A Review of Selected Presentations From the 2021 ASCO Annual Meeting
• June 4-8, 2021
Niraparib Efficacy and Safety in Patients With BRCA-Mutated Ovarian Cancer: Results From Three Phase 3 Niraparib Trials
Niraparib is an orally available poly(ADP-ribose) polymerase (PARP) inhibitor.1,2 Niraparib is approved for the maintenance treatment of adult patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer after first-line or later platinum-based chemotherapy, or after 3 or more prior chemotherapy regimens. The mutated BRCA gene is present in up to one-fourth of patients with epithelial ovarian cancers, and the outcomes of patients with BRCA-mutated tumors are superior to those of patients with tumors that harbor the wild-type BRCA gene.3,4 A retrospective analysis evaluated the efficacy and safety of niraparib in patients with BRCA-mutated ovarian cancer in data drawn from the PRIMA, NOVA, and NORA trials.5-8 All 3 trials were randomized, double-blind, placebo-controlled phase 3 studies. The PRIMA study evaluated niraparib among patients with advanced ovarian cancer that had responded to first-line platinum-based chemotherapy.5 The NOVA and NORA trials evaluated niraparib maintenance therapy among patients with recurrent, platinum-sensitive ovarian cancer.6,7 Subgroup analysis according to BRCA mutation status was prespecified for all 3 trials.
Across the 3 trials, 526 patients had BRCA-mutated ovarian cancer (Figure 1).8 The BRCA1 mutation was the most common, observed in 60.6% to 80.0% of patients across the 3 niraparib and 3 placebo arms. In all 3 trials, progression-free survival (PFS) was superior with niraparib vs placebo in patients who had BRCA-mutated disease. In the PRIMA trial, which evaluated niraparib maintenance after first-line therapy, the hazard ratios (HRs) for PFS were 0.40 (95% CI, 0.27-0.62) in patients with any BRCA mutation, 0.39 (95% CI, 0.23-0.66) for patients with the BRCA1 mutation, and 0.35 (95% CI, 0.15-0.84) for patients with the BRCA2 mutation. In the NOVA trial, which evaluated niraparib maintenance after 2 or more lines of therapy, the HRs for PFS were 0.27 (95% CI, 0.17-0.41) for patients with any germline BRCA mutation, 0.39 (95% CI, 0.23-0.66) for patients with the BRCA1 mutation, and 0.12 (95% CI, 95% CI, 0.05-0.33) for patients with the BRCA2 mutation. The NORA trial also evaluated niraparib as maintenance therapy in patients who had received at least 2 lines of therapy. The HR for PFS in patients with a germline BRCA mutation was 0.22 (95% CI, 0.12-0.39). In the combined population from all 3 niraparib treatment arms, the most common treatment-emergent adverse events (AEs) were thrombocytopenia (54.8%-66.3%), anemia (50.1%-64.3%), and neutropenia (30.2%-58.8%; Figure 2).
References
1. Gogineni V, Morand S, Staats H, et al. Current ovarian cancer maintenance strategies and promising new developments. J Cancer. 2021;12(1):38-53.
2. Zejula [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2020.
3. Huang YW. Association of BRCA1/2 mutations with ovarian cancer prognosis: an updated meta-analysis. Medicine (Baltimore). 2018;97(2):e9380.
4. Konstantinopoulos PA, Spentzos D, Karlan BY, et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol. 2010;28(22):3555-3561.
5. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 nvestigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
6. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
7. Wu XH, Zhu JQ, Yin RT, et al. Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial∗. Ann Oncol. 2021;32(4):512-521.
8. González-Martin A, Matulonis U, Korach J, et al. Niraparib efficacy and safety in patients with BRCA-mutated ovarian cancer: results from three phase 3 niraparib trials [ASCO abstract 5518]. J Clin Oncol. 2021;39(15 suppl).
Mirvetuximab Soravtansine, a Folate Receptor Alpha (FRα)–Targeting Antibody-Drug Conjugate, in Combination With Bevacizumab in Patients With Platinum-Agnostic Ovarian Cancer: Final Analysis
PARP inhibitor therapy has led to an increase in the population of patients with recurrent ovarian cancer who could benefit from treatment with a platinum-free regimen.1 Mirvetuximab soravtansine is an antibody-drug conjugate that binds to folate receptor alpha (FRα) and delivers the maytansinoid DM4 into tumor cells.2 Among patients with platinum-resistant ovarian cancer and high expression of FRα, single-agent mirvetuximab soravtansine has yielded confirmed objective response rates (ORRs) of up to 47%.3,4 In patients with platinum-resistant ovarian cancer and medium- or high-level expression of FRα, mirvetuximab soravtansine plus bevacizumab yielded confirmed ORRs ranging from 39% to 56%.5 In an open-label, phase 3 trial of single-agent chemotherapy with or without bevacizumab, the addition of bevacizumab improved median PFS from 3.4 to 6.7 months (HR, 0.48; 95% CI, 0.38-0.60; P<.001) and increased the ORR from 12% to 27%.6
The combination of mirvetuximab soravtansine plus bevacizumab was evaluated in patients with ovarian cancer as part of the phase 1b FORWARD II trial.7 Enrolled patients had recurrent ovarian cancer and had received up to 3 prior regimens. They were suitable candidates for treatment with a nonplatinum doublet that included bevacizumab. Patients with platinum-sensitive ovarian cancer had responded to the most recent platinum therapy, and their disease had not progressed within 6 months. Patients with platinum-resistant ovarian cancer had experienced a recurrence within 6 months after receiving their last platinum dose. The tumors of enrolled patients had medium or high expression of FRα according to the percentage of cells staining positive and the intensity of the staining (medium expressors: ≥50% to <75% and ≥2+ intensity; high expressors: ≥75% and ≥2+ intensity).
Mirvetuximab soravtansine (6 mg/kg, adjusted for ideal body weight) and bevacizumab (15 mg/kg) were administered on day 1 of each 3-week cycle. The 60 enrolled patients were a median age of 60 years (range, 44-83). The most common malignancy was epithelial ovarian cancer (68%), followed by fallopian tube cancer (25%) and primary peritoneal cancer (7%). Patients had received a median of 2 prior therapies (range, 1-4). The level of FRα expression was medium in 45% and high in 55% of patients. All patients had received prior treatment with a platinum compound and a taxane; 40% had received prior bevacizumab therapy, and 35% had received prior treatment with a PARP inhibitor. The platinum-free interval was 6 months or less in 53% of patients.
