Ainhoa Madariaga

Safety of antibody-drug conjugates in gynecologic cancers: current evidence and management approaches

Mirvetuximab soravtansine: an oasis in the desert?

New horizons for platinum-resistant ovarian cancer: insights from the 2023 American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) Annual Meetings

Platinum-resistant ovarian cancer is difficult to treat and has a poor prognosis. Patients with platinum-resistant ovarian cancer have limited treatment options and often have a limited benefit from existing chemotherapeutic agents. There is a lack of contemporary effective anticancer drugs and reliable predictive biomarkers for this aggressive cancer. Recent cutting-edge research presented at the 2023 American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) Annual Meetings has provided insights into several potential therapeutic targets, such as DNA damage repair proteins, cell-cycle regulators, and immune-modulating agents. In addition, antibody-drug conjugates have provided new practice-changing results in platinum-resistant ovarian cancer. Here, we review the results of research presented at this annual event, with a focus on clinical trials investigating novel treatment approaches for platinum-resistant ovarian cancer, in addition to predictive and prognostic biomarkers for optimal patient selection, and other topics, such as real-world evidence.

Randomized Phase II Study of Bevacizumab with Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant/Refractory High-Grade Ovarian Cancer (NCI Trial)

Abstract Purpose: Mesothelin (MSLN) is highly expressed in high-grade serous/endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody–drug conjugate directed at the MSLN antigen with a tubulin polymerization inhibitor. We assessed the safety, activity, and pharmacokinetics of the combination AR/bevacizumab (Bev; ARB) versus weekly paclitaxel/Bev (PB) in patients with platinum-resistant/refractory HGOC (prrHGOC). Patients and Methods: Following a run-in phase I study to assess ARB safety, patients with prrHGOC with centrally confirmed MSLN-positive expression were randomized to ARB or PB (weekly paclitaxel 80 mg/m2 with Bev 10 mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate, safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events. Results: The combination of Bev (10 mg/kg) biweekly with AR (2.2 mg/kg) weekly was well tolerated. About phase II results, MSLN positivity was 88%, and 57 patients were randomized (28 ARB and 29 PB). Forty-two percentage of patients received prior Bev, and 23% were platinum-refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB, respectively [P = 0.03; HR = 2.02 (1.06–3.86)]. The overall response rate was 21% with ARB and 65% with PB. The most common treatment-related grade ≥3 adverse events were anemia (18%) with ARB and neutropenia (24%) with PB. Higher baseline levels of circulating IL6 were associated with worse PFS, and its levels decreased with PB treatment. Conclusions: Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as the standard of care.

Electronic malignant bowel obstruction symptom monitoring smartphone application for patients with gynecologic cancers

An ambispective, real-world multi-center study of DOstarlimab in patients with Recurrent or Advanced DNA mismatch repair deficient/microsatellite instability-high endometrial cancer (GEICO 120-R/DORA study)

Patients with advanced or recurrent endometrial cancer who experience progression following platinum-based chemotherapy have limited treatment options. The phase I GARNET trial showed the high efficacy of dostarlimab in treating mismatch repair deficient (dMMR) and/or microsatellite instability-high (MSI-H) endometrial cancer. DORA is a multi-center, ambispective, observational real-world study evaluating the efficacy and safety of dostarlimab. The study included patients with dMMR/MSI-H endometrial cancer who had experienced tumor progression on or after a platinum-based treatment and had received at least 1 cycle of dostarlimab within the Spanish Expanded Access Program. The primary endpoints were objective response rate and duration of response. A total of 129 patients from 57 of the Spanish Research Group for Gynaecological Cancer (GEICO) affiliated hospitals were enrolled, with 125 evaluable for radiological response. The median duration of dostarlimab administration was 8.8 months (interquartile range; 13.2), and 73 patients (57%) remained on therapy at the data cutoff. With a median follow-up of 11.6 months (range; 0.8-30.1), the objective response rate was 53.6% (95% CI 44.4 to 62.5). Complete response was observed in 27 patients (21.6%), and partial response in 40 (32%), with a median time to response of 2.9 months (95% CI 2.6 to 3.6). The median duration of response was not reached. The probability of maintaining the response at 12 and 24 months was 84.98% (95% CI 70.8 to 92.5) and 73.39% (95% CI 50.5 to 86.9), respectively. Treatment was discontinued due to toxicity in 4.7% of patients. Dostarlimab monotherapy in dMMR/MSI-H endometrial cancer patients shows similar efficacy in real-world practice to that observed in the GARNET trial.

Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma

AbstractThis multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9–39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0–20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16–53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3–35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling (PTEN, TP53, homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.

