Clinical Trials In Ovarian Cancer Research Articles

Abstract 6279: Estrogen signaling in low-grade serous ovarian carcinoma

Abstract High level of estrogen in the blood of women has been linked to the progression and possibly development of ovarian cancer. Almost all low-grade serous ovarian cancer (LGSOC) expresses estrogen receptor alpha (ERα protein encoded by the gene ESR1) and develops during reproductive age of women. However, recent studies suggested that a higher expression of ERα correlates with better survival. In a phase II clinical trial, hormonal therapies have been shown to be associated with a clinical benefit rate of 61% for recurrent ER-positive LGSOC patients. The study also indicated that women with recurrent LGSOC who received hormonal therapies had a significantly longer progression-free survival but not overall survival. Endocrine therapies have proven to be effective in treating breast cancer. Unfortunately, in ovarian cancer clinical trials (GOG0281 and PARAGON), these treatments have not achieved comparable results, with an objective response rate of only approximately 14%. To understand the ESR1 regulation in LGSOC, we have performed RNAseq and ChIPseq analyses of LGSOC tumor tissues. We also forced over-expression of ESR1 in LGSOC cell lines. Using RNAseq data, we aligned the sequencing reads to all the known ESR1 transcript variants. We found that ESR1 transcript variant 1, 2, 3 and X11 were the major transcripts expressed. Variants 1, 2 and 3 encode the regular 66 kDa ESR1 protein, while the X11 variant encodes a 52 kDa ESR1 protein. Both 66 kDa and 52 kDa ESR1 proteins were also detected in LGSOC tumor tissues by western blots. To further explore the function of ESR1 66kDa in LGSOC, we over-expressed ESR1 variant 1 in two LGSOC cell lines (HOC-7 and HCC5075) by transfecting with an expression plasmid. Total proteins were extracted from the mock control and transfected cells for functional proteomic analysis by reverse phase protein arrays (RPPA). From the RPPA data, overexpressing ESR1 in LGSOC cell lines suppressed DNA repair pathways but activated cell cycle and mitosis pathways. To further delineate the ESR1 DNA binding sites in LGSOC, we performed ChIPseq analysis of these tumor samples as well as two ovarian cancer cell lines that express ESR1 protein. Our results demonstrated that ESR1 regulated “cistromes” in ER positive ovarian carcinoma is very different from that in ER positive breast cancer as much less ESR1 binding sites were found in LGSOC. There are ESR1 binding sites common to both types of cancers, but we found quite a few unique ESR1 binding sites. We are trying to integrate the ChIPseq and RNAseq data and hopefully identify, for the first time, an ovarian cancer specific ERα cistrome. ER expression may not always correlate with activation of ESR1 signaling pathways, which may be one of the reasons underlying endocrine therapy resistance in ovarian cancer. The results of an integrated analyses will also give us insight on the management of ER positive LGSOC by identifying new genetic targets that may be used in combination with endocrine therapy. Citation Format: Yvonne TM Tsang, Chun Wai Oscar Ng, David Gershenson, K-Kwok wong. Estrogen signaling in low-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6279.

Deciphering tumor immune microenvironment differences between high-grade serous and endometrioid ovarian cancer to investigate their potential in indicating immunotherapy response

BackgroundOvarian cancer is a significant public health concern with a poor prognosis for epithelial ovarian cancer. To explore the potential of immunotherapy in treating epithelial ovarian cancer, we investigated the immune microenvironments of 52 patients with epithelial ovarian cancer, including 43 with high-grade serous ovarian cancer and 9 with endometrioid ovarian cancer.ResultsFresh tumor tissue was analyzed for genetic mutations and various parameters related to immune evasion and infiltration. The mean stromal score (stromal cell infiltration) in high-grade serous ovarian cancer was higher than in endometrioid ovarian cancer. The infiltration of CD8 T cells and exhausted CD8 T cells were found to be more extensive in high-grade serous ovarian cancer. Tumor Immune Dysfunction and Exclusion scores, T cell exclusion scores, and cancer-associated fibroblasts (CAF) scores were also higher in the high-grade serous ovarian cancer group, suggesting that the number of cytotoxic lymphocytes in the tumor microenvironment of high-grade serous ovarian cancer is likely lower compared to endometrioid ovarian cancer.ConclusionsThe high mean stromal score and more extensive infiltration and exhaustion of CD8 T cells in high-grade serous ovarian cancer indicate that high-grade serous ovarian cancer exhibits a higher level of cytotoxic T cell infiltration, yet these T cells tend to be in a dysfunctional state. Higher Tumor Immune Dysfunction and Exclusion scores, T cell exclusion scores, and CAF scores in high-grade serous ovarian cancers suggest that immune escape is more likely to occur in high-grade serous ovarian cancer, thus endometrioid ovarian cancer may be more conducive to immunotherapy. Therefore, it is crucial to design immunotherapy clinical trials for ovarian cancer to distinguish between high-grade serous and endometrioid ovarian cancer from the outset. This distinction will help optimize treatment strategies and improve outcomes for patients with different subtypes.