In the overall study population, the confirmed ORR was 50% (Figure 3). The ORR was 33% among those with medium-level expression of FRα and 64% among patients with high-level expression of FRα. The median duration of response was 9.7 months among the overall population (n=30), 8.3 months among 9 patients with medium-level FRα expression, and 11.8 months among 21 patients with high-level FRα expression. Among the patients with platinum-resistant ovarian cancer, the ORR was 59% and the median duration of response was 9.4 months. Among patients with platinum-sensitive ovarian cancer, the ORR was 69% and the median duration of response was 12.7 months. The median PFS was 10.6 months in patients whose tumors showed a high level of FRα expression vs 5.4 months in patients whose tumors showed a medium level of FRα expression. Within the cohort of patients with high-level expression of FRα, the median PFS was 9.7 months in those with platinum-resistant disease and 13.3 months in those with platinum-sensitive disease. Grade 3/4 AEs observed in at least 5% of patients included hypertension (17%), neutropenia (13%), and increased level of alanine transaminase (5%).
References
1. Valabrega G, Scotto G, Tuninetti V, Pani A, Scaglione F. Differences in PARP inhibitors for the treatment of ovarian cancer: mechanisms of action, pharmacology, safety, and efficacy. Int J Mol Sci. 2021;22(8):4203.
2. Ab O, Whiteman KR, Bartle LM, et al. IMGN853, a folate receptor-α (FRα)-targeting antibody-drug conjugate, exhibits potent targeted antitumor activity against FRα-expressing tumors. Mol Cancer Ther. 2015;14(7):1605-1613.
3. Moore KN, Matulonis U, O’Malley DM, et al. Mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in platinum-resistant epithelial ovarian cancer (EOC) patients (pts): Activity and safety analyses in phase I pooled expansion cohorts [ASCO abstract 5547]. J Clin Oncol. 2017;35 (15 suppl).
4. Moore KN, Oza AM, Colombo N, et al. A Phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC) [ESMO abstract 4093]. Ann Oncol. 2019;30(suppl 5).
5. O’Malley DM, Matulonis UA, Birrer MJ, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020;157(2):379-385.
6. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-1308.
7. O’Malley DM, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate, in combination with bevacizumab in patients with platinum-agnostic ovarian cancer: final analysis [ASCO abstract 5504]. J Clin Oncol. 2021;39(15 suppl).
Real-Life Data of Niraparib Maintenance Treatment in Patients With Recurrent Platinum-Sensitive Ovarian Cancer
In the NOVA study and other clinical trials, niraparib demonstrated a benefit as maintenance therapy in patients with recurrent, platinum-sensitive ovarian cancer.1 A retrospective, multicenter cohort study evaluated the real-world efficacy and safety of niraparib maintenance therapy in patients with ovarian cancer that had responded to platinum-based chemotherapy.2 The primary endpoint was the time to first subsequent treatment, measured from the first dose of niraparib. The study included 106 patients with ovarian cancer, of whom 31% had received 3 or more prior lines of therapy, 42% had received prior treatment with bevacizumab, and 3% had received prior treatment with a PARP inhibitor. The median age of the patients was 64 years (range, 38-81), and more than 90% had at least one comorbidity. A germline BRCA mutation was present in 9% of the patients. According to investigator assessment, outcomes after the most recent chemotherapy before enrollment had included a complete response (CR) in 13%, a partial response (PR) in 75%, and stable disease in 7% (5% of the patients were not evaluable). The cancer antigen 125 (CA-125) level exceeded 35 kU/L in 41% of patients. The daily starting dose of niraparib was 100 mg in 2%, 200 mg in 31%, and 300 mg in 67% of patients.
After a median follow-up of 15.3 months, 67% of the patients had disease progression, 60% had started a new line of treatment, and 24% had died.2 Niraparib treatment was ongoing in 24% of the patients. The median duration of niraparib treatment was 7.6 months (range, 0.4-27.3). The median time to the first subsequent treatment was 11.7 months (95% CI, 9.2-14.2) for the entire study population (Figure 4) and 10.2 months (95% CI, 7.4-12.9) for patients without a germline BRCA mutation. The median time from the last chemotherapy dose to progression was 6.5 months in the patients with elevated CA-125 vs 12 months in those with a normal level (P<.001). The median PFS was 6.9 months for the entire study population vs 6.4 months for patients without a germline BRCA mutation.
Grade 3/4 hematologic AEs were observed in 25% of patients, and grade 3/4 nonhematologic AEs were observed in 17% of patients. The proportion of patients experiencing a grade 3/4 AE was lower in the real-world setting than in the NOVA clinical trial (Figure 5). AEs necessitated dose interruption or dose reduction in 38% and 44% of patients, respectively. The proportions of patients who discontinued niraparib therapy because of an AE were similar in the real-world setting (13.2%) and the NOVA trial (14.7%). Fewer dose reductions (P<.001) and fewer dose interruptions (P=.042) occurred among patients who received an individualized dose of niraparib based on weight and platelet count.
References
1. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
2. Vilming B, Dahl F, Ingebrigtsen VA, et al. Real-life data of niraparib maintenance treatment in patients with recurrent platinum-sensitive ovarian cancer [ASCO abstract 5560]. J Clin Oncol. 2021;39(15 suppl).
Maintenance Gemogenovatucel-T in Newly Diagnosed Advanced Ovarian Cancer: Efficacy Assessment of Homologous Recombination Proficient Patients in the Phase 2b VITAL Trial
Gemogenovatucel-T is a cellular therapy that is created by genetically modifying a patient’s tumor cells via the introduction of a plasmid with 2 genes. One gene interferes with the function of furin; this downregulates the activity of transforming growth factor beta 1 (TGFβ1) and TGFβ2, resulting in an increase in immune activity. The second gene encodes granulocyte-macrophage colony–stimulating factor, which increases the activity of antigen-presenting cells. Gemogenovatucel-T was evaluated in the double-blind, placebo-controlled, phase 2b VITAL trial as first-line maintenance therapy in women with advanced, high-grade ovarian cancer.1 This double-blind study enrolled patients with stage III/IV, high-grade serous, endometrioid, or clear cell ovarian cancer and a CR after surgery and up to 8 cycles of chemotherapy with carboplatin and paclitaxel. After stratification according to the extent of surgical cytoreduction and neoadjuvant vs adjuvant chemotherapy, 91 patients were randomly assigned to receive between 4 and 12 monthly injections of gemogenovatucel-T at 1 × 107 cells per injection or placebo. The primary endpoint was recurrence-free survival. Of the 91 patients, 47 received gemogenovatucel-T and 44 received placebo.
After a median follow-up of 40 months, the median recurrence-free survival was 11.5 months in the patients who received treatment with the genetically modified autologous tumor cells vs 8.4 months in the placebo arm (HR, 0.69; 90% CI, 0.44-1.07; P=.078; Figure 6). The median overall survival (OS) was not reached in the experimental arm vs 16.0 months in the placebo arm (HR, 0.630; P=.110). The most common grade 1 to 3 toxicity in both arms was the combined event of general disorders and injection site reactions, which occurred in 63.2% of the gemogenovatucel-T arm vs 59.6% of the placebo arm. Musculoskeletal and connective tissue disorders were reported in 3% vs 15.6%, respectively. Gastrointestinal disorders occurred in 5% vs 2.8%.
