of this study was to investigate the efficacy, toxicity, and effects on quality of life of MP-T. Patients and Methods A randomized phase III trial compared standard MP with MP-T (thalidomide 200 mg/d) in newly diagnosed patients with multiple myeloma older than age 65 years. Maintenance therapy with thalidomide 50 mg/d was administered to patients after MP-T until relapse. The primary end point was event-free survival (EFS); response rate, overall survival (OS), and progression-free survival (PFS) were secondary end points. Results An intent-to-treat analysis of 333 evaluable patients showed significantly higher response rates in MP-T–treated patients compared with MP-treated patients a response (≥ partial response: 66% v 45%, respectively; P < .001; and ≥ very good partial response [VGPR]: 27% v 10%, respectively; P < .001). EFS was 13 months with MP-T versus 9 months with MP (P < .001). OS was 40 months with MP-T versus 31 months with MP (P = .05). Conclusion This study demonstrates that thalidomide improves the response rate and VGPR in elderly patients with newly diagnosed MM. MP-T also results in a better EFS, PFS, and OS.

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