Disparities in clinical trial enrollment at a Canadian comprehensive cancer center: A 15-year retrospective study.

INTRODUCTION: Disparities in clinical trials (CTs) enrollment perpetuate inequities in treatment access and outcomes, but there is a paucity of Canadian data. The objective of this study was to examine disparities in cancer CT enrollment at a large Canadian comprehensive cancer center. METHODS: Retrospective study of CT enrollment among new patient consultations from 2006 to 2019, with follow-up to 2021 (N = 154,880), with the primary outcome of enrollment as a binary variable. Factors associated with CT enrollment were evaluated using multivariable Bayesian hierarchical logistic regression with random effects for most responsible physician (MRP) and geography, adjusted for patient characteristics (sex, age, language, geography, and primary care provider [PCP]), area-level marginalization (residential instability, material deprivation, dependency, and ethnic concentration), disease (cancer site and stage), and MRP (department, sex, language, and training). A sensitivity analysis of the cumulative incidence of enrollment was conducted to account for differences in disease type and follow-up length. RESULTS: CT enrollment was 11.2% overall, with a 15-year cumulative incidence of 18%. Lower odds of enrollment were observed in patients who were female (adjusted odds ratio [AOR], 0.82; 95% confidence interval [CI], 0.78-0.86), ≥65 years (AOR vs. <40, 0.61; 95% CI, 0.56-0.66), non-English speakers (0.72; 95% CI, 0.67-0.77), living ≥250 km away (AOR vs. <15 km, 0.71; 95% CI, 0.62-0.80), and without a PCP. Disease characteristics accounted for the largest proportion of observed variation (20.8%), with significantly greater odds of enrollment in patients with genitourinary cancers and late-stage disease. CONCLUSION: Significant sociodemographic disparities were observed, suggesting the need for targeted strategies to increase diversity in access to cancer CTs in Canada.

Antibody-Drug Conjugates: Advancing from Magic Bullet to Biological Missile.

Precision drug development is focusing on targeting tumor cell surface proteins for therapeutic delivery, maximizing biomarker identified on-target damage to the tumor while minimizing toxicity. A recent article demonstrated high expression of B7-H4 antigen on resistant ovarian cancer cells and described preclinical activity of B7-H4-directed antibody-drug conjugate. See related article by Gitto et al., p. 1567.

High grade adverse event reporting and enrolment in gynecologic oncology clinical trials.

OBJECTIVE: The primary objective is to assess factors associated with treatment related high grade (CTCAE grade ≥ 3) adverse event (AE) reporting among participants in gynecologic oncology clinical trials. METHODS: All AEs recorded in the Princess Margaret Clinical Trial adverse event database between 01/2016 and 12/2018 were evaluated. Gynecologic oncology clinical trials assessing systemic therapy were included. Inferential statistics on risk factors of related grade ≥ 3 adverse event reporting and GEE logistic models with Odds Ratios (OR) were performed. Multivariable analysis adjusting for age, clinical trial phase, sponsor, and therapy type. RESULTS: The gynecology cancer clinical trials accrued 317 unique patients (359 nested on trials) in 42 systemic therapy trials. In the period, 17,175 related AEs were reported in the gynecological cancer trials, 7.4% were grade ≥ 3. On multivariable analysis, no odds differences of grade ≥ 3 related AEs were detected according to study phase. Patients in immunotherapy clinical trials had lower odds of related grade ≥ 3 AEs than patients on targeted or other therapy (adjusted OR [aOR] 0.43; 95% CI 0.24-0.75). There was greater odds of related grade ≥ 3 AEs in clinical trials assessing combination vs single therapeutics (aOR 2.26, 95% CI 1.34-3.80). Patients aged ≥65 (aOR 1.77; 95% CI 1.08-2.89) had greater odds of related grade ≥ 3 AEs than patients aged 50 to 65 years. When compared to other disease sites, the odds of having a grade  ≥ 3 related AE reported in gynecology clinical trials was no different. CONCLUSIONS: In this cohort, factors influencing the odds of related grade ≥ 3 AE reporting in gynecologic trials included type of therapy and age. The study phase did not correlate with odds of high-grade AE reporting.

Methodical Manipulation of the TME in Ovarian Cancer.