A post hoc analysis evaluated outcomes among subgroups of patients classified according to their homologous recombination status.2 Among patients with homologous recombination proficiency, the median PFS was 10.6 months in the experimental arm (n=25) vs 5.7 months in the placebo arm (n=20; HR, 0.386; P=.007). OS was not reached vs 26.9 months (HR, 0.342; P=.019), respectively. The restrictive mean survival time also was significantly better among the patients treated with gemogenovatucel-T, in terms of both recurrence-free survival (20.02 vs 10.77 months; P=.017) and OS (38.15 vs 27.81 months; P=.008). Among the patients with homologous recombination proficiency, the rate of 2-year OS was 92% in the treatment arm vs 55% in the placebo arm (P=.002); the rate of 3-year OS was 70% vs 40% (P=.019).
STRING analysis was used to identify a subgroup of patients who were likely to benefit from treatment with gemogenovatucel-T according to their homologous recombination proficiency status and TP53 mutation status.3 Among this subset of patients, the median recurrence-free survival was 21.1 months with the treatment vs 5.6 months with the placebo (P=.001). OS was not reached vs 26.9 months (P=.02).
References
1. Rocconi RP, Grosen EA, Ghamande SA, et al. Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Oncol. 2020;21(12):1661-1672.
2. Rocconi RP, Ghamande SA, Barve MA, et al. Maintenance vigil immunotherapy in newly diagnosed advanced ovarian cancer: Efficacy assessment of homologous recombination proficient (HRP) patients in the phase IIb VITAL trial [ASCO abstract 5502]. J Clin Oncol. 2021;39(15 suppl).
3. Swiss Institute of Bioinformatics. STRING: Protein-Protein Interaction Networks. https://string-db.org. Accessed July 8, 2021.
Safety Assessment of Niraparib Individualized Starting Dose in Patients With Platinum-Sensitive Recurrent Ovarian Cancer: The Randomized, Double-Blind, Placebo-Controlled, Phase III NORA Trial
The double-blind, multicenter, phase 3 NORA trial evaluated the safety and efficacy of niraparib as maintenance therapy in women with recurrent, platinum-sensitive ovarian cancer.1,2 Patients who had received 2 or more prior lines of platinum-based chemotherapy were randomly assigned in a 2:1 ratio to receive niraparib or placebo. In the phase 3 NOVA trial, improved safety without any loss of efficacy was observed in patients who received individualized dosing rather than the 300-mg standard dose.3,4 Namely, patients with a baseline body weight below 77 kg (170 pounds) or a platelet count below 150 × 103/µL received an average dose of niraparib of 207 mg daily.3,4 On the basis of these findings, the NORA trial followed an individualized dosing strategy as well as the standard dosing strategy. Patients with a body weight below 77 kg or a platelet count below 150 × 103/µL received niraparib at the lower dose of 200 mg/day. Among the 265 patients, 16 received niraparib at a fixed starting dose of 300 mg daily. The remaining 249 patients received an individualized starting dose of niraparib (n=166) or placebo (n=83). The NORA trial demonstrated a significant prolongation of median PFS with niraparib vs placebo (18.3 vs 5.4 months; P<.0001), irrespective of BRCA status.
Except for anemia, the incidence of treatment-emergent AEs was highest during the first 6 months after the initiation of treatment (Figure 7).2 Treatment-emergent AEs of grade 3 or higher were more common in the niraparib arm (50.8% vs 19.3%), as were serious AEs (17.5% vs 11.4%) and treatment-emergent AEs necessitating dose reduction (59.9% vs 13.6%). Treatment-emergent AEs led to discontinuation of therapy in 4% of the niraparib arm vs 5.7% of the placebo arm. In the NOVA trial, in which the experimental treatment consisted of niraparib at 300 mg daily, 14.7% of patients in the niraparib arm discontinued study treatment owing to a treatment-emergent AE.3,4 In the NORA trial, the most common treatment-emergent AEs reported with niraparib were hematologic and included reductions in counts of white blood cells, neutrophils, and platelets, as well as anemia. Gastrointestinal treatment-emergent AEs of interest included nausea, vomiting, and constipation. Other treatment-emergent AEs of interest included insomnia, heart palpitations, and hypertension.
With most types of AEs, the median time to the first occurrence of a treatment-emergent AE of any grade was shorter in the niraparib group than in the placebo arm, except for anemia, palpitations, and reduced neutrophil count. In the niraparib group, the median times to the first occurrence of anemia, reduced neutrophil count, and reduced platelet count of grade 3 or higher were 87, 28, and 22 days, respectively. Most treatment-emergent AEs were adequately controlled by modifying the dose of niraparib.
References
1. Wu XH, Zhu JQ, Yin RT, et al. Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial∗. Ann Oncol. 2021;32(4):512-521.
2. Wang J, Wu X, Zhu J, et al. Safety assessment of niraparib individualized starting dose in patients with platinum-sensitive recurrent ovarian cancer: a randomized, double-blind, placebo-controlled, phase III NORA trial [ASCO abstract 5535]. J Clin Oncol. 2021;39(15 suppl).
3. Berek JS, Matulonis UA, Peen U, et al. Safety and dose modification for patients receiving niraparib. Ann Oncol. 2018;29(8):1784-1792.
4. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
EFFORT: Efficacy of Adavosertib in PARP Resistance: a Randomized 2-Arm Noncomparative Phase 2 Study of Adavosertib With or Without Olaparib in Women With PARP-Resistant Ovarian Cancer
The noncomparative phase 2 EFFORT study evaluated the combination of adavosertib and olaparib in patients with ovarian cancer that had progressed following treatment with a PARP inhibitor.1 Eligible patients had histologically confirmed recurrent epithelial ovarian, peritoneal, or fallopian tube cancer that had progressed during maintenance treatment with any single-agent PARP inhibitor. The trial enrolled patients treated with an unlimited number of prior therapies. Patients in arm 1 received adavosertib (300 mg daily on days 1-5 and 8-12) in a 21-day cycle. Patients in arm 2 received adavosertib (150 mg twice daily on days 1-3 and 8-10) plus olaparib (200 mg twice daily on every day of the cycle). Tumors were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2
The study enrolled 39 patients into the adavosertib arm and 41 into the adavosertib-plus-olaparib arm. Patient characteristics in the 2 arms were well balanced.1 Patients had a median age of 60 years (range, 36-76) and had received a median of 4 prior therapies (range, 1-11). More than 90% of patients had high-grade serous carcinoma. The BRCA status was negative in 44% and positive in 48%, and 36% had platinum-sensitive disease. The patients had received a median of 1 line of therapy after previous treatment with a PARP inhibitor (range, 0-5). Prior PARP inhibitors included olaparib (51%), niraparib (22.5%), rucaparib (22.5%), and talazoparib (4%). Prior PARP inhibitors had been administered as maintenance therapy in 45% of patients and as treatment in 55% of patients. Prior PARP inhibitor therapy led to a clinical benefit in 86% of patients.
