Recurrent Ovarian Cancer Research Articles

Budget Impact Analysis of Olaparib in Combination with Bevacizumab for Maintenance Therapy for Ovarian Cancer in Argentina.

To perform a budget impact analysis (BIA) of introducing olaparib as maintenance therapy in women who have BRCA mutations (BRCAm) with platinum-sensitive recurrent ovarian cancer (PSROC) in combination with bevacizumab in Argentina. A BIA model was used to analyse over a 5-year time horizon the change in the health system's budget following the adoption of olaparib as maintenance therapy in BRCAm patients with PSROC. The BIA for each year was estimated by comparing the cost difference between the current scenario (treatment with bevacizumab) and the new scenario (the addition of olaparib) for a third-party payer. The BIA is estimated at the national health system level, and by healthcare sectors in Argentina (public sector, social security and private sector). International and national epidemiological data were used to determine the target patient population. Clinical efficacy, safety outcomes and duration of treatments were obtained from the pivotal clinical study report. Relevant direct medical costs were obtained from public data in Argentina and expert consultation. All the costs are reported in US dollars as of October 2022 ($1 = 152.59 Argentine pesos). A scenario analysis assessed the full coverage of the homologous recombination deficiency (HRD) test in Argentina. In addition, one-way sensitivity analysis was conducted to evaluate the model robustness. For a third-party payer with a cohort of 1,000,000 women covered, the estimated target population was 2 individuals in year 1 and 6 individuals in year 5. The incorporation of olaparib, with a wholesale price per pack of $3176.32, was associated with a weighted average of the budget impact per member per month (PMPM) of $0.062 for the national health system, being above the estimated health system budget impact threshold ($0.0153). By healthcare sector, the results of budget impact PMPM for year 5 ranged between $0.08 (public sector) and $0.114 (private sector). For all perspectives, the variables that most influenced the budget impact was the incidence of ovarian cancer, the drug acquisition cost and the treatment duration. The introduction of olaparib for the treatment of BRCAm women with PSROC has a high budget impact for all three health systems in Argentina.

Efficacy and safety of luveltamab tazevibulin vs investigator’s choice of chemotherapy in patients with recurrent platinum-resistant ovarian cancer (PROC) expressing folate receptor alpha (FRα): The REFRaME-01 (GOG-3086, ENGOT-79ov, and APGOT-OV9) phase 2/3 study.

TPS5637 Background: The treatment of recurrent epithelial ovarian cancer remains a challenge, particularly for tumors with low to moderate expression levels of FRα. Luveltamab tazevibulin (luvelta) is an anti–FRα-targeting antibody-drug conjugate with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR=4), which induces cytotoxic and immunologic cell death. Luvelta was designed to treat multiple cancers with a broad range of FRα expression. Luvelta demonstrated preliminary antitumor activity in women with recurrent ovarian cancer, selected for FRα expression level of ≥25% at any intensity (tumor proportion score [TPS]). In PROC, this cutoff represents an estimated 80% of patients (pts). In a phase 1 study of luvelta in relapsed ovarian cancer, the overall response rate (ORR) was 37.5% with a median duration of response (DOR) of 5.5 months and a median progression-free survival (PFS) of 6.1 months. ORR was higher at 5.2 mg/kg compared with 4.3 mg/kg (43.8% vs 31.3%). The safety profile was manageable, with the most common grade ≥3 adverse events consisting of neutropenia, arthralgia, and anemia (Oaknin et al. J Clin Oncol 2023;41[16 suppl]:5508). These results support further investigation in pts with PROC whose tumors have a broad range of FRα expression. Herein, we describe a phase 2/3 pivotal study (REFRaME-01)of luvelta in this pt population. Methods: This randomized, global, open-label, 2-part phase 2/3 pivotal study has been designed to assess the efficacy and safety of luvelta vs investigator’s choice (IC) chemotherapy in pts with recurrent PROC expressing FRα (NCT05870748). Eligible pts are adults (≥18 years) with relapsed PROC, 1–3 prior lines of therapy (which must include bevacizumab), measurable disease, Eastern Cooperative Oncology Group performance status ≤1, and TPS for FRα expression ≥25% using Ventana validated IHC assay. Part 1 (phase 2) consists of a luvelta dose-optimization stage in which pts are randomized 1:1 to receive intravenous (IV) luvelta every 3 weeks (Q3W) at 4.3 mg/kg or IV luvelta Q3W at 5.2 mg/kg with prophylactic G-CSF for 2 cycles followed by 4.3 mg/kg luvelta from cycle 3 onward. Part 1 data will be used to select the optimal dosing regimen. In part 2 (phase 3) ~550 pts will be enrolled and randomized 1:1 to the optimal luvelta dosing regimen or IC chemotherapy (gemcitabine, paclitaxel, pegylated liposomal doxorubicin, or topotecan). Primary endpoints are PFS and ORR, with response evaluated per RECIST v1.1. Secondary endpoints include overall survival, DOR, safety, and quality of life. Clinical trial information: NCT05870748 .