Wee1 Inhibition in Recurrent Serous Uterine Cancer: Science Paving the Way in a Challenging Disease

Clinician perceptions of asynchronous care for patients with ovarian cancer on PARP inhibitor therapy

Asynchronous care is an alternative model of care involving information transmission without a simultaneous interaction between people. This study aimed to understand clinician perspectives about providing asynchronous care to patients with ovarian cancer who are clinically stable and receiving poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi) maintenance therapy at a large academic teaching hospital. The Theoretical Domains Framework (TDF) was used to undertake this study. Interviews were conducted with oncologists, physician assistants, and nurses who actively manage this patient population. Data were analyzed according to TDF domains to generate themes and understand supports, barriers, and buy-in related to this model of care. Overall, 73% of the 15 clinicians (50% of the oncologists) participating in this study were willing to provide asynchronous care to patients on PARPi who were clinically stable. Several themes emerged representing considerations for moving forward with this model of care, including selecting the ideal patients, streamlined access to information, safe and effective escalations, perceived acceptability of the asynchronous model by clinicians, reimbursement, and an opportunity and willingness to innovate. Participants recognized the potential benefits of an asynchronous care model for patients on PARPi therapy who are clinically stable and the opportunity to innovate while optimizing the use of limited clinic resources. Continued work toward discovery and implementation of an asynchronous care model should account for findings uncovered by application of the TDF.

Heterogeneity and treatment landscape of ovarian carcinoma

Ovarian carcinoma is characterized by heterogeneity at the molecular, cellular and anatomical levels, both spatially and temporally. This heterogeneity affects response to surgery and/or systemic therapy, and also facilitates inherent and acquired drug resistance. As a consequence, this tumour type is often aggressive and frequently lethal. Ovarian carcinoma is not a single disease entity and comprises various subtypes, each with distinct complex molecular landscapes that change during progression and therapy. The interactions of cancer and stromal cells within the tumour microenvironment further affects disease evolution and response to therapy. In past decades, researchers have characterized the cellular, molecular, microenvironmental and immunological heterogeneity of ovarian carcinoma. Traditional treatment approaches have considered ovarian carcinoma as a single entity. This landscape is slowly changing with the increasing appreciation of heterogeneity and the recognition that delivering ineffective therapies can delay the development of effective personalized approaches as well as potentially change the molecular and cellular characteristics of the tumour, which might lead to additional resistance to subsequent therapy. In this Review we discuss the heterogeneity of ovarian carcinoma, outline the current treatment landscape for this malignancy and highlight potentially effective therapeutic strategies in development.

Identifying Mechanisms of Resistance by Circulating Tumor DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at Time of PARP Inhibitor Progression

Abstract Purpose: To evaluate the use of blood cell–free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC). Experimental Design: We used targeted sequencing (TS) to analyze 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared with whole-exome sequencing (WES) of baseline tumor tissues. Results: At baseline (time of initial PARPi progression), cfDNA tumor fractions were 0.2% to 67% (median, 3.25%), and patients with high ctDNA levels (>15%) had a higher tumor burden (sum of target lesions; P = 0.043). Across all timepoints, cfDNA detected 74.4% of mutations known from prior tumor WES, including three of five expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including seven TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed five of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (P = 0.001). Conclusions: Longitudinal testing of cfDNA by TS provides a noninvasive tool for detection of tumor-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation.

Impact of lymphadenectomy and intra-operative tumor rupture on survival in early-stage mucinous ovarian cancers

Mucinous ovarian carcinoma is a rare subtype of epithelial ovarian cancer with scarce literature guiding its management. We aimed to investigate the optimal surgical management of clinical stage I mucinous ovarian carcinoma by examining the prognostic significance of lymphadenectomy and intra-operative rupture on patient survival. We conducted a retrospective cohort study of all pathology-reviewed invasive mucinous ovarian carcinomas diagnosed between 1999 and 2019 at two tertiary care cancer centers. Baseline demographics, surgical management details, and outcomes were collected. Five-year overall survival, recurrence-free survival, and the association of lymphadenectomy and intra-operative rupture on survival were examined. Of 170 women with mucinous ovarian carcinoma, 149 (88%) had clinical stage I disease. Forty-eight (32%; n=149) patients had a pelvic and/or para-aortic lymphadenectomy, but only 1 patient with grade 2 disease was upstaged due to positive pelvic lymph nodes. Intra-operative tumor rupture was documented in 52 cases (35%). On multivariable analysis, after adjusting for age, final stage, and use of adjuvant chemotherapy, there was no significant association between intra-operative rupture with overall survival (HR 2.2 (0.6-8.0); p=0.3) or recurrence-free survival (HR 1.3 (0.5-3.3); p=0.6), or lymphadenectomy with overall survival (HR 0.9 (0.3-2.8); p=0.9) or recurrence-free survival (HR 1.2 (0.5-3.0); p=0.7). Advanced stage was the only factor that was significantly associated with survival. In clinical stage I mucinous ovarian carcinoma, systematic lymphadenectomy has low utility, as very few patients are upstaged and recurrence typically occurs in the peritoneum. Furthermore, intra-operative rupture does not appear to independently confer a worse survival, and therefore these women may not benefit from adjuvant treatment based on rupture alone.