There were 35 evaluable patients in each treatment arm. The ORR was 23% (95% CI, 12%-38%) with adavosertib monotherapy vs 29% (95% CI, 16%-44%) with adavosertib plus olaparib (Figure 8). The median duration of response was 5.5 months in the adavosertib monotherapy arm vs 6.4 months in the combination arm. The clinical benefit rate was 63% (95% CI, 48%-76%) vs 89% (95% CI, 76%-96%), respectively. The median PFS was 5.5 months (95% CI, 3.9-6.9) vs 6.8 months (95% CI, 4.3-8.3).
Adavosertib alone and in combination with olaparib demonstrated activity in patients with or without a BRCA mutation. Among the patients with mutated BRCA, the ORR was 20% with adavosertib monotherapy vs 19% with adavosertib plus olaparib. The median duration of response was 5.6 months vs 6.4 months, and the clinical benefit rate was 67% vs 81%. The duration of clinical benefit was 5.6 months in both arms. Among the patients with wild-type BRCA, the ORR was 31% with adavosertib monotherapy vs 39% with adavosertib plus olaparib. The median duration of response was 4.1 months vs 8.7 months, and the clinical benefit rate was 69% vs 94%. The duration of clinical benefit was 4.1 months vs 8.4 months.
In the adavosertib monotherapy arm, 97% of patients experienced a treatment-related AE, 5% of patients discontinued study treatment, 54% required a dose reduction, and 72% required a dose interruption. The most common treatment-related AEs were diarrhea (33%), neutropenia (21%), thrombocytopenia (18%), fatigue (18%), and nausea (18%). Grade 4 treatment-related AEs included neutropenia (5%) and thrombocytopenia (8%). In the adavosertib/olaparib combination arm, all patients developed at least 1 treatment-related AE, and 10% of patients discontinued both study drugs. Reductions in the doses of both adavosertib and olaparib were required in 56% of patients, whereas reductions in the dose of only adavosertib or only olaparib were required in 10% and 5% of patients, respectively. Doses of both adavosertib and olaparib were interrupted in 85% of patients. The most common treatment-related AEs in the combination arm included diarrhea (34%), anemia (27%), and thrombocytopenia (27%). Grade 4 treatment-related AEs included thrombocytopenia (10%) and neutropenia (7%).
References
1. Westin SN, Coleman RL, Fellman B, et al. EFFORT: efficacy of adavosertib in PARP resistance: a randomized 2-arm non-comparative phase 2 study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer [ASCO abstract 5505]. J Clin Oncol. 2021;39(15 suppl).
2. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Optimal Treatment Duration of Bevacizumab Combined With Carboplatin and Paclitaxel in Patients With Primary Epithelial Ovarian, Fallopian Tube or Peritoneal Cancer: A Multicenter Open-Label Randomized 2-Arm Phase 3 ENGOT/GCIG Trial of the AGO Study Group, GINECO, and NSGO (AGO-OVAR 17/BOOST, GINECO OV118, ENGOT Ov-15, NCT01462890)
As was shown in the GOG-218 study and the ICON7/AGO-OVAR 11 trial, the addition of 12 or 15 months of bevacizumab to standard treatment with carboplatin plus paclitaxel significantly increases PFS.1,2 In both trials, the improvement in PFS reached a maximum after the last bevacizumab cycle, suggesting that longer treatment with bevacizumab could be beneficial. The phase 3 AGO-OVAR 17/Boost, GINECO OV118, ENGOT Ov-15 trial evaluated whether PFS and other efficacy endpoints could be further improved by continuing bevacizumab treatment for up to 30 months.3 Enrolled patients had histologically confirmed International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV epithelial ovarian, fallopian tube, or peritoneal cancer. The patients had undergone primary debulking surgery no more than 8 weeks before the start of treatment and more than 4 weeks before the first dose of bevacizumab. All patients received standard treatment with paclitaxel and carboplatin. Patients were randomly assigned to receive bevacizumab at 15 mg/kg every 3 weeks for 22 cycles (15 months) in the control arm or bevacizumab at the same dose for 44 cycles (30 months) in the experimental arm. The primary endpoint was PFS according to RECIST 1.1 criteria.4 The trial was designed to have a power of 80% to detect a PFS HR of 0.66 favoring 30 months of bevacizumab after 697 events. However, a low event rate led the study to close after 673 (97%) of the planned events had been observed.
The trial enrolled 927 patients. The median follow-up was 85 months. The patients’ median age was 61 years (range, 21-89). Residual tumor was noted in 58% of patients, and 79% had high-grade serous disease. Most of the patients (84%) had ovarian cancer. Half of the patients had FIGO stage IIB to IIIC disease with no residual tumor, and half had FIGO stage IIB to IIIC disease with residual tumor or FIGO stage IV disease.
Serious AEs were observed in 45% of patients, and grade 3 to 5 AEs occurred in 65%. In a comparison of the 15-month vs the 30-month bevacizumab arm, the most common AEs of special interest included hypertension of grade 3 or higher (20% vs 25%), intestinal perforation or fistula of any grade (5% vs 4%), thromboembolic events of grade 3 or higher (4% vs 3%), and proteinuria of grade 3 or higher (2% vs 4%).
Extending bevacizumab treatment to 30 months did not improve efficacy. The median PFS was 24.2 in the 15-month arm vs 26.0 months in the 30-month arm, (HR, 0.99; 95% CI, 0.85-1.15; P=.90; Figure 9). The restricted mean PFS was 39.5 vs 39.3 months (P=.92). Among the subgroup of patients with FIGO stage IIB to IIIC disease and no residual tumor, the median PFS was 38.4 vs 38.8 months (HR, 0.93; 95% CI, 0.74-1.18; P=.55), and the restricted mean PFS was 51.0 vs 53.2 months (P=.53). Among the patients with FIGO stage IIB to IIIC disease and residual tumor or FIGO stage IV disease, the median PFS was 19.3 months with 15 months of therapy vs 18.2 months with 30 months of therapy (HR, 1.06; 95% CI, 0.87-1.29; P=.58). The restricted mean PFS was 27.8 vs 25.5 months (P=.35). Among the entire population, the median OS was 54.3 months in the 15-month arm vs 60.0 months in the 30-month arm (HR, 1.04; 95% CI, 0.87-1.23; P=.68). The restricted mean OS was 60.4 vs 60.8 months (P=.87). The standard of care remains 15 months of bevacizumab as a part of first-line treatment in patients with advanced ovarian cancer.