Reflections on the changes in ascites and serum VEGF1 levels before and after intraperitoneal infusion of bevacizumab.

e17539 Background: This study analyzes the levels of VEGF1 in ascites and serum before and after intraperitoneal infusion of bevacizumab, aiming to explore the optimal administration route for treating recurrent ovarian cancer accompanied by ascites. Methods: Sixty-seven patients with advanced recurrent ovarian cancer and significant ascites were treated with intraperitoneal infusion of bevacizumab combined with chemotherapy. Under ultrasound guidance, a peritoneal drainage tube was placed, and the volume of ascites was measured before the infusion. The effects of the treatment were assessed by measuring the ascites volume during the 2nd to 3rd treatment (final ascites drainage) and by analyzing and comparing the levels of Vascular Endothelial Growth Factor 1 (VEGF1) in both ascites and serum. Results: The average volumes of ascites before and after treatment were 4229.97 ml and 5.42 ml, respectively (P<0.0001), with an overall response rate (ORR) of 89.6% (60/67). Before and after treatment, the levels of VEGF1 in ascites were 283.86 pg/mL and 18.76 pg/mL, respectively (P<0.0001). Before and after treatment, serum levels of VEGF1 were 80.67 pg/mL and 61.25 pg/mL, respectively (P<0.0001). Before treatment, the level of VEGF1 in ascites at 283.86 pg/mL was significantly higher than in serum, which was 80.67 pg/mL (P<0.0001). The reduction in VEGF1 levels following intraperitoneal infusion was over tenfold greater in serum compared to ascites. When the cutoff value for VEGF1 in ascites was set at 37.12 pg/mL, the sensitivity was 80.28%, and the specificity was 91.55%. Conclusions: The combined treatment of intraperitoneal infusion of bevacizumab with chemotherapy is an effective strategy for controlling ascites in recurrent ovarian cancer. Keywords: Bevacizumab, Intraperitoneal Infusion, Recurrent Ovarian Cancer, Ascites, Vascular Endothelial Growth Factor 1 (VEGF1).

A phase 1/2 study of ubamatamab (REGN4018), a MUC16×CD3 bispecific antibody, administered alone or in combination with cemiplimab (anti–PD-1) in patients with recurrent ovarian cancer or MUC16+ endometrial cancer.

TPS5632 Background: Mucin 16 (MUC16) is a cell surface glycoprotein that is overexpressed in ovarian cancer (OC) and endometrial cancer (EC). Ubamatamab is a MUC16 × cluster of differentiation 3 (MUC16×CD3) bispecific antibody that bridges MUC16 on tumor cells and CD3 on T cells to promote T-cell–mediated cytotoxicity. Cemiplimab, a monoclonal antibody targeting the programmed cell death-1 (PD-1) receptor, enhanced MUC16×CD3 activity in preclinical models. In Phase 1 of this first-in-human study (NCT03564340), ubamatamab alone and in combination with cemiplimab demonstrated an acceptable safety profile, durable clinical activity across a range of doses, and linear pharmacokinetics (PK) in patients (pts) with recurrent OC (Liu et al. IGCS 2023. Plenary 03). Phase 2 will assess the efficacy of ubamatamab alone and in combination with cemiplimab in pts with recurrent OC. Ubamatamab will also be evaluated for recurrent advanced or metastatic EC that is MUC16+. Methods: For individuals with recurrent OC, elevated serum cancer antigen (CA)-125 ≥2× the upper limit of normal, and up to four prior lines of cytotoxic therapy, weekly dosing of ubamatamab alone or in combination with cemiplimab will be evaluated in monotherapy and combination therapy expansion cohorts. A Phase 2 cohort will also be randomized 1:1:1 to receive ubamatamab 250 mg IV Q3W or 800 mg IV Q3W or ubamatamab 250 mg IV Q3W + cemiplimab 350 mg IV Q3W. For the EC cohort (≥25% of tumor cells MUC16+, as assessed by immunohistochemistry [IHC]) pts with advanced or metastatic EC that has progressed or is recurrent after prior anti–PD-1 therapy and prior platinum-based chemotherapy will be enrolled. The initial EC cohort will receive ubamatamab 250 mg IV Q3W. Based upon observed safety and activity, additional cohorts may be enrolled to receive ubamatamab 800 mg IV Q3W and/or ubamatamab 250 mg IV Q3W + cemiplimab 350 mg IV Q3W. To limit the risk of cytokine release syndrome, all pts will receive ubamatamab once-weekly step-up dosing prior to addition of cemiplimab and/or Q3W dosing. Expansion cohorts will use a Simon 2-stage study design, with an interim analysis after the first 20 pts. Any treatment arm with ≥3 objective responses may be expanded to 50 pts. In Phase 2, the primary endpoint will be the objective response rate for each arm (RECIST v1.1). Secondary endpoints include duration of response and progression-free survival, safety, PK, and change from baseline in quality of life. Exploratory objectives include clinical correlation with serum CA-125, MUC16 IHC, and immune markers. The study is currently enrolling to these OC and EC expansion cohorts. Clinical trial information: NCT03564340 .