Pathologic response to neoadjuvant chemotherapy in ovarian cancer and its association with outcome: A surrogate marker of survival

ObjectiveWe aimed to validate whether pathologic response (pR) to neoadjuvant chemotherapy (NACT) using a three-tier chemotherapy response score (CRS) is associated with clinical outcome in ovarian cancer (OC) and could be used as surrogate marker for survival. MethodsWe conducted a retrospective study of OC patients with FIGO stage III/IV disease who received NACT and graded response as no or minimal (CRS 1), partial (CRS 2), or complete/near-complete (CRS 3) pR using tissue specimens obtained from omentum. Uni- and multivariate survival analyses were performed accounting for age, FIGO stage, debulking and BRCA status as well as neoadjuvant use of bevacizumab. ResultsCRSs 1, 2 and 3 were found in 41(31%), 62 (47%) and 30 (22%) of the 133 examined cases. Response to NACT was associated with significantly improved progression-free (PFS, p < 0.001) and overall survival (OS, p = 0.011). Complete/ near-complete pathologic response (CRS3) was associated with improved PFS (median 24.8 vs. 12.5 months, unadjusted HR 0.28 [95%CI 0.15–0.54], p < 0.001; adjusted hazard ration (aHR) 0.31 [95% CI 0.14–0.72], p = 0.007) and OS (median 63.3 vs. 32.1 months, unadjusted HR 0.27 [95%CI 0.10–0.68], p = 0.006; aHR 0.32 [95% CI 0.09–1.11], p = 0.072) when compared to no or minimal response (CRS1). ConclusionsWe validate a three-tier CRS for assessment of pathologic response to NACT in OC and demonstrate its prognostic independence of BRCA status or neoadjuvant bevacizumab use. Improving pR rates may be a useful goal of NACT in OC with the expectation of improved survival. The CRS may be a useful endpoint in clinical trials in OC.

Disparities in clinical trial participation in ovarian cancer: A real-world analysis

BackgroundSignificant disparities exist in clinical trial participation in non-gynecologic cancers, but little is known about disparities in ovarian cancer trial participation. Our objective was to examine patient, sociodemographic (race/ethnicity, insurance), cancer, and health system factors associated with clinical trial participation in ovarian cancer. MethodsWe conducted a retrospective cohort study of patients with epithelial ovarian cancer diagnosed from 2011 to 2021, using a real-world electronic health record derived database, representing around 800 sites of care in US academic and community practices. We used multivariable Poisson regression modeling to analyze the association of ever participating in an ovarian cancer clinical drug trial with patient, sociodemographic, health system, and cancer factors. ResultsOf the 7540 patients with ovarian cancer, 5.0% (95% CI 4.5–5.5) ever participated in a clinical drug trial. Patients of Hispanic or Latino ethnicity were 71% less likely to participate in clinical trials (RR 0.29, 95% CI 0.13–0.61) than non-Hispanic patients, and patients whose race was unknown or other than Black or White were 40% less likely to participate in clinical trials (RR 0.68, 95% CI 0.52–0.89). Patients who had Medicaid insurance were 51% less likely (RR 0.49, 95% CI 0.28–0.87) and those with Medicare were 32% (RR 0.48–0.97) less likely to participate in clinical trials than privately-insured patients. ConclusionIn this national cohort study, only 5% of patients with ovarian cancer participated in clinical drug trials. Interventions are needed to decrease race, ethnicity, and insurance disparities in clinical trial participation.