The complex interplay between ovarian cancer cells and the tumor microenvironment (TME) modulates progression, with dynamic cellular interactions influenced by external modulators, including neoadjuvant chemotherapy (NACT). A recent article described the alterations within the TME following NACT, either with or without bevacizumab, in ovarian cancer. See related article by Tavira et al., p. 176.

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.

Treatment of Ovarian Cancer Beyond PARP Inhibition: Current and Future Options.

Ovarian cancer is the leading cause of gynecological cancer death. Improved understanding of the biologic pathways and introduction of poly (ADP-ribose) polymerase inhibitors (PARPi) during the last decade have changed the treatment landscape. This has improved outcomes, but unfortunately half the women with ovarian cancer still succumb to the disease within 5 years of diagnosis. Pathways of resistance to PARPi and chemotherapy have been studied extensively, but there is an unmet need to overcome treatment failure and improve outcome. Major mechanisms of PARPi resistance include restoration of homologous recombination repair activity, alteration of PARP function, stabilization of the replication fork, drug efflux, and activation of alternate pathways. These resistant mechanisms can be targeted to sensitize the resistant ovarian cancer cells either by rechallenging with PARPi, overcoming resistance mechanism or bypassing resistance pathways. Augmenting the PARPi activity by combining it with other targets in the DNA damage response pathway, antiangiogenic agents and immune checkpoint inhibitors can potentially overcome the resistance mechanisms. Methods to bypass resistance include targeting non-cross-resistant pathways acting independent of homologous recombination repair (HRR), modulating tumour microenvironment, and enhancing drug delivery systems such as antibody drug conjugates. In this review, we will discuss the first-line management of ovarian cancer, resistance mechanisms and potential strategies to overcome these.

Mirvetuximab Soravtansine in Platinum-Resistant Ovarian Cancer.

Ovarian cancer is the second leading cause of death from gynecologic malignancies worldwide. Management of platinum-resistant disease is challenging and clinical outcomes with standard chemotherapy are poor. Over the past decades, significant efforts have been made to understand drug resistance and develop strategies to overcome treatment failure. Antibody drug conjugates (ADCs) are a rapidly growing class of oncologic therapeutics, which combine the ability to target tumor-specific antigens with the cytotoxic effects of chemotherapy. Mirvetuximab soravtansine is an ADC comprising an IgG1 monoclonal antibody against the folate receptor alpha (FRα) conjugated to the cytotoxic maytansinoid effector molecule DM4 that has shown promising clinical activity in patients with FR-α-positive ovarian cancer. This review summarizes current evidence of mirvetuximab soravtansine in platinum-resistant ovarian cancer, focusing on clinical activity, toxicity, and future directions.

Molecular Results and Potential Biomarkers Identified from the Phase 3 MILO/ENGOT-ov11 Study of Binimetinib versus Physician Choice of Chemotherapy in Recurrent Low-Grade Serous Ovarian Cancer.

PURPOSE: We present the results of a post hoc tumor tissue analysis from the phase 3 MILO/ENGOT-ov11 study (NCT01849874). PATIENTS AND METHODS: Mutation/copy-number analysis was performed on tissue obtained pre-randomization. The Kaplan-Meier method was used to estimate progression-free survival (PFS). Unbiased univariate analysis, Cox regression, and binary logistic regression were used to test associations between mutation status and outcomes, including PFS and binary response by local RECIST 1.1. RESULTS: MILO/ENGOT-ov11 enrolled 341 patients, ranging in age from 22 to 79, from June, 2013 to April, 2016. Patients were randomized 2:1 to binimetinib or physician's choice of chemotherapy (PCC). The most commonly altered gene was KRAS (33%). In 135 patients treated with binimetinib with response rate (RR) data, other detected MAPK pathway alterations included: NRAS (n = 11, 8.1%), BRAF V600E (n = 8, 5.9%), RAF1 (n = 2, 1.5%), and NF1 (n = 7, 5.2%). In those with and without MAPK pathway alterations, the RRs with binimetinib were 41% and 13%, respectively. PFS was significantly longer in patients with, compared with those without, MAPK pathway alterations treated with binimetinib [HR, 0.5; 95% confidence interval (CI) 0.31-0.79]. There was a nonsignificant trend toward PFS improvement in PCC-treated patients with MAPK pathway alterations compared with those without (HR, 0.82; 95% CI, 0.43-1.59). CONCLUSIONS: Although this hypothesis-generating analysis is limited by multiple testing, higher RRs and longer PFS were seen in patients with low-grade serous ovarian cancer (LGSOC) treated with binimetinib, and to a lesser extent in those treated with PCC, who harbored MAPK pathway alterations. Somatic tumor testing should be routinely considered in patients with LGSOC and used as a future stratification factor.