Decision making factors regarding hospice care: A qualitative exploration in patients with recurrent ovarian cancer.

e24035 Background: Women with recurrent ovarian cancer (ROC) often must make end-of-life choices involving hospice care. We qualitatively explored patients’ (pt) understanding of hospice, and main decision-making factors. Methods: Pts were recruited by purposive sampling for semi-structured interviews, which were recorded, transcribed, and consensus coded. Results: 40 pts completed interviews. Median age = 63.4 yrs and time since diagnosis = 5.5 yrs. Important facilitators and barriers to hospice emerged. Key facilitators included: 1) desire to reduce care burden on family; 2) desire for a high quality death; and 3) acceptance (not afraid to die). On reducing care burden, one pt noted: “ I would think that the single most important factor would be the relief that it would give my family members. That they would not bear nearly as large a burden if hospice were to pick up part of that...” On desire for a high quality death, and acceptance: “ I’d wanna go out with as much dignity as possible...if it’s my time to go, let me go. I don’t wanna be...connected to all kinds of IVs and tubes and things just to keep my heart beating .”. Key barriers were: 1) lack of knowledge about hospice; 2) equating hospice to ‘giving up’; 3) loss of faith; and 4) letting go of perceived life-extending medical care like hydration or nutrition. Lack of knowledge was a prevalent theme: “ You only do hospice when it’s at the very end of the road. But maybe that’s not true. Maybe you do that to get some special care for a couple of months to get you through a tough...time. I guess I don’t know.” On giving up: “I would not say I'm a fan of it (hospice) at all...I would rather go out fighting....to me it's like giving up...I can't really imagine that I would actually do that.’Regarding loss of faith or letting go of perceived life-extending care: “ Well, my thoughts on how it works is I'm really not sure. They're there to keep you comfortable in your last days, but I don't know because I've heard so many horror stories with hospice...yeah they keep your pain down, but they don't give you faith. They don't give you hydration... it's like, God, pretty much starving you to death. But I don't know if that's true. I mean, that's just what I've heard.” A pivotal decision making factor that could be either a facilitator or barrier was family support for hospice, reinforcing the need for shared decision-making among the pt, family and clinical care team. One pt stated: “ It's an emotional toll, financial toll, it’s a physical toll on the family...and I would just want to talk to my family about all aspects of it, and then they would go from there, what they would want to do, or what I would want to.” Conclusions: Understanding perceived barriers and facilitators to hospice care through elicitation of pt beliefs and values and focusing efforts on educating pts and their support systems about the role of hospice can empower women with ROC to make informed pt-centered decisions about their end-of-life care.

Open-label, phase 2 study of adebrelimab combined with fuzuloparib in the treatment of patients with HRD-positive, recurrent platinum-resistant ovarian cancer.

TPS5634 Background: Adebrelimab, a humanized anti-PD-L1 monoclonal antibody, selectively targets PD-L1 molecules to inhibit the PD-1/PD-L1 pathway, reversing tumor-induced immune tolerance and revitalizing the immune system's capacity to combat tumors. Fuzuloparib, a novel PARP inhibitor, impedes the activity of poly (ADP-ribose) polymerase, halting the DNA repair mechanism for single-stranded breaks, resulting in DNA damage accumulation and consequent cancer cell apoptosis. Emerging evidence strongly supports that PARP inhibitors significantly extend progression-free survival in homologous recombination-deficient (HRD)-positive ovarian cancer. The TOPACIO study demonstrated that the combination of niraparib and pembrolizumab for platinum-resistant ovarian cancer achieved an objective response rate (ORR) of 18%, with durable responses in patients. This underscores the potential of integrating PARP inhibitors with immune checkpoint inhibitors in clinical protocols. For platinum-resistant recurrent ovarian cancer, known for its challenging prognosis, we propose conducting exploratory clinical trials on the combination of adebrelimab and fuzuloparib, aiming to establish robust evidence for future clinical applications. Methods: This open-label, single-arm, Phase 2 study aims to evaluate the anti-tumor activity and safety of adebrelimab in combination with fuzuloparib in approximately 37 patients with HRD-positive, recurrent platinum-resistant epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer (hereinafter referred to as ovarian cancer). The primary endpoint is to determine the objective response rate of the combined treatment regimen, as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints encompass disease control rate, progression-free survival overall survival, along with the assessment of safety and tolerability. Patients must be aged 18-70 years with an Eastern Cooperative Oncology Group performance status of 0–1 and have recurrent histologically confirmed ovarian cancer with HRD-positive tumor. Patients must have progressed within less than 6 months after the last treatment with platinum-containing chemotherapy. HRD status confirmed by testing BRCA gene, loss of heterozygosity, telomeric allelic imbalance and large-scale transition. Adebrelimab (20 mg/kg) is administered intravenously every 3 weeks and fuzuloparib (100mg) is administered orally twice daily as until the patient experiences disease progression, intolerable toxicity, or other study treatment discontinuation criteria are met. This clinical trial is in progress and 7 patients have been enrolled. Clinical trial information: NCT05753826 .