Enrollment representation of age, race, and ethnicity in ovarian cancer registrational clinical trials (2010-2020): An evaluation by the U.S. Food and Drug Administration.

e18527 Background: Ovarian cancer is the fifth leading cause of cancer mortality among U.S. women. Because clinical trials have historically not been demographically representative of real-world patients, an understanding of the extent of disparities is an important step in addressing them. We aimed to evaluate the representation of older adults and racial and ethnic minorities in trials for ovarian cancer drugs. Methods: We conducted a pooled analysis of all trials that were submitted to the U.S. Food and Drug Administration (FDA) from January 1, 2010 to December 31, 2020 in support of marketing applications for epithelial ovarian, fallopian tube, or primary peritoneal indications. Demographic data (age, race, and ethnicity) for adult participants were analyzed alongside incident ovarian cancer case data (diagnosis between 2010 and 2019) from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program. Enrollment to Incidence Ratio (EIR) is reported and defined as the percentage of participants divided by percentage of U.S. incident ovarian cancer cases. An EIR between 0.80-1.20 indicates adequate representation; &lt;0.80 or &gt;1.20 indicates underrepresentation or overrepresentation, respectively. Participants with race or ethnicity categories reported as unknown or missing, or insufficient for calculation were not included in this analysis. A sensitivity analysis was conducted to evaluate the exclusion of trials enrolling only BRCA+ participants. Results: The analysis included 8,211 participants enrolled across 15 clinical trials. Age was available for all participants; race/ethnicity was not reported for 16.3% of participants. With increasing age, EIR decreased (Table). Non-Hispanic (NH) White participants had the highest EIR of all racial/ethnic groups, while NH Black and Hispanic participants had the lowest EIR. Results were similar when excluding trials enrolling only BRCA+ participants. Conclusions: Adults aged ≥75, NH Black, and Hispanic participants were underrepresented in registrational trials for new ovarian cancer therapies. To enhance understanding of the correlation between age, race, and ethnicity, further analyses are necessary. Prospective measures are essential, as discussed in recent FDA guidances, to enroll an adequately representative population in ovarian cancer clinical trials.[Table: see text]

Patient-reported outcomes of maintenance rucaparib in patients with recurrent ovarian carcinoma in ARIEL3, a phase III, randomized, placebo-controlled trial

PurposeTo compare NFOSI-18 Disease Related Symptoms – Physical (DRSP), Total score, and side effect bother between maintenance rucaparib (600 mg twice daily) vs. placebo in the phase III ARIEL3 trial. MethodsARIEL3 (NCT01968213) included patients with ovarian carcinoma who responded to second-line or later platinum-based chemotherapy. The NFOSI-18 DRS-P and Total scales were secondary endpoints. The NFOSI-18 contains a side effect impact item (GP5): “I am bothered by side effects of treatment.” We compared treatment arms on change from baseline of DRS-P and Total scores using mixed models with repeated measures (MRMM). Time to first and confirmed deterioration of NFOSI-18 DRS-P and Total scales were analyzed using Cox regression. We also calculated the proportion of patients reporting moderate to high side effect bother on GP5. ResultsIn the intention-to-treat (ITT) cohort, mean change from baseline favored the placebo. Compared to placebo, rucaparib was associated with higher risk of deterioration [e.g., 4-point deteriorator definition hazard ratio (HR): 1.85; 95% CI: 1.46, 2.36; median time to first deterioration on DRSP: 1.9 vs. 7.0 months]. Confirmed deterioration results resembled those for first deterioration. Proportions of patients reporting moderate/high side effect bother on GP5 fluctuated around 20% across treatment cycles. Results in BRCA mutant and homologous recombination deficient cohorts were generally similar to those from the ITT cohort. ConclusionThis placebo-controlled study in the maintenance therapy setting provides a unique view of the impact of PARP inhibition on the patient-reported outcomes that are commonly used in ovarian cancer clinical trials. Information regarding the adverse side effect impact of PARP inhibitors should be weighed against their clinical benefit.

Patient-Reported Outcomes in Ovarian Cancer: Facilitating and Enhancing the Reporting of Symptoms, Adverse Events, and Subjective Benefit of Treatment in Clinical Trials and Clinical Practice.