First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma.

AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase II doses (RP2D) were AZD5153 30 mg once daily or 15 mg twice daily (monotherapy) and 10 mg once daily (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAE) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.

Emerging peptide therapeutics for the treatment of ovarian cancer.

INTRODUCTION: The discovery of therapeutic proteomic targets has resulted in remarkable advances in oncology. Identification of functional and hallmark peptides in ovarian cancer can be leveraged for diagnostic and therapeutic targeting. These targets are expressed in different tumor cell locations, making them excellent candidates for theranostic imaging, precision therapeutics, and immunotherapy. The ideal target is homogeneously overexpressed in malignant cells with no expression in healthy cells, thereby avoiding off-tumor bystander toxicity. Several peptides are currently undergoing extensive evaluation for the development of vaccines, antibody-drug conjugates, monoclonal antibodies, radioimmunoconjugates, and cell therapy. AREAS COVERED: This review focuses on the significance of peptides as promising targets in ovarian cancer. English peer-reviewed articles and abstracts were searched in MEDLINE, PubMed, Embase, and major conference databases. EXPERT OPINION: Peptides and proteins expressed in tumor cells are an exciting area of research with great potential and may significantly influence precision therapeutics and immunotherapeutic strategies. Accurate utilization of peptide expression as a predictive biomarker has the potential to greatly enhance treatment precision. The ability to measure receptor expression paves the way for its use as a predictive biomarker for therapeutic targeting and requires critical validation of sensitivity and specificity for each indication to guide therapy.

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.

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.

Chasing Immune Checkpoint Inhibitors in Ovarian Cancer: Novel Combinations and Biomarker Discovery.

A deep understanding of the tumor microenvironment and the recognition of tumor-infiltrating lymphocytes as a prognostic factor have resulted in major milestones in immunotherapy that have led to therapeutic advances in treating many cancers. Yet, the translation of this knowledge to clinical success for ovarian cancer remains a challenge. The efficacy of immune checkpoint inhibitors as single agents or combined with chemotherapy has been unsatisfactory, leading to the exploration of alternative combination strategies with targeted agents (e.g., poly-ADP-ribose inhibitors (PARP)and angiogenesis inhibitors) and novel immunotherapy approaches. Among the different histological subtypes, clear cell ovarian cancer has shown a higher sensitivity to immunotherapy. A deeper understanding of the mechanism of immune resistance within the context of ovarian cancer and the identification of predictive biomarkers remain central discovery benchmarks to be realized. This will be critical to successfully define the precision use of immune checkpoint inhibitors for the treatment of ovarian cancer.

A phase I study of the Wee1 kinase inhibitor adavosertib (AZD1775) in combination with chemoradiation in cervical, upper vaginal, and uterine cancers.

OBJECTIVE: Wee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aimed to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers. METHODS: A multi-institutional, open-label phase I trial was designed to assess dose escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45-50 Gy in 1.8-2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m2 and adavosertib 100 mg/m2 on days 1, 3 and 5 of each week during chemoradiation. The primary endpoint was to determine the recommended phase II dose of adavosertib. Secondary endpoints included toxicity profile and preliminary efficacy. RESULTS: Ten patients were enrolled (nine locally advanced cervical and one endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg by mouth daily on days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level -1 (adavosertib 100 mg by mouth daily on days 3 and 5), one out of five patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. The overall response rate at 4 months was 71.4%, including four complete responses. At 2 years follow-up, 86% of patients were alive and progression-free. CONCLUSION: The recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising, yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities.

Assessment of Homologous Recombination Deficiency in Ovarian Cancer.

Accurately assessing homologous recombination deficiency (HRD) to use as a predictive biomarker is an area of intense research in ovarian cancer. Validated assays have demonstrated utility in determining maintenance therapy following platinum sensitive chemotherapy. Novel functional assays promise the potential to reflect HRD in real time and predict response to PARP inhibitors. See related articles by Pikkusaari et al., p. 3110 and Blanc-Durand et al., p. 3124.