In situ tumor vaccine with optimized nanoadjuvants and lymph node targeting capacity to treat ovarian cancer and metastases

Tumor vaccine, a promising modality of tumor immunotherapy, needs to go through the process of tumor antigen generation and loading, antigen drainage to lymph nodes (LNs), antigen internalization by dendritic cells (DCs), DC maturation, and antigen cross-presentation to activate T-cells. However, tumor vaccines are often unable to satisfy all the steps, leading to the limitation of their application and efficacy. Herein, based on a smart nanogel system, an in situ nano-vaccine (CpG@Man-P/Tra/Gel) targeting LNs was constructed to induce potent anti-tumor immune effects and inhibit the recurrence and metastasis of ovarian cancer. The CpG@Man-P/Tra/Gel exhibited MMP-2-sensitive release of trametinib (Tra) and nano-adjuvant CPG@Man-P, which generated abundant in situ depot of whole-cell tumor antigens and formed in situ nano-vaccines with CpG@Man-P. Benefiting from mannose (Man) modification, the nano-vaccines targeted to LNs, promoted the uptake of antigens by DCs, further inducing the maturation of DCs and activation of T cells. Moreover, CpG@Man-P with different particle sizes were prepared and the effective size was selected to evaluate the antitumor effect and immune response in vivo. Notably, combined with PD-1 blocking, the vaccine effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis of ovarian cancer.

A phase I/II study of maplirpacept in combination with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer (OC): Phase 1 results.

e17546 Background: CD47, an overexpressed factor correlated with poor clinical characteristics and prognosis in OC, is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a signal to suppress macrophage phagocytosis. Maplirpacept (PF-07901801) is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4, enhancing phagocytosis by blocking CD47. Blockade of CD47, both alone and combined with doxorubicin, has shown anti-tumor activity in vitro and in vivo in xenograft animal models. PLD 40mg/m2 conveyed poor efficacy (PFS 4 months; ORR 8%), as did bevacizumab + PLD (PFS 5 months; ORR 14%) (AURELIA), highlighting the need for new treatments for platinum-resistant OC. C4971002 [NCT05261490] is an open label, multicenter dose-escalation and expansion study evaluating the safety, preliminary anti-tumor activity, pharmacokinetics and -dynamics of maplirpacept in combination with PLD in patients with platinum-resistant recurrent OC. Methods: The study included adults with platinum-resistant recurrent epithelial OC (PD ≤6 months after platinum-based therapy or unable/unwilling to receive platinum-based therapy). PLD while platinum-resistant or directly prior to study was not permitted. Patients received maplirpacept (12mg/kg Dose Level [DL] 1; 24mg/kg DL2; 48mg/kg DL3) weekly in Cycle 1 and every 2 weeks in Cycle 2+, and PLD (40mg/m2) on Day 1 of each 4-week cycle. Assessments of adverse events (AEs) were based on CTCAE v5.0. Response assessments (RECIST v1.1) were performed every 8 weeks. Results of the Phase I portion, aiming to evaluate the DLTs, the MTD and the RP2D, are presented as of 18 December 2023, after all patients completed the 28-day DLT assessment period. Results: 10 patients were treated (DL1 n=3; DL2 n=3; DL3 n=4) with a median (min, max) age of 69 (53, 77) years, 80% ECOG 1, 60% serous adenocarcinoma. Median (min, max) treatment duration was 14 (8, 32) weeks. Most common adverse events are shown in the table. No DLTs occurred in the assessment period. 1 serious AE (gait disturbance & muscle weakness) related to maplirpacept was reported (DL3). 2 deaths occurred >120 days after 1st dose, both due to disease. 5 (50%) patients had a best response of stable disease, 2 of which were treated into at least Cycle 6. Conclusions: Despite immature anti-tumor activity, maplirpacept + PLD was tolerable at all dose levels, not reaching the MTD. The encouragingly tolerable dose of 48mg/kg thus represents the RP2D which could support further development for this population. Clinical trial information: NCT05261490 . [Table: see text]

