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Efficacy and safety of niraparib in patients aged 65 years and older with advanced ovarian cancer: Results from the PRIMA/ENGOT-OV26/GOG-3012 trial

Valabrega, Giorgio; Pothuri, Bhavana; Oaknin, Ana; Graybill, Whitney S; Sánchez, Ana Beatriz; McCormick, Colleen; Baurain, Jean-François; Tinker, Anna V; Denys, Hannelore; O'Cearbhaill, Roisin E; Hietanen, Sakari; Moore, Richard G; Knudsen, Anja Ør; de La Motte Rouge, Thibault; Heitz, Florian; Levy, Tally; York, Whitney; Gupta, Divya; Monk, Bradley J; González-Martín, Antonio
OBJECTIVE:To evaluate the impact of age on the efficacy and safety of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy. METHODS:Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016). Patients in the intent-to-treat population were categorized according to age at baseline (<65 years vs ≥65 years), and progression-free survival (PFS), safety, and health-related quality of life (HRQOL) were evaluated for each age subgroup (clinical cutoff date, May 17, 2019). Safety findings were also evaluated according to a fixed starting dose (FSD) or an individualized starting dose (ISD). RESULTS:Of 733 randomized patients, 289 (39.4%) were ≥65 years (190 niraparib, 99 placebo) at baseline. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) were similar in patients aged <65 years (13.9 vs 8.2 months; HR, 0.61 [0.47-0.81]) and ≥65 years (13.7 vs 8.1 months; HR, 0.53 [0.39-0.74]). The incidences of any-grade and grade ≥3 treatment-emergent adverse events (TEAEs) were similar across age subgroups; in the niraparib arm, TEAEs leading to dose discontinuation occurred in 7.8% of patients <65 years and 18.4% of patients ≥65 years. ISD use lowered the incidence of grade ≥3 thrombocytopenia events in niraparib-treated patients compared with the FSD (<65 years: 42.8% vs 18.0%; ≥65 years 57.0% vs 26.1%). HRQOL was comparable across age subgroups. CONCLUSION/CONCLUSIONS:Niraparib efficacy, safety, and HRQOL were generally comparable across age subgroups, although patients ≥65 years had a higher rate of discontinuations due to TEAEs. ISD use reduced grade ≥3 thrombocytopenia events regardless of age.
PMID: 38833992
ISSN: 1095-6859
CID: 5665262

Progression-free survival and safety at 3.5 years of follow-up: results from the randomized phase 3 PRIMA/ENGOT-OV26/GOG-3012 trial of niraparib maintenance treatment in patients with newly diagnosed ovarian cancer - a plain language summary

González-Martín, Antonio; Pothuri, Bhavana; Vergote, Ignace; Graybill, Whitney; Lorusso, Domenica; McCormick, Colleen C; Freyer, Gilles; Backes, Floor; Heitz, Florian; Redondo, Andrés; Moore, Richard G; Vulsteke, Christof; O'Cearbhaill, Roisin E; Malinowska, Izabela A; Shtessel, Luda; Compton, Natalie; Mirza, Mansoor R; Monk, Bradley J
WHAT IS THIS SUMMARY ABOUT?/UNASSIGNED:in 2023. The PRIMA study included adult patients with newly diagnosed advanced high-risk ovarian cancer whose tumors shrunk or became undetectable after treatment with chemotherapy with or without surgery. The PRIMA study evaluated how well the drug niraparib, also known as Zejula, worked at delaying or preventing ovarian cancer from coming back (recurring) or getting worse (progressing) compared with placebo (a substance with no effects that a doctor gives to a patient instead of a drug). The first results from the PRIMA study were published in 2019, when patients had participated in the PRIMA study for about 1.2 years. The article this PLSP is based on reports longer-term data from the PRIMA study, when patients had participated in the PRIMA study for about 3.5 years. Patients were monitored (or followed) for a longer time to understand how well niraparib continued to work and to evaluate whether the safety of niraparib changed with additional time being monitored. WHAT WERE THE RESULTS?/UNASSIGNED:Patients who took niraparib had more time before their cancer came back or got worse than patients who took placebo. In terms of safety, no new types of side effects with niraparib treatment were observed with additional time being monitored as part of the PRIMA study. WHAT DO THE RESULTS MEAN?/