Symptom screening with Targeted Early Palliative care (STEP) versus usual care for patients with advanced cancer: a mixed methods study.

PURPOSE: Although early palliative care is recommended, resource limitations prevent its routine implementation. We report on the preliminary findings of a mixed methods study involving a randomized controlled trial (RCT) of Symptom screening with Targeted Early Palliative care (STEP) and qualitative interviews. METHODS: Adults with advanced solid tumors and an oncologist-estimated prognosis of 6-36 months were randomized to STEP or symptom screening alone. STEP involved symptom screening at each outpatient oncology visit; moderate to severe scores triggered an email to a palliative care nurse, who offered referral to in-person outpatient palliative care. Patient-reported outcomes of quality of life (FACT-G7; primary outcome), depression (PHQ-9), symptom control (ESAS-r-CS), and satisfaction with care (FAMCARE P-16) were measured at baseline and 2, 4, and 6 months. Semi-structured interviews were conducted with a subset of participants. RESULTS: From Aug/2019 to Mar/2020 (trial halted due to COVID-19 pandemic), 69 participants were randomized to STEP (n = 33) or usual care (n = 36). At 6 months, 45% of STEP arm patients and 17% of screening alone participants had received palliative care (p = 0.009). Nonsignificant differences for all outcomes favored STEP: difference in change scores for FACT-G7 = 1.67 (95% CI: -1.43, 4.77); ESAS-r-CS = -5.51 (-14.29, 3.27); FAMCARE P-16 = 4.10 (-0.31, 8.51); PHQ-9 = -2.41 (-5.02, 0.20). Sixteen patients completed qualitative interviews, describing symptom screening as helpful to initiate communication; triggered referral as initially jarring but ultimately beneficial; and referral to palliative care as timely. CONCLUSION: Despite lack of power for this halted trial, preliminary results favored STEP and qualitative results demonstrated acceptability. Findings will inform an RCT of combined in-person and virtual STEP.

An Attempt to Stretch the Benefit: Rechallenge with PARP Inhibitors in Ovarian Cancer.

PARP inhibitors exploit synthetic lethality in homologous recombination-deficient (HDR) cells and are standard-of-care treatment in newly diagnosed and relapsed epithelial ovarian cancer (EOC). A recent article demonstrated that a second course of olaparib can be safely administered to women with BRCA-mutated EOC. See related article by Morgan et al., p. 2602.

Maveropepimut-S, a DPX-Based Immune-Educating Therapy, Shows Promising and Durable Clinical Benefit in Patients with Recurrent Ovarian Cancer, a Phase II Trial.

PURPOSE: Patients with platinum-resistant ovarian cancer respond poorly to existing therapies. Hence there is a need for more effective treatments. PATIENTS AND METHODS: The DeCidE1 trial is a multicenter, randomized, open-label, single-arm phase II study to evaluate the safety and effectiveness of maveropepimut-S with cyclophosphamide in patients with recurrent ovarian cancer. Median follow-up for evaluable subjects was 4.4 months. Data were collected from March 2019 to June 2021. Subjects received two injections of 0.25 mL maveropepimut-S 3 weeks apart, followed by one 0.1-mL doses, every 8 weeks up to progression. Oral cyclophosphamide, 50 mg twice daily, was administered in repeating weekly on and off cycles. RESULTS: Twenty-two patients were enrolled. Median age was 58 years (38-78 years). Among the evaluable population, the objective response rate (ORR) was 21% [90% confidence interval (CI), 7.5%-41.9%], with a disease control rate (DCR) of 63% (90% CI, 41.8%-81.3%), including 4 (21%) patients with partial responses, 8 (42%) stable disease, and 7 (37%) progressive disease. The ORRs were consistent across subgroups based on platinum sensitivity, and DCR was higher in the platinum-resistant subpopulation. Four SD patients maintained clinical benefit up to 25 months. Most treatment-related adverse events (TRAE) were grade 1 and 2 (87% of unique events). Most common AEs were injection site reactions. Eight subjects reported grade 3 and no grade 4 AEs. Survivin-specific T-cell responses were observed in treated patients with clinical benefit. CONCLUSIONS: Maveropepimut-S with intermittent low-dose cyclophosphamide is well-tolerated, with clinical benefit for patients with recurrent ovarian cancer. Observed responses are irrespective of the platinum status.

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

This 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.