54P Real-world data of patients with recurrent BRCA-mutated platinum-sensitive ovarian cancer treated with olaparib maintenance: Surgical outcome subgroup analysis from the C-PATROL study

54P Real-world data of patients with recurrent BRCA-mutated platinum-sensitive ovarian cancer treated with olaparib maintenance: Surgical outcome subgroup analysis from the C-PATROL study

Real-world clinical outcomes and prognostic factors of olaparib maintenance in Korean patients with primary or recurrent high-grade ovarian cancer with exploratory analysis of location of BRCA1 and BRCA2 mutations.

e17561 Background: Olaparib is approved for first-line (1L) and second or subsequent-line (2L+) maintenance therapy in BRCA-mutated ovarian cancer (OC). However, the correlation between location of BRCA mutation and benefit of olaparib maintenance therapy has not been thoroughly investigated. We aimed to analyze real-world clinical outcomes and identify prognostic factors for olaparib maintenance therapy in Korean patients with BRCA-mutated OC, focusing on BRCA mutation sites. Methods: This retrospective cohort study included Korean patients with BRCA-mutated OC who received olaparib as 1L or 2L+ at the single center between January 2015 and April 2023. Survival outcomes and toxicity were correlated with BRCA mutation location summaries and patient characteristics by maintenance therapy line. Results: For the 1L group (n = 70), 2-year PFS and 3-year OS were 75.5% (95% CI, 56.4–87.1) and 98.5% (95% CI, 90.0–99.8). For the 2L+ group (n = 83), 2-year PFS and 3-year OS were 54.8% (95% CI, 56.4–87.1) and 87.3% (95% CI, 76.7–93.3). Primary stage (IV vs. ≤ III) was a prognostic factor for PFS in the 1L group (adjusted hazard ratio [aHR], 5.74; 95% CI, 1.23–26.73; P = 0.026). Notably, Korean-specific pathogenic variant p.Leu1780Pro BRCA1 mutation carriers (n= 8) showed significantly worse PFS than non-carriers (n = 32) in the 1L group (Log-rank P = 0.014). For the 2L+ group, platinum-free interval ≥ 12 months was a good prognostic factor for both PFS (aHR, 0.42; 95% CI, 0.23–0.75) and OS (aHR, 0.31; 95% CI, 0.11–0.91). Additionally, somatic BRCA1 mutation was a poor prognostic factor for PFS in the 2L+ group (hazard ratio [HR], 3.39; 95% CI, 1.22–9.38; P = 0.029). In the 1L group, the longer interval between the last chemotherapy and maintenance therapy was associated with the lower risk of hematologic toxicity induced by olaparib (odd ratio [OR], 0.75; 95% CI 0.57–0.99; P = 0.04). In addition, age ≥ 65 years (OR, 3.33; 95% CI, 1.05–10.63; P = 0.04) and the dose reduction of the last chemotherapy (OR, 3.80; 95% CI, 1.02–14.18; P = 0.047) were associated with a higher risk of hematologic toxicity in the 1L group. In the 2L+ group, germline BRCA1 (OR, 0.36; 95% CI, 0.14–0.92; P = 0.03) and BRCA2 (OR, 7.47; 95% CI, 1.96–28.39; P = 0.003) mutations showed contrariwise risks for hematologic toxicity. Drug discontinuation due to toxicity was 1.4% and 6.0% in the 1L and the 2L+ groups and no acute myeloid leukemia/myelodysplastic syndrome cases were observed. Conclusions: Olaparib maintenance therapy was effective and tolerable in Korean patients with BRCA-mutated OC. Prognostic factors for survival outcomes and risk factors of hematologic toxicity in olaparib maintenance therapy were different between 1L and 2L+. The prognostic significance of Korean-specific p.Leu1780Pro BRCA1 mutation on olaparib should be further researched.

Relationship of cancer stem cell functional assay and objective response rate of patients with recurrent platinum-resistant ovarian cancer in a randomized trial.

Relationship of cancer stem cell functional assay and objective response rate of patients with recurrent platinum-resistant ovarian cancer in a randomized trial.

Gemcitabine plus cisplatin in recurrent ovarian, fallopian tube, and primary peritoneal cancer.

Gemcitabine plus cisplatin in recurrent ovarian, fallopian tube, and primary peritoneal cancer.

A randomized, multicenter, open-label phase III trial of hyperthermic intraperitoneal chemotherapy in platinum-resistant recurrent ovarian cancer (KOV-HIPEC-02).