References
1. Burger RA, Brady MF, Bookman MA, et al; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483.
2. Perren TJ, Swart AM, Pfisterer J, et al; ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496.
3. Pfisterer J, Joly F, Kristensen G, et al. Optimal treatment duration of bevacizumab combined with carboplatin and paclitaxel in patients with primary epithelial ovarian, fallopian tube or peritoneal cancer: a multicenter open-label randomized 2-arm phase 3 ENGOT/GCIG trial of the AGO Study Group, GINECO, and NSGO (AGO-OVAR 17/BOOST, GINECO OV118, ENGOT Ov-15, NCT01462890) [ASCO abstract 5501]. J Clin Oncol. 2021;39(suppl 15).
4. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Efficacy of Niraparib Maintenance Therapy in Chinese Women With Platinum-Sensitive Recurrent Ovarian Cancer With and Without Secondary Cytoreductive Surgery: Results From the NORA Trial
Secondary cytoreductive surgery may benefit women with recurrent, platinum-sensitive ovarian cancer, but use of the procedure remains controversial.1 A retrospective subgroup analysis evaluated the efficacy and safety of niraparib maintenance therapy in Chinese patients enrolled in the NORA trial who underwent secondary cytoreductive surgery.2,3 The NORA trial enrolled patients with recurrent, platinum-sensitive ovarian cancer whose most recent platinum-based chemotherapy had yielded a PR or CR. Among 265 Chinese women who had recurrent, platinum-sensitive ovarian cancer, 69 underwent secondary cytoreductive surgery and 196 did not. Compared with placebo, niraparib was associated with a reduction in the risk for disease progression or death in patients who underwent secondary cytoreductive surgery (HR, 0.32; 95% CI, 0.13-0.78; P=.0102) and in patients who did not undergo secondary cytoreductive surgery (HR, 0.34; 95% CI, 0.23-0.50; P<.001). Among the patients who underwent secondary cytoreductive surgery, the median PFS was not reached (95% CI, 18.33 months to not estimable) with niraparib vs 5.75 months (95% CI, 3.68 months to not estimable) with placebo (P=.0102; Figure 10). Among patients who did not undergo secondary cytoreductive surgery, the median PFS was 10.28 months (95% CI, 7.49-18.37) with niraparib vs 4.90 months (95% CI, 3.71-5.52) with placebo (P<.0001).
Safety outcomes were similar among the patients who did or did not undergo secondary cytoreductive surgery.3 Among the patients who did undergo secondary cytoreductive surgery, the most common treatment-emergent AEs of any grade with niraparib vs placebo were decreased neutrophil count (52.1% vs 38.1%), anemia (47.9% vs 23.8%), and decreased platelet count (47.9% vs 19.0%). The most common treatment-emergent AEs of at least grade 3 were decreased neutrophil count (22.9% vs 0%), anemia (18.8% vs 0%), and decreased platelet count (14.6% vs 0%). Among the patients who did not undergo secondary cytoreductive surgery, the most common treatment-emergent AEs of any grade with niraparib vs placebo were decreased neutrophil count (61.2% vs 43.3%), anemia (55.8% vs 29.9%), and decreased platelet count (57.4% vs 26.9%). The most common treatment-emergent AEs of at least grade 3 were decreased neutrophil count (19.4% vs 10.4%), anemia (13.2% vs 3.0%), and decreased platelet count (10.1% vs 1.5%).
References
1. Marchetti C, Rosati A, Scaletta G, et al. Secondary cytoreductive surgery in platinum-sensitive recurrent ovarian cancer before olaparib maintenance: still getting any benefit? A case-control study. Gynecol Oncol. 2019;155(3):400-405.
2. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
3. Wu L, Wu X, Zhu J, et al. Efficacy of niraparib maintenance therapy in Chinese women with platinum-sensitive recurrent ovarian cancer with and without secondary cytoreductive surgery: results from the NORA trial [ASCO abstract 5534]. J Clin Oncol. 2021;39(15 suppl).
Efficacy and Safety Results From the NeoPembrOV Study, a Randomized Phase 2 Trial of Neoadjuvant Chemotherapy With or Without Pembrolizumab Followed by Interval Debulking Surgery and Standard Systemic Therapy ± Pembrolizumab for Advanced High-Grade Serous Carcinoma: a GINECO Study
For some patients with advanced ovarian, peritoneal, or tubal cancer, primary debulking surgery may not result in complete tumor resection and is therefore not appropriate. Treatment with neoadjuvant chemotherapy and interval debulking has been proposed as a viable alternative for these patients.1-3 The multicenter, open-label, noncomparative phase 2 NeoPembrOV study evaluated whether the addition of pembrolizumab to standard neoadjuvant chemotherapy could increase the optimal debulking rate.4 Patients were randomly assigned in a 1:2 ratio to receive standard neoadjuvant therapy with carboplatin and paclitaxel or the same treatment plus pembrolizumab. After 4 cycles of neoadjuvant therapy, patients underwent interval debulking surgery. Patients then received 5 more cycles of chemotherapy (without or with pembrolizumab), plus optional bevacizumab. Maintenance therapy, which was continued for up to 24 months, consisted of bevacizumab or observation in the standard therapy arm and of pembrolizumab with or without bevacizumab in the experimental arm. The primary endpoint was the rate of complete resection at interval debulking surgery, which was evaluated in a blinded, central review by 2 surgical experts.
The study included 30 patients in the standard arm (arm A) and 61 in the experimental arm (arm B). Patient characteristics in the 2 arms were well balanced. In arm A, 10% of patients had mutated BRCA and 80% had wild-type BRCA. (The BRCA status was unknown in 10%.) In arm B, 21% of patients had mutated BRCA and 67.2% had wild-type BRCA. (The status was unknown in 11%.) Use of bevacizumab was anticipated in 96.6% of patients in arm A vs 88.1% in arm B.
Interval debulking surgery was performed in 96.7% of the patients in arm A vs 95.1% of those in arm B. Cytoreductive surgery achieved complete resection in 72.4% of patients in arm A vs 77.5% of those in arm B, thereby meeting the study’s primary endpoint. In arm A vs arm B, after 4 cycles of neoadjuvant chemotherapy, the CR rate was 6.9% vs 3.3%, the PR rate was 55.2% vs 70.0%, and the proportion of patients with stable disease was 37.9% vs 23.3%. In arm A, the best response consisted of a CR in 75.9%, a PR in 10.3%, and stable disease in 13.8%. In arm B, there rates were 75.0%, 16.7%, and 8.3%, respectively. The median PFS was 20.8 months in arm A vs 19.3 months in arm B (Figure 11).
Among the patients who received pembrolizumab plus standard chemotherapy, the most common grade 3/4 AEs during neoadjuvant therapy were neutropenia (13.1%) and anemia).