Patient-reported outcomes (PROs) provide a valid, standardized way of assessing symptoms, adverse events and the subjective benefit of treatment from the patient's perspective. Assessment of PROs is critical in ovarian cancer due to the high morbidity of the disease and its treatments. Several well-validated PRO measures are available to assess PROs in ovarian cancer. Their inclusion in clinical trials can provide evidence on the benefits and harms of new treatments based on patients' experiences to guide improvements in clinical practice and health policy. Aggregate PRO data collected in clinical trials can be used to inform patients about likely treatment impacts and assist them to make informed treatment decisions. In clinical practice, PRO assessments can facilitate monitoring of a patient's symptoms throughout treatment and follow-up to guide their clinical management; in this context, an individual patient's responses can facilitate communication with their treating clinician about troublesome symptoms and their impact on their quality of life. This literature review aimed to provide clinicians and researchers with a better understanding of why and how PROs can be incorporated into ovarian cancer clinical trials and routine clinical practice. We discuss the importance of assessing PROs throughout the ovarian cancer disease and treatment trajectory in both clinical trials and clinical practice, and provide examples from existing literature to illustrate the uses of PROs as the goals of treatment change in each setting.

Health-related quality of life analysis in ovarian cancer clinical trials involving PARP inhibitors: a critical methodological perspective.

The poly (ADP-ribose) polymerase inhibitors (PARPi) have yielded significant clinical benefits as maintenance therapy in women with newly diagnosed and relapsed platinum-sensitive advanced ovarian cancer. These drugs were approved based on progression-free survival, the primary endpoint of their respective pivotal trials. Health-related quality of life (HRQoL) and/or patient-reported outcomes were included in these trials as a secondary exploratory endpoint. Nevertheless, many weaknesses in the analysis of HRQoL across these trials can be noticed. Heterogeneity and suboptimal HRQoL analysis in oncology trials contribute to misconceptions about this endpoint among oncologists and prevent quality of life as being an endpoint used for approvals. In this article, we discuss these HRQoL results from a methodological perspective and propose some solutions for improvement that could be used by regulatory and academic institutions running ovarian cancers trials. Notably, we suggest to measure and analyze HRQoL data after disease progression, to focus dedicated papers on the statistical analyses of HRQoL recommended by the SISAQOL consortium (linear mixed model for repeated measures and time-to-event approaches) and to communicate on available guidelines to ensure compliance with best international practices regarding the measurement and analysis of HRQoL.

Abstract 1129: Interrogating JAK/STAT signaling in ovarian cancer as a potential oncogenic driver and therapeutic target

Abstract Ovarian cancer is the 7th most common cancer in women. It is the most fatal of all female reproductive cancers, due to the 5-year overall survival of 10-30% and over half of patients being diagnosed with late-stage disease. Despite initial response to front line platinum- and taxol-based chemotherapies, over 70% of patients develop recurrent and chemotherapy resistant disease and nearly all of these women die of their disease. Recently, the use of targeted therapies such as bevacizumab and PARP inhibitors have been shown to improve progression-free survival. However, these regimens have thus far failed to improve overall survival in patients without specific genetic signatures, highlighting the urgent need for alternative therapies. We have identified lestaurtinib as a potent inhibitor of many ovarian cancer cell lines, including platinum and PARP inhibitor resistant models, and patient derived organoid models. RNA-sequencing following lestaurtinib treatment identified JAK/STAT signaling as one of the most profoundly downregulated pathways. Additionally, it was recently reported via single cell RNA sequencing of patient tumors that downstream mediators of the JAK/STAT pathway are among the most highly expressed genes in ovarian tumor cells. Further, we have discovered that STAT1 and STAT3 are constitutively activated in chemotherapy and PARP inhibitor resistant cell lines as reflected by high levels of Tyr701/705 and Ser727 phosphorylation suggesting induction of this pathway may drive resistance. Selective siRNA-mediated knockdown of STAT1/3 resulted in significant growth inhibition confirming their importance in maintaining cell viability. Surprisingly, we have identified profound differences in the ability of various JAK/STAT inhibitors to suppress ovarian cancer cell growth. For example, ruxolitinib, the only JAK/STAT inhibitor currently in clinical trials for ovarian cancer, failed to inhibit the growth sensitive, platinum resistant or PARP inhibitor resistant cell lines. Our preliminary data indicate that JAK/STAT inhibitor efficacy in preventing ovarian cancer cell growth is related to their ability to block specific phosphorylation events on STAT1/3 proteins. We believe that precise and selective inhibition of STAT1 and STAT3 signaling represents a robust, durable, and novel approach for the treatment of highly aggressive and resistant forms of ovarian cancer. Further we plan to elucidate the molecular mechanisms by which STAT1 and STAT3 function to support ovarian cancer cell viability and growth, in order to substantially advance our understanding of JAK/STAT signaling in ovarian cancer and to identify the most effective ways to pharmacologically inhibit JAK/STAT signaling in ovarian cancer cells. Outcomes from this work will have both immediate and long-term impacts for our patients and will lay the foundation for future biomarker-driven clinical trials. Citation Format: Esther Rodman, Michael Emch, Elizabeth Bruinsma, Xiaonan Hou, John Weroha, John Hawse. Interrogating JAK/STAT signaling in ovarian cancer as a potential oncogenic driver and therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1129.