TPS5635 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreductive surgery has emerged to achieve a higher concentration of chemotherapeutic agents and treat micro-metastases on peritoneal surfaces. At advanced staged ovarian cancer treated with neoadjuvant chemotherapy, HIPEC during interval cytoreductive surgery with cisplatin 75-100mg/m2 increases progression-free survival and overall survival (OV-HIPEC-01 and KOV-HIPEC-01). In chemotherapy-naïve ovarian cancer patients, survival benefit is not identified with HIPEC (KOV-HIPEC-01). And the meta-analysis revealed the survival benefit after recent exposure of chemotherapy. In ovarian cancer, HIPEC is thought to overcome chemotherapy resistance. Methods: This trial (KOV-02) is currently actively enrolling, a multicenter, open-label, 1:1 randomized, phase III trial that will enroll 140 patients in platinum-resistant recurrent epithelial ovarian cancer. The trial is registered on ClinicalTrials.gov (NCT05316181). Institutional review board approval was obtained. The first patient was enrolled on April 07, 2022. The experimental arm will receive cytoreductive surgery and HIPEC (Doxorubicin 35mg/m2 and mitomycin 15mg/m2, 41.5-42.0°C) followed by physician-choice chemotherapy, and the control arm will receive physician-choice chemotherapy until disease progression or intolerable toxicity. The primary objective of the trial is to evaluate progression-free survival (PFS) between the HIPEC group and the control group. Secondary objectives are overall survival (OS), cancer-specific survival, safety, and quality of life. Assuming that the enrollment period is three years and the follow-up period is two years, the total number of events required is 121. Based on the log-rank test, the total number of subjects required to prove HR 0.6 with a two-sided alpha of 0.05 and 80% power is 126. Considering 10% drop-out, 140 patients are finally studied. Clinical trial information: NCT05316181 .

Use of Gynecologic Cancer Intergroup (GCIG) CA125 criteria to evaluate cell cycle checkpoint kinase 1 inhibitor (CHK1i) prexasertib response and disease progression (PD) in recurrent high-grade serous ovarian cancer (HGSOC).

e17536 Background: Data suggest discordance between serum biomarker CA125 and Response Evaluation Criteria in Solid Tumors (RECIST) response and/or PD in chemotherapies and PARP inhibitors. Here, we investigated the impact of CA125 on prognosis and its relationship with RECIST response/PD in HGSOC patients treated with a CHK1i, prexasertib. Methods: All relapsed HGSOC patients in this post-hoc analysis were treated with prexasertib at 105 mg/m2 IV every 14 days in a 28-day cycle until RECIST v1.1 PD, unacceptable toxicity, or consent withdrawal (NCT02203513). CA125 was assessed every cycle and CT scans obtained every two cycles. GCIG CA125 response was defined as >50% reduction confirmed after 28 days and PD as > 2X upper limit of normal (ULN) if baseline was normal or doubling of nadir if baseline was elevated. Patients with baseline CA125 < 2X ULN or nadir > 750 units/mL were not eligible for analysis. Clinical benefit rate (CBR; CR + PR + SD ≥ 6 months) was analyzed by Fisher’s exact test. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier curves and univariate (UV) and multivariate (MV) hazard ratios by Cox regression models. Positive predictive value (PPV) and negative predictive value (NPV) confidence intervals (CI) were estimated by the Wilson-Brown method. Results: Eighty-one patients received at least two cycles of prexasertib between January 2015 and November 2020, out of which 72 were evaluable by both RECIST and GCIG CA125 response criteria. CBR in the CA125 response (CA125-R) group (24/32; 75%) was significantly higher than the CA125 non-responder (CA125-N) group (12/40; 30%; p<0.001). CA125 response tended to occur prior to RECIST response (median: 28 days; IQR: 28, 30). PFS was improved in CA125-R at 8.0 months vs. CA125-N at 3.5 months (UV HR: 0.34, 95% CI: 0.21-0.56; MV HR: 0.35, 95% CI: 0.20-0.59). OS was improved in CA125-R at 19.8 months vs. CA125-N at 10.3 months (HR: 0.43, 95% CI: 0.26-0.71; MV HR: 0.45, 95% CI: 0.27-0.75). No significant differences in PFS or OS were observed between subgroups by BRCA mutation status, platinum-sensitivity, FIGO stage, baseline CA125 value, or previous PARP inhibitor therapy in MV analysis. Out of 70 patients evaluable by RECIST and CA125 PD criteria, 43 patients had CA125 PD and 24 of those had RECIST PD occur within one cycle of CA125 PD (PPV: 59%; 95% CI: 43-72). Of the 27 patients without a CA125 PD, 9 patients also did not have a RECIST PD (NPV: 33%; 95% CI: 19-52). Conclusions: GCIG CA125 response is an independent predictor of response to CHK1i in HGSOC prior to the first restaging scans and is associated with a higher CBR and improved PFS and OS. However, GCIG CA125 PD has poor PPV and NPV within a one cycle window, indicating that CA125 alone is not sufficient in monitoring for PD in HGSOC treated with CHK1i.

First results of the NOGGO PERCEPTION: Phase II investigational study of pembrolizumab in combination with chemotherapy in platinum-sensitive recurrent low-grade serous ovarian cancer.

e17550 Background: Low-grade serous ovarian cancer (LGSOC), a rare ovarian malignancy, exhibits a very limited responsiveness to chemotherapy. There is a pressing need for new therapeutic combinations with modern agents to enhance response rates and prognosis in this patient subgroup. Immune checkpoint inhibitors offer a promising pathway, having shown effectiveness in various malignant diseases, including selected cases of ovarian cancer. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: This clinical trial is a multi-center, single-arm phase 2 study to evaluate pembrolizumab therapy concomitant to platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin & carboplatin plus gemcitabine) and as maintenance in recurrent LGSOC cases. Eligible for the trial are LGSOC patients with progression or recurrence at least six months after most previous platinum-containing therapy and in good general performance (ECOG 0/1). The primary objective is the 12 months progression free survival (PFS) rate. Secondary end-points include overall survival, response rate (RR), PFS and RR according to Ki67 expression levels, time to first subsequent therapy and its response, safety and quality of life. The trial is planned according to Simon’s two-stage design with total sample size up to 33 patients. The null hypothesis is PFS-rate of at least 12 months of 20%. During the first stage 18 patients were enrolled and since 5 patients showed PFS of 12 months the study has been continued within stage 2 to enrol additional 15 patients. The trial can be claimed as successful, if at least 11 patients show PFS after 12 months. Assuming a true PFS-rate of 40%, this trial has 5% type I error rate and 80% power. Results: Data from 18 patients enrolled into this trial from FPI up to the time of interim analysis have been analyzed. 5 patients had reached the primary endpoint. 6 patients progressed or died before they reached the primary endpoint. At this time, 10 patients are still undergoing treatment and 7 patients may still reach the primary endpoint. Patients have a median age of 60 years (range: 43-81), ECOG score of 0 was recorded in 16 patients (88.9%) and most received one prior line of chemotherapy (61.1%, range: 1-5). 14 patients (77.8%) received carboplatin + PLD and 4 patients (22.2%) received carboplatin + gemcitabine as chemotherapy. 10 patients (55.6%) had at least one SAE. 3 patients (16.7%) had at least one SAE with relation to study treatment. 1 SAE resulted in a fatal outcome but was assessed not be related to study treatment. Conclusions: The interim analysis showed positive results, strengthening the hypothesis that pembrolizumab is an effective agent capable of extending progression-free survival in the studied patient population. Clinical trial information: NCT04575961 .

57P Prognostic impact of functional domain of BRCA1/2 mutation in platinum-sensitive recurrent epithelial ovarian cancer patients receiving PARP inhibitors

57P Prognostic impact of functional domain of BRCA1/2 mutation in platinum-sensitive recurrent epithelial ovarian cancer patients receiving PARP inhibitors

Weekly BH009 in patients with squamous cell carcinoma of the head and neck (SCCHN) and ovarian cancer: Interim phase I results.

e17545 Background: BH009 is a novel polysorbate 80-free formulation of docetaxel that will eliminate hypersensitivity reactions associated with polysorbate 80. BH009 has completed a bioavailability study compared to Taxotere and was found to have a better safety profile to Taxotere with the potential for higher doses. As a result, we conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD), and the safety profile of a weekly BH009 regimen in the treatment of patients with advanced SCCHN and Ovarian cancer. Methods: This phase I study assessed safety of BH009 in patients with advanced SCCHN and Ovarian cancer. BH009 was administered at escalating doses (starting dose 40 mg/m2) as a 1-h i.v. infusion for three consecutive weeks every 28 days without dexamethasone premedication. Results: Up to January 2024, 11 patients were treated with BH009 (4 at 40 mg/m2, 7 at 50 mg/m2). 2 patients with SCCHN, and 9 patients with ovarian cancer. 100% of ovarian cancer patients were recurrent platinum-resistant ovarian cancer (PROC) patients. 82% (9/11) of patients had received prior taxanes, of whom 33% (3/9) had received prior docetaxel. There were no DLT observed in 40 mg/m2 dose groups, and one DLT was observed in the 50 mg/m2 group (grade 3 febrile neutropenia). The MTD for BH009 is expected to exceed 50 mg/m2, which would be higher than that of Taxotere under the same dosing regimen (≥50mg/m2 vs 42mg/m2*), and the overall tolerability was better than Taxotere. In this study, treatment-related adverse events (TRAEs) occurred in 100% (11/11) patients. The most common grade 3/4 TRAEs were Leukopenia (36%, n=4), Anaemia (36%, n=4), and Neutropenia (55%, n=6). Non-hematologic toxicities were generally mild with no grade 4 toxicity observed. No AEs that led to death were related to BH009. Up to January 2024, the DCR is 50% (3/6) after 2 courses of treatment. The ORR in 6 evaluable patients was 33% (2/6, 1 patient with SCCHN at 40 mg/m2, 1 patient with ovarian cancer at 50 mg/m2). One patient (17%, 1/6) with ovarian cancer at 50 mg/m2 dose group received a complete response to the target lesion and the non-target lesion was partially responded after 2 courses of BH009, and this patient had been previously treated with docetaxel, carboplatin, and bevacizumab. Conclusions: The weekly BH009 for three consecutive weeks every 28 days is a feasible schedule with a favorable toxicity profile, and the overall tolerability is better than Taxotere. BH009 has the potential to increase the dose of administration and improve the clinical efficacy. Dose escalation is ongoing. Clinical trial information: NCT06232863 . [Table: see text]