References
1. Coleridge SL, Bryant A, Kehoe S, Morrison J. Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer. Cochrane Database Syst Rev. 2021;2(2):CD005343.
2. Dahm-Kähler P, Holmberg E, Holtenman M, et al. Implementation of National Guidelines increased survival in advanced ovarian cancer—a population-based nationwide SweGCG study. Gynecol Oncol. 2021;161(1):244-250.
3. Wang D, Zhang G, Peng C, Shi Y, Shi X. Choosing the right timing for interval debulking surgery and perioperative chemotherapy may improve the prognosis of advanced epithelial ovarian cancer: a retrospective study. J Ovarian Res. 2021;14(1):49.
4. Ray-Coquard I, Savoye AM, Mouret-Reynier MA, et al. Efficacy and safety results from NeoPembrOV study, a randomized phase 2 trial of neoadjuvant chemotherapy with or without pembrolizumab followed by interval debulking surgery and standard systemic therapy ± P for advanced high-grade serous carcinoma: a GINECO study [ASCO abstract 5500]. J Clin Oncol 2021;39(15 suppl).
Highlights in Ovarian Cancer From the 2021 American Society of Clinical Oncology Annual Meeting: Commentary
Mansoor Raza Mirza, MD
Presentations in ovarian cancer at the 2021 American Society of Clinical Oncology (ASCO) annual meeting provided important information regarding the management of ovarian cancer. New data were presented for treatments such as bevacizumab, checkpoint inhibitors, niraparib and other poly(ADP-ribose) polymerase (PARP) inhibitors, and the antibody-drug conjugate mirvetuximab soravtansine.
Extended Treatment With Bevacizumab
Dr Jacobus Pfisterer presented long-awaited data from a phase 3 trial evaluating the optimal duration of bevacizumab in combination with carboplatin and paclitaxel.1
In 2011, two phase 3 trials showed that the use of concomitant and maintenance bevacizumab improved progression-free survival.2,3 In addition, a subgroup analysis of the ICON7 trial showed that this use of bevacizumab also improved overall survival in a high-risk population.4 These data led to the use of concomitant and maintenance bevacizumab in patients with ovarian cancer. The duration of bevacizumab reached approximately 15 months in the GOG-218 trial and was 12 months in the ICON7 trial. When the treatment was stopped, the benefits ended. The hypothesis behind the current study was that progression-free survival and overall survival might be prolonged by administration of bevacizumab as maintenance therapy for an extended period (eg, until disease progression or at least double the duration of current treatment).
The trial by Pfisterer and colleagues enrolled patients who had undergone primary debulking surgery.1 All patients received paclitaxel plus carboplatin. The patients were randomly assigned to receive treatment with bevacizumab for 15 months (the standard-of-care arm) or for 30 months (the experimental arm). Bevacizumab was administered concomitantly with chemotherapy and continued as maintenance therapy for 15 or 30 months. This European trial recruited 927 patients with stage IIB to 4 disease. High-grade serous disease was reported in 79% of patients, and 58% of patients had no residual disease. A stratification factor was stage IIB to IIIC disease with no residual tumor vs stage IIB to IIIC disease with residual tumor or stage IV disease.
Prolonged treatment with bevacizumab did not improve progression-free survival or overall survival. No benefits were seen in the intention-to-treat population or in subgroup analyses of patients with or without residual disease or with stage IIB to III disease or higher. These results were shocking. Previous trials had raised the possibility that bevacizumab could be active for a longer time. For example, in the MITO16 trial, rechallenge with bevacizumab improved outcome in patients who had received initial treatment with bevacizumab followed by chemotherapy and maintenance for progressive disease.5
The trial was well-designed, and there were no issues with the enrolled population. Prolonged treatment with bevacizumab did not increase the rate of adverse events. The outcome may be attributable to improvements in surgery compared with 20 years ago. The burden of disease is much lower in these patients, which may decrease the efficacy of bevacizumab. As shown in the ICON7 trial, benefits are seen in high-risk patients.4 The patients without residual disease had no benefit. The take-home message from this study is that bevacizumab should not be administered beyond 15 months, which is the standard of care.
Checkpoint Inhibitors
Dr Isabelle Laure Ray-Coquard presented results from the phase 2 NeoPembrOV study.6 This French trial evaluated whether neoadjuvant treatment with chemotherapy in combination with an immune checkpoint inhibitor would be superior to standard-of-care chemotherapy in patients with ovarian cancer. The trial design was innovative. The trial enrolled patients scheduled for neoadjuvant therapy with carboplatin/paclitaxel. The enrollment criteria did not specify any type of biomarker profiles. The patients were randomly assigned to receive pembrolizumab in addition to chemotherapy or chemotherapy alone. After 3 treatment cycles, all patients underwent interval debulking surgery to identify any improvements in pathologic or radiologic response. Unfortunately, the combination of immunotherapy plus chemotherapy did not improve outcome. The study investigators plan to perform a biomarker analysis to see if any subgroups benefitted from the combination regimen.
The trial was initiated before results were available for other major phase 3 trials in this setting. Results are now available for these trials. A trial in patients who were resistant to platinum therapy evaluated treatment with pegylated liposomal doxorubicin alone, pegylated liposomal doxorubicin plus avelumab, or avelumab alone.7 The addition of avelumab did not improve outcome. A trial in the first-line setting evaluated carboplatin/paclitaxel with or without avelumab.8 That trial was stopped based on lack of efficacy. A third trial evaluated frontline therapy with carboplatin/paclitaxel plus bevacizumab, with or without atezolizumab.9 There were no differences between the treatment arms.
Currently, there is no clear goal in how to move forward with immune checkpoint inhibitors in ovarian cancer. It will be necessary to consider how to introduce immune checkpoint inhibitors into the armamentarium. The NeoPembrOV study confirmed other randomized data showing no benefit with the addition of immune checkpoint inhibitors to chemotherapy among the entire population of patients with ovarian cancer.6-9 Thus far, no studies have shown benefits of immune therapy as a single agent or in combination with chemotherapy or bevacizumab. These agents are not suitable for the entire population, and biomarkers cannot be used to guide treatment at this time. Several recent trials have evaluated the combination of a PARP inhibitor plus immunotherapy with or without bevacizumab, and results are expected shortly.10-13
PARP Inhibitors
In the past 5 years, the management of ovarian cancer has completely changed with the introduction of PARP inhibitors. PARP inhibitors are used in multiple lines of therapy, including first-line settings and as maintenance, and they have dramatically improved outcome. In the first-line setting, the longest survival data is from the phase 3 SOLO1 study of maintenance olaparib, which showed that the 5-year survival of patients with the BRCA mutation was approximately 50%.14,15 This long-term finding is incredible, especially because the treatment was given for only 2 years.