Abstract 1232: Xerna࣪ TME Panel: A pan-cancer RNA-based investigational assay designed to predict patient responses to angiogenic and immune targeted therapies

Abstract While numerous anti-angiogenic and immune targeting therapies have become standard-of-care treatments for oncology, predictive biomarkers for these agents have been either entirely lacking or challenged by inconsistencies across indications. We have developed and validated the Xerna TME Panel as a novel machine learning-based RNA-sequencing biomarker assay that guides patient selection for tumor microenvironment (TME)-targeted therapies across multiple tumor types. Gene expression data sets from both public sources and clinical practice representing over 5000 samples across 7 different tumor types were analyzed using the Xerna TME Panel. The Xerna TME Panel consists of an artificial neural net that learns complex gene expression interactions between angiogenesis and tumor immune biologies and robustly classifies patient samples into one of four TME biomarker subtypes: Angiogenesis (A), Immune Suppressed (IS), Immune Active (IA), or Immune Desert (ID). The vast majority (&amp;gt;75%) of all samples were assigned a TME class designation with confidence scores in the upper quartile and had nearly bimodal distributions for biomarker-positive versus -negative classifications. When compared to other independent gene signatures, such as those describing angiogenesis/mesenchymal biology, inflammation, and immune suppression, the expression profiles from the Xerna TME subtypes showed enrichment of those biological processes. Each TME subtype represented between ~15-40% of subjects of each tumor type, indicating balanced representation of subgroups within the patient populations. The Xerna TME designations were prognostic across tumor types, with “A” tumors generally associated with the worst survival and “IA” tumors associated with the best survival. The predictive ability of the Xerna TME Panel to enrich for tumor responses to targeted therapies in gastric cancer was also evaluated. In a ramucirumab+paclitaxel clinical cohort, the Xerna TME Panel high Angiogenesis score tumors (A and IS) demonstrated a 48% response rate compared to a 31% for low Angiogenesis score tumors (IA and ID). In an immune checkpoint inhibitor (ICI) cohort, high Immune score tumors (IA and IS) showed a response rate of 34% vs. 5% for low Immune score tumors (A and ID). Within the microsatellite stable patients (MSS), which historically have low response rates to ICIs, the Xerna TME Panel was able to enrich for responses between Immune high vs. Immune low score patients (25% vs. 3%). Currently in use to prospectively enroll patients into a Phase 3 ovarian cancer clinical trial and in development as a companion diagnostic (CDx) assay, the Xerna TME Panel is a robust, pan-cancer biomarker assay capable of characterizing TME dominant biologies to further advance the matching of patients with targeted therapeutics. Citation Format: Seema Iyer, Luka Ausec, Daniel Pointing, Matjaz Zganec, Robert Cvitkovic, Miha Stajdohar, Valerie Chamberlain Santos, Kerry Culm, Mokenge Malafa, Jeeyun Lee, Rafael Rosengarten, Laura Benjamin, Mark T. Uhlik. Xerna࣪ TME Panel: A pan-cancer RNA-based investigational assay designed to predict patient responses to angiogenic and immune targeted therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1232.

Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246-Sensitive Disease Subtype.

Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag-driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.

The anti-proliferative and anti-metastatic effects of ONC206 are potentiated by olaparib in serous ovarian cancer

The anti-proliferative and anti-metastatic effects of ONC206 are potentiated by olaparib in serous ovarian cancer

AVB-500, a selective inhibitor of GAS6-AXL, shows improved therapeutic efficacy in combination with paclitaxel in uterine serous carcinoma