55P Long-term responders (LTR) with niraparib maintenance in platinum-sensitive recurrent high-grade serous ovarian cancer (PSROC) focusing on subsequent therapies and post-progression outcomes (GEICO-88R study)

55P Long-term responders (LTR) with niraparib maintenance in platinum-sensitive recurrent high-grade serous ovarian cancer (PSROC) focusing on subsequent therapies and post-progression outcomes (GEICO-88R study)

Clinical factors predicting objective response to bevacizumab-based chemotherapies in advanced and recurrent epithelial ovarian cancer.

Bevacizumab-based chemotherapies are commonly administered in the treatment of patients diagnosed with epithelial ovarian cancer (EOC). The primary aim of this study was to assess the factors that predict the objective response to bevacizumab-based therapies in cases of advanced and recurrent EOC. The retrospective data of 264 patients with EOC from the current study were collected between 2009 and 2022 at our clinic. Survival analyses were conducted utilizing the Kaplan-Meier method and the log-rank test. Binary logistic regression analysis was employed to assess the factors predicting the objective response. A predominant subset of patients (83%) presented with serous adenocarcinoma, exhibiting a high-grade differentiation at 87%. The vast majority (80%) of the cohort experienced disease recurrence. Three-fourths of the cases received bevacizumab in combination with platinum-based doublet chemotherapy. In the multivariate analysis, clinical factors such as a disease recurrence (P=0.031), upfront tumor debulking surgery before bevacizumab (P=0.009), doublet chemotherapy (P=0.003), and the presence of malignant pleural effusion (P=0.024) emerged as significant determinants influencing the Objective Response Rate (ORR) in patients undergoing bevacizumab-based therapy. The ORR was 67.5% (N.=178), comprising 15.2% complete responses (N.=40) and 52.1% partial responses (N.=138). The median Progression-Free Survival (PFS) and Overall Survival (OS) were estimated at 10.2 months (95% CI, 8.60-11.9) and 20.1 months (95% CI, 16.0-24.2), respectively. The responses to bevacizumab-based chemotherapies could be predict by the presence of malignant pleural effusion, disease recurrence, upfront tumor debulking surgery and doublet regimen of chemotherapy.

Triptonide induces apoptosis and inhibits the proliferation of ovarian cancer cells by activating the p38/p53 pathway and autophagy

Ovarian cancer is a common malignant tumor in women, and 70 % of ovarian cancer patients are diagnosed at an advanced stage. Drug chemotherapy is an important method for treating ovarian cancer, but recurrence and chemotherapy resistance often lead to treatment failure. In this study, we screened 10 extracts of Tripterygium wilfordii, a traditional Chinese herb, and found that triptonide had potent anti-ovarian cancer activity and an IC50 of only 3.803 nM against A2780 cell lines. In addition, we determined that triptonide had a better antitumor effect on A2780 cell lines than platinum chemotherapeutic agents in vitro and that triptonide had no significant side effects in vivo. We found that triptonide induced apoptosis in ovarian cancer cells through activation of the p38/p53 pathway and it also induced cell cycle arrest at the S phase. In addition, we demonstrated that triptonide could activate lethal autophagy, which led to growth inhibition and cell death in ovarian cancer cells, resulting in an anti-ovarian cancer effect. Triptonide exerts its anti-ovarian cancer effect through activation of the p38/p53 pathway and induction of autophagy to promote apoptosis, which provides a new candidate drug and strategy for the treatment of ovarian cancer.