Niraparib was first approved by the US Food and Drug Administration for the maintenance of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, based on results from the NOVA trial.16 The NOVA trial was the first phase 3 study of a PARP inhibitor in ovarian cancer. The results showed that niraparib was extremely effective as maintenance therapy in patients with platinum-sensitive disease who had responded to chemotherapy. Results were seen among several subgroups of patients: those with BRCA-mutated or BRCA–wild-type disease, and, among the BRCA–wild-type patients, those who were homologous recombination deficiency (HRD)-positive or HRD-negative. In patients with relapsed disease, improvements were seen in both BRCA-mutated and BRCA–wild-type patients. In the phase 3 PRIMA trial, niraparib administered in the frontline setting improved progression-free survival.17 Some patients required dose reductions and dose interruptions owing to hematologic toxicities, primarily thrombocytopenia.
The study investigators of the NOVA trial, including myself, evaluated different aspects of the trial to identify factors that contributed to toxicities and to improve tolerability.16 We found 2 important factors: the patient’s body weight and thrombocyte count at baseline. The standard 300-mg dose of niraparib may be too high for some patients.
A reduced dose of niraparib was tested in 2 recent trials: PRIMA and NORA.17,18 In both of these trials, the initial protocol designated a fixed dose of 300 mg/daily for all patients. The trials were subsequently amended to follow an individualized starting dose of 200 mg/daily for patients with a baseline body weight below 77 kg and/or a platelet count of less than 150,000/mm3. The NORA trial was the first phase 3 trial of niraparib in patients with platinum-sensitive recurrent ovarian cancer conducted in Asia.18 In both trials, niraparib led to dramatic improvements. In addition, adjusting the dose of niraparib according to body weight and thrombocyte count greatly improved the toxicity profile compared with the standard regimen used in the NOVA trial.16-18
Dr Antonio González-Martin presented an analysis of data from the PRIMA, NOVA, and NORA trials to assess the efficacy and safety of niraparib in patients with BRCA mutations.19 The analysis showed that niraparib had tremendous efficacy in all 3 trials, whether in the first-line setting in PRIMA or the relapsed setting in NOVA and NORA. The toxicity profile was much better in the NORA and PRIMA trials, which followed the individualized dosing strategy. (Toxicity was especially low in the PRIMA trial.) In the NORA trial, the dose adjustment was made for almost all patients. The NORA trial indirectly showed that efficacy is not affected by dose adjustments. Patients who began treatment at 200 mg instead of 300 mg had similarly high efficacy with a much more controlled toxicity profile.
Dr Xiaohua Wu was the primary investigator of the NORA trial.18 At the 2021 ASCO meeting, Dr Wu and colleagues presented a retrospective subgroup analysis of the NORA trial that evaluated efficacy according to whether a patient had undergone secondary cytoreductive surgery.20 No difference in efficacy was found; both subgroups benefitted from treatment. This analysis was important, in that it confirmed that patients should receive maintenance therapy with niraparib regardless of whether they underwent cytoreductive surgery.
Another retrospective analysis of the NORA trial evaluated the safety profile of niraparib according to the individualized starting dose.21 Most of the patients in this Chinese trial weighed less than 77 kg, and they began treatment at 200 mg. The analysis clearly showed that grade 3/4 toxicity was well controlled with individualized dosing.
Dr Bente Vilming of Norway presented an important real-world study of niraparib, with a focus on patients with BRCA–wild-type disease.22 The investigators aimed to compare the efficacy and toxicity reported in the NOVA trial vs that observed in real-world settings. Results from the NOVA trial showed that the dose of niraparib should be lowered in patients who weigh less. This dosing strategy was already implemented in Norway when the real-world evidence data were collected.
This study showed that the toxicity profile was far better in the real-world setting than in the NOVA trial.16,22 For most treatments, toxicities are higher in the real world vs in clinical trials. The reverse was seen with niraparib because data from the NOVA trial were used to devise a strategy to manage toxicity in clinical care. This analysis is important because it shows that the dose-reduction strategy is effective.
Treatment After PARP Inhibitors
Dr Shannon Westin presented the results of a phase 2 trial that evaluated adavosertib with or without olaparib in patients who are resistant to PARP inhibitors.23 There are several different mechanisms of resistance. Adavosertib inhibits the WEE1 kinase. The idea behind the trial was to see if it is possible to make tumors reverse their homologous recombination (HR) reversion back so that they become HR-deficient. A previous trial evaluating an ataxia telangiectasia mutated and Rad3-related (ATR) inhibitor was stopped because a sister trial in breast cancer showed no benefit at the interim analysis.24
In the trial presented by Dr Westin, the patients were randomly assigned to treatment with adavosertib alone or in combination with olaparib.23 All of the patients had received earlier treatment with a PARP inhibitor. The clinical activity in this small randomized phase 2 trial was impressive. The objective response rate was 23% with adavosertib alone and 29% with adavosertib in combination with olaparib. Response is important, but so is tumor shrinkage. The rate of disease control was also impressive. The toxicity profile was well tolerated. Larger phase 3 trials should examine whether it is possible to overcome PARP resistance.
Novel Treatments
Dr David O’Malley presented final results of a phase 1b trial evaluating mirvetuximab soravtansine, an antibody-drug conjugate that targets the folate receptor alpha (FRα), plus bevacizumab in patients with platinum-resistant ovarian cancer.25 An earlier analysis showed activity in the subgroups of patients with medium or high expression of FRα.26 The final analysis showed that mirvetuximab soravtansine clearly improved overall response and progression-free survival in these settings.25 A hypothesis drawn from these findings is that higher expression of FRα might correspond to better response rates. In the current trial, the patients were not stratified according to level of expression, so confirmation of this hypothesis is needed. An ongoing phase 3 trial is evaluating mirvetuximab soravtansine.27 If the results are positive, this agent will become a new treatment option for patients in the future.
Disclosure
Dr Mirza has received personal compensation for serving on advisory boards of AstraZeneca, Biocad, GSK, Karyopharm, Merck, Riche, and Zai Lab. He has received personal compensation as an invited speaker for AstraZeneca and GSK. He has received personal compensation from Karyopharm as a member of the Board of Directors and as a holder of stocks/shares. He has received research grants directed to his institution, with no personal financial interests, from Apexigen, AstraZeneca, GSK, and Ultimovacs. He has served as a trial chair for Deciphera, with compensation directed toward his institution and with no personal financial interests.
References
1. Pfisterer J, Joly F, Kristensen G, et al. Optimal treatment duration of bevacizumab combined with carboplatin and paclitaxel in patients with primary epithelial ovarian, fallopian tube or peritoneal cancer: a multicenter open-label randomized 2-arm phase 3 ENGOT/GCIG trial of the AGO Study Group, GINECO, and NSGO (AGO-OVAR 17/BOOST, GINECO OV118, ENGOT Ov-15, NCT01462890 [ASCO abstract 5501]. J Clin Oncol. 2021;39(suppl 15).