Across barriers: poly ADP-ribose polymerase inhibitors beyond progression in high grade serous ovarian cancer with brain metastases

New approaches for targeting platinum-resistant ovarian cancer

Platinum is the backbone of systemic treatment in ovarian cancer and development of platinum resistance is associated with poor survival. Here, we perform a comprehensive review of the literature regarding resistance mechanisms and advances in therapy for platinum resistant ovarian cancer, with a focus on high-grade serous carcinoma. Platinum resistance can be intrinsic or acquired. Resistance mechanisms are complex and diverse. Intracellular mechanisms include restoration of homologous recombination repair, reduced intracellular accumulation of platinum, blocked cellular replication and inhibition of apoptosis. These act in concert with immunosuppressive, angiogenic and stromal changes in the tumour microenvironment to drive treatment resistance. Current molecular stratification lacks prognostic and predictive validity, limited in part by the extreme genomic complexity of high-grade serous ovarian cancer. Clinical trials represent an important option for patients as standard of care treatment options have limited efficacy. The most promising trials appear to focus on rational combinations of chemotherapy, immunotherapy, anti-angiogenics, PARP inhibitors, targeted therapy and/or antibody-drug conjugates. Resistance mechanisms are multifactorial with capacity to evolve over time, making clinical detection challenging. It is increasingly apparent that clinical trials must incorporate correlative studies to elucidate predictive biomarkers. They must also adopt endpoints that can appropriately measure benefit for palliative treatments. Future research must aim to deepen our understanding of the biology of this disease, and deliver meaningful benefit in terms of improved quality of life and overall survival for women with platinum resistant ovarian cancer.

Efficacy and safety updates of poly ADP-ribose polymerase (PARP) inhibitor maintenance in ovarian cancer from ASCO 2020

Manage wisely: poly (ADP-ribose) polymerase inhibitor (PARPi) treatment and adverse events

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have transformed the treatment landscape in front-line and recurrent high-grade serous ovarian cancer. Maintenance strategies with PARPi have been assessed in randomized phase III trials in ovarian cancer; switch maintenance in the case of olaparib, niraparib, and rucaparib; and concurrent followed by continuation maintenance with veliparib. These studies have shown progression-free survival advantage with PARPi maintenance, with no major adverse changes in the quality of life; however, overall survival data remain immature to date. PARPi have also been incorporated in clinical practice as a single-agent treatment strategy in high-grade serous ovarian cancer, mainly in women who harbor alterations in the

Adjuvant treatment in early stage cervical cancer—does more equal better?

Proactive assessment of patient reported outcomes in ovarian cancer studies: a systematic review and call for action in future studies

This systematic review aims to evaluate the proactive or real-time assessment of patient reported outcomes in studies involving patients with ovarian cancer undergoing systemic therapy. PubMed, Embase, and Cochrane databases were searched (from database inception until February 2022), and prospective ovarian cancer studies (experimental or observational) that incorporated patient reported outcomes, including quality of life, were included. The primary objective was to assess the ratio of studies incorporating real-time use of patient reported outcomes among those studies performing patient reported outcomes. A secondary objective was to describe the patient reported outcome reporting. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 checklist was followed. Descriptive statistics were used. 3071 articles were screened, with 117 included in the final analysis. Studies were published between 1990 and 2022, and consisted of 35 735 patients (median 140 patients per study; interquartile range 58-415). Median time from patient enrollment initiation to study publication was 7 years (range 1-15). Most studies were experimental/clinical trials (n=93, 79%) followed by observational (n=23, 20%). Therapeutic strategies were assessed in 98% (91/93) of experimental studies, most frequently chemotherapy (n=53, 58%), followed by antiangiogenics or poly-ADP ribose polymerase (PARP) inhibitors (n=8, 9%, each). Patient reported outcomes were the primary endpoint in 7.5% (7/93) and 83% (19/23) of experimental and observational studies, respectively. The ratio of real-time patient reported outcomes assessment/ evaluation was 0.9% (1/117). Completion of patient reported outcome questionnaires involves time and effort for patients with ovarian cancer. Responses to these questionnaires were only assessed in real time in <1% of analyzed studies. Efforts should be made to incorporate proactive assessment of patient reported outcomes to optimize patient care and safety.