<h3>Objectives:</h3> The receptor tyrosine kinase AXL is highly expressed in uterine serous cancer (USC) and has been found to mediate chemoresistance. Recently, in a Phase I clinical trial in ovarian cancer, AVB-500 has been shown in combination with paclitaxel to be safe and tolerable. The objectives of this study were to determine if AVB-500 improves response to paclitaxel in USC in preclinical studies and to explore how GAS6/AXL expression modulates the immune environment via changes in cytokine secretion profiling. <h3>Methods:</h3> AVB-500 (AVB) was supplied by Aravive Biologics. XTT cell viability was performed with two USC tumor cells - ARK1 and primary cells derived from ascites of a patient with platinum refractory USC (PUC1). Cells were treated with paclitaxel (P) alone and with a combination of AVB-500 and paclitaxel (AVB+P). Western blot analysis for apoptosis marker, cleaved PARP (c-PARP) was completed with ARK1 cells treated with AVB, P, and AVB+P. <i>in vivo</i> studies were performed using NOD-SCID mice injected with 1 x 107 ARK1 cells intraperionteally (IP). Treatment groups included vehicle, AVB, P, and AVB+P. Tumor nodule number, volume, and weight were assessed for each treatment group. Profiling of 80 inflammatory cytokines was performed with conditioned media (CM) collected from ARK1 control and AXL knockdown (KD) cells using Human Cytokine Array C5 (RayBiotech). Per manufacturer's criteria, proteins were significantly upregulated if the signal intensity ≥1.50 fold, and significantly downregulated if the signal intensity ≤0.65 fold. <h3>Results:</h3> We found that the USC cell line ARK1 had decreased viability when treated with A+P than when treated with P alone (IC50 11.5nM vs 39.2nM). In addition, the relative percent viability was lower in the AVB+P treated cells for every concentration of P (0.156 nM to 320 nM, p<0.05). Similarly, PUC1 had decreased viability when treated with AVB+P than with P alone (IC50 20.9nM vs 43.3nM). Western blot revealed greater apoptosis in the AVP+P treated cells as seen by c-PARP expression when compared to P alone. An <i>in vivo</i> metastatic IP model had significantly fewer tumors when treated with AVB+P compared to P alone with number of tumor nodules ≤1mm (2.750 vs 7.889, p=0.028) as well as decreased tumor weight (0.025 g vs 0.079 g, p<0.001) and smaller tumor volume (16.75 mm3 vs 72.33 mm3, p=0.002). Mouse weights were similar between treatment groups, indicating a favorable safety profile of the AVB+P combination. Furthermore, the CM from ARK1 cells with and without AXL expression were compared and the following significant changes were identified in the AXL non-expressing CM: decrease in cytokines involved in tumor cell proliferation and survival (TNF<b>-</b>α TNF-β<b>,</b> IGF, HGF, and TGF<b>-</b>β3), decrease in pro-tumor cytokines (IL-10, IL-13, and IL-16), and a decrease in angiogenesis factors (angiogenin, PDGF, FGF-6, and FGF-7). <h3>Conclusions:</h3> The combination of AVB-500 and paclitaxel has demonstrates a superior therapeutic efficacy compared to paclitaxel alone in USC pre-clinical models. In addition, cytokine expression profiles for tumor cell proliferation, pro-tumor cytokines, and angiogenesis factors suggest a mechanism by which GAS6/AXL signaling leads to immune suppression and evasion. Experiments in additional USC cell lines and patient-derived xenograft models are ongoing.

Disparities in the enrollment of racial and ethnic minorities in clinical trials of poly ADP ribose polymerase inhibitors for women's cancers

<h3>Objectives:</h3> Disparities persist in the enrollment of diverse racial and ethnic groups in clinical trials for ovarian and breast cancers. We sought to analyze the enrollment of participants by race/ethnicity in phase II and III clinical trials involving poly ADP ribose polymerase (PARP) inhibitors for ovarian and breast cancers and compare these to the racial/ethnic prevalence of ovarian and breast cancer in the United States. <h3>Methods:</h3> This study was designed as a retrospective review of clinical trials registered with Clinicaltrials.gov. Studies included evaluated PARP inhibitors for the treatment of ovarian, fallopian tube, primary peritoneal, and breast cancers. Enrollment rates for clinical trials were stratified by race/ethnicity and type of cancer. Enrollment fractions (EF) were calculated using prevalence data from the Surveillance, Epidemiology, and End Results (SEER) Database. Odds ratios (OR) and 95% Confidence Intervals (CI) were calculated to compare minority enrollment rates to Non-Hispanic (NH) White enrollment rates. <h3>Results:</h3> A 48 trials were identified, 17 of which met inclusion criteria (12 ovarian, 2 breast and 3 breast and ovarian). For ovarian cancer trials, enrollment fractions were NH-White 1.5%, NH-Black 0.3%, Hispanic 0.5%, and Asian/Pacific Islander the largest at 2.4%. For breast cancer trials, the EF for NH-White participants was 0.005%, for NH-Black patients was 0.008%, for Hispanic patients was 0.003%, and for Asian/Pacific Islander patients, still the highest at 0.009%. Patients identified as NH-Black and Hispanic were significantly underrepresented compared to those identified as NH-White in clinical trials for ovarian cancer (OR 0.23, 95% CI [0.18-0.29] and OR 0.3, 95% CI [0.25-0.38] respectively, <i>p</i>-value of < 0.0001). In breast cancer trials, both NH-Black and Asian/Pacific Islander groups were significantly overrepresented compared to the NH-White (OR 1.54, 95% CI [1.02, 2.33] p=0.042, and OR 1.81, 95% CI [1.01, 3.26] p=0.047 respectively). EF comparisons for ovarian and breast cancer are noted in Table 1. <h3>Conclusions:</h3> NH-Black and Hispanic participants are significantly underrepresented in clinical trials evaluating PARP inhibitors for ovarian cancer compared to NH-White cohorts. Phase II and III trials assessing PARP inhibitors for ovarian and breast cancer do not accurately represent the populations diagnosed with these malignancies. Enrollment strategies are needed to increase diversity in PARP inhibitor clinical trials for women's cancers.

Abstract 1046: Synergistic cytotoxic effect of sulfated glycolipid PG545 in combination with ATR inhibition in ovarian cancer cells

Abstract Despite the advances in the molecular understanding of ovarian cancer (OC), improvements in therapy are still needed. PG545 is a highly sulfated small molecule and is currently in Phase I clinical investigation, which has shown promising antitumor activity in multiple tumor models, including ovarian, endometrial and pancreatic cancers. Ataxia telangiectasia and Rad3-related protein (ATR), plays a crucial role in maintaining genomic integrity by responding to a large spectrum of DNA damage, including double strand breaks (DSBs) that interfere with replication. Several ATR inhibitors have been developed, but resistance is likely to occur. This study aimed to investigate the potential synergistic effect of combining PG545 with ATR inhibition in OC. Proliferation and clonogenic assay showed that combination of PG545 with ATR shRNA or ATR inhibitor (ATRi; VE-822) synergistically decreased cell survival compared with single-agent treatments in two OC cell lines, OVCAR5 and OVCAR8 cells. PG545 monotherapy induced DNA damage, activated the ATR signaling pathways as well as the S and G2/M cell cycle checkpoints. The combination of PG545 and ATRi inhibited the phosphorylation of ATR and Chk1, induced γH2AX and lead to a marked increase in pan-nuclear γH2AX-positive cells. Moreover, ATRi diminished the cell cycle effects of PG545 and markedly enhanced PG545-induced apoptosis in OC cell lines. Taken together, our results indicate that the combination of PG545 with ATR inhibition may be promising options to be considered in future clinical trials of OC. Citation Format: Yinan Xiao, Chaolin Deng, Ye Guan, Ling Jin, Upasana Ray, Prabhu Thirusangu, Julie Staub, Haotian Xu, Viji Shridhar. Synergistic cytotoxic effect of sulfated glycolipid PG545 in combination with ATR inhibition in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1046.

Efficacy and safety of anti-PD-1-based therapy in combination with PARP inhibitors for patients with advanced solid tumors in a real-world setting

BackgroundRationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited.MethodEfficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).ResultsThis retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0–42.0%), with a DCR of 85.0% (95% CI, 73.4–96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events.ConclusionPARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.

The role of blinded independent radiologic review in ovarian cancer clinical trials: Discerning the value

Clinical trials are the cornerstone of medical research whereby hypothesis testing leads to meaningful advancements in care. Clinical trials require close monitoring for patient benefit and safety, as well as proper design to minimize bias and ensure applicability and validity. Clinical trialists have an ethical commitment to perform high quality research and optimize the deployment of limited resources including patients and funds.

Incorporating patient centered benefits as endpoints in randomized trials of maintenance therapies in advanced ovarian cancer: A position paper from the GCIG symptom benefit committee

BackgroundQuality of life and patient reported outcome measures (PROMs) are important secondary endpoints and incorporated in most contemporary clinical trials. There have been deficiencies in their assessment and reporting in ovarian cancer clinical trials, particularly in trials of maintenance treatment where they are of particular importance. The Gynecologic Cancer InterGroup (GCIG) symptom benefit committee (SBC) recently convened a brainstorming meeting with representation from all collaborative groups to address questions of how to best incorporate PROMs into trials of maintenance therapies to support the primary endpoint which is usually progression free survival (PFS). These recommendations should harmonize the collection, analysis and reporting of PROM's across future GCIG trials. MethodsThrough literature review, trials analysis and input from international experts, the SBC identified four relevant topics to address with respect to promoting the role of PROMs to support the PFS endpoint in clinical trials of maintenance treatment for OC. ResultsThe GCIG SBC unanimously accepted the importance of integrating PROM's in future maintenance trials and developed four guiding principles to be considered early in trial design. These include 1) adherence to SPIRIT-PRO guidelines, 2) harmonization of selection, collection and reporting of PROM's; 3) combining Health Related Quality of Life (HRQL) measures with clinical endpoints and 4) common approaches to dealing with incomplete HRQL data. ConclusionsClose attention to incorporating HRQL and PROM's is critical to interpret the results of ovarian cancer clinical trials of maintenance therapies. There should be a consistent approach to assessing and reporting patient centered benefits across all GCIG trials to enable cross trial comparisons which can be used to inform practice.

SPR965, a Dual PI3K/mTOR Inhibitor, as a Targeted Therapy in Ovarian Cancer.

SPR965 is an inhibitor of PI3K and mTOR C1/C2 and has demonstrated anti-tumorigenic activity in a variety of solid tumors. We sought to determine the effects of SPR965 on cell proliferation and tumor growth in human serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer (KpB model) and identify the underlying mechanisms by which SPR965 inhibits cell and tumor growth. SPR965 showed marked anti-proliferative activity by causing cell cycle arrest and inducing cellular stress in ovarian cancer cells. Treatment with SPR965 significantly inhibited tumor growth in KpB mice, accompanied by downregulation of Ki67 and VEGF and upregulation of Bip expression in ovarian tumors. SPR965 also inhibited adhesion and invasion through induction of the epithelial–mesenchymal transition process. As expected, downregulation of phosphorylation of AKT and S6 was observed in SPR965-treated ovarian cancer cells and tumors. Our results suggest that SPR965 has significant anti-tumorigenic effects in serous ovarian cancer in vitro and in vivo. Thus, SPR965 should be evaluated as a promising targeted agent in future clinical trials of ovarian cancer.

Measuring Quality of Life in Ovarian Cancer Clinical Trials-Can We Improve Objectivity and Cross Trial Comparisons?

Simple SummaryRegarded as the “disease that whispers” ovarian cancer remains difficult to diagnose and treat due to other complex conditions that may occur together. As research into new treatments for ovarian cancer continues, growing efforts to understand how treatments may be impact the day to day lives of women is also growing. Known as Patient Reported Outcomes or PROs and quality of life (QoL), the research community is improving how this important information communicated by women with ovarian cancer is captured across their cancer journey, and importantly, how this information can be used further refine treatments. Understanding the impact treatment has on day to day living is important, as new treatments should not only help control cancer cells, but also help keep women living with ovarian cancer living their lives to the fullest.Epithelial ovarian cancer (EOC) remains a lethal disease for the majority of women diagnosed with it worldwide. For the majority of patients, diagnosis occurs late, in the advanced setting. Disease-induced as well as treatment-related adverse events can negatively impact quality of life (QoL). Research to date has captured these data through use of patient-related outcomes (PROs) and, increasingly, has become an area of increased attention and focus in clinical trial reporting. QoL/PRO measurements in EOC clinical trials at different transition points in a patient’s journey are increasingly being recognized by patients, clinicians and regulatory agencies as the key determinants of treatment benefit. Various context-specific PROs and PRO endpoints have been described for clinical trials in EOC. Standardized approaches and checklists for incorporating PRO endpoints in clinical trials have been proposed. In a real-world clinical practice setting, PRO/QoL measures, which are meaningful, valid, reliable, feasible and acceptable to patients and clinicians, need to be implemented and used. These may assist by serving as screening tools; helping with the identification of patient preferences to aid in decision making; improving patient–provider communication; facilitating shared decision making. Importantly, they may also improve quality of care through an increasingly patient-centered approach. Potential areas of future research include assessment of anxiety, depression and other mental health issues. In good prognostic groups, such as maintenance clinical trials, following patients beyond progression will capture possible downstream effects related to delaying the psychological trauma of relapse, symptoms due to disease progression and side-effects of subsequent chemotherapy. Identifying PRO endpoints in next-generation-targeted therapies (including immunotherapies) also warrants investigation.