2. Perren TJ, Swart AM, Pfisterer J, et al; ICON7 Investigators. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365(26):2484-2496.
3. Burger RA, Brady MF, Bookman MA, et al; Gynecologic Oncology Group. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365(26):2473-2483.
4. González Martín A, Oza AM, Embleton AC, et al; ICON7 Investigators. Exploratory outcome analyses according to stage and/or residual disease in the ICON7 trial of carboplatin and paclitaxel with or without bevacizumab for newly diagnosed ovarian cancer. Gynecol Oncol. 2019;152(1):53-60.
5. Pignata S, Lorusso D, Joly F, et al; MITO16b/MANGO–OV2/ENGOT–ov17 Investigators. Carboplatin-based doublet plus bevacizumab beyond progression versus carboplatin-based doublet alone in patients with platinum-sensitive ovarian cancer: a randomised, phase 3 trial. Lancet Oncol. 2021;22(2):267-276.
6. Ray-Coquard I, Savoye AM, Mouret-Reynier MA, et al. Efficacy and safety results from NeoPembrOV study, a randomized phase 2 trial of neoadjuvant chemotherapy with or without pembrolizumab followed by interval debulking surgery and standard systemic therapy ± P for advanced high-grade serous carcinoma: a GINECO study [ASCO abstract 5500]. J Clin Oncol 2021;39(15 suppl).
7. Pujade-Lauraine E, Fujiwara K, Ledermann JA, et al. Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study. Lancet Oncol. 2021;22(7):1034-1046.
8. Ledermann JA, Colombo N, Oza A, et al. Avelumab in combination with and/or following chemotherapy vs chemotherapy alone in patients with previously untreated epithelial ovarian cancer: results from the phase 3 JAVELIN Ovarian 100 trial [SGO abstract LBA25]. Gynecol Oncol. 2020;159(suppl 1).
9. Moore KN, Bookman M, Sehouli J, et al. Atezolizumab, bevacizumab, and chemotherapy for newly diagnosed stage III or IV ovarian cancer: placebo-controlled randomized phase III trial (IMagyn050/GOG 3015/ENGOT-OV39). J Clin Oncol. 2021;39(17):1842-1855.
10. ClinicalTrials.gov. Study of chemotherapy with pembrolizumab (MK-3475) followed by maintenance with olaparib (MK-7339) for the first-line treatment of women with BRCA non-mutated advanced epithelial ovarian cancer (EOC) (MK-7339-001/KEYLYNK-001/ENGOT-ov43/GOG-3036). https://clinicaltrials.gov/ct2/show/NCT03740165. Identifier: NCT03740165. Accessed July 30, 2021.
11. ClinicalTrials.gov. Durvalumab treatment in combination with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab and olaparib treatment in advanced ovarian cancer patients (DUO-O). https://clinicaltrials.gov/ct2/show/NCT03737643. Identifier: NCT03737643. Accessed July 30, 2021.
12. ClinicalTrials.gov. A phase 3 comparison of platinum-based therapy with TSR-042 and niraparib versus standard of care (SOC) platinum-based therapy as first-line treatment of stage III or IV nonmucinous epithelial ovarian cancer (FIRST). https://clinicaltrials.gov/ct2/show/NCT03602859. Identifier: NCT03602859. Accessed July 30, 2021.
13. ClinicalTrials.gov. A study in ovarian cancer patients evaluating rucaparib and nivolumab as maintenance treatment following response to front-line platinum-based chemotherapy (ATHENA). https://clinicaltrials.gov/ct2/show/NCT03522246 Identifier: NCT03522246. Accessed July 30, 2021.
14. Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;379(26):2495-2505.
15. Banerjee S, Moore K, Colombo N, et al. Maintenance olaparib for patients (pts) with newly diagnosed, advanced ovarian cancer (OC) and a BRCA mutation (BRCAm): 5-year (y) follow-up (f/u) from SOLO1 [ESMO abstract 811MO]. Ann Oncol. 2020;31(suppl 4).
16. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164.
17. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 nvestigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402.
18. Wu XH, Zhu JQ, Yin RT, et al. Niraparib maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer using an individualized starting dose (NORA): a randomized, double-blind, placebo-controlled phase III trial*. Ann Oncol. 2021;32(4):512-521.
19. González-Martin A, Matulonis U, Korach J, et al. Niraparib efficacy and safety in patients with BRCA-mutated ovarian cancer: results from three phase 3 niraparib trials [ASCO abstract 5518]. J Clin Oncol. 2021;39(15 suppl).
20. Wu L, Wu X, Zhu J, et al. Efficacy of niraparib maintenance therapy in Chinese women with platinum-sensitive recurrent ovarian cancer with and without secondary cytoreductive surgery: results from the NORA trial [ASCO abstract 5534]. J Clin Oncol. 2021;39(15 suppl).
21. Wang J, Wu X, Zhu J, et al. Safety assessment of niraparib individualized starting dose in patients with platinum-sensitive recurrent ovarian cancer: a randomized, double-blind, placebo-controlled, phase III NORA trial [ASCO abstract 5535]. J Clin Oncol. 2021;39(15 suppl).
22. Vilming B, Dahl F, Ingebrigtsen VA, et al. Real-life data of niraparib maintenance treatment in patients with recurrent platinum-sensitive ovarian cancer [ASCO abstract 5560]. J Clin Oncol. 2021;39(15 suppl).
23. Westin SN, Coleman RL, Fellman B, et al. EFFORT: efficacy of adavosertib in PARP resistance: a randomized 2-arm non-comparative phase 2 study of adavosertib with or without olaparib in women with PARP-resistant ovarian cancer [ASCO abstract 5505]. J Clin Oncol. 2021;39(15 suppl).
24. McMullen M, Karakasis K, Loembe B, Dean E, Parr G, Oza AM. DUETTE: a phase II randomized, multicenter study to investigate the efficacy and tolerability of a second maintenance treatment in patients with platinum-sensitive relapsed epithelial ovarian cancer, who have previously received poly(ADP-ribose) polymerase (PARP) inhibitor maintenance treatment. Int J Gynecol Cancer. 2020;30(11):1824-1828.
25. O’Malley DM, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate, in combination with bevacizumab in patients with platinum-agnostic ovarian cancer: final analysis [ASCO abstract 5504]. J Clin Oncol. 2021;39(15 suppl).
26. O’Malley DM, Matulonis UA, Birrer MJ, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020;157(2):379-385.
27. ClinicalTrials.gov. A study of mirvetuximab soravtansine in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression (SORAYA). https://clinicaltrials.gov/ct2/show/NCT04296890. Identifier: NCT04296890. Accessed July 19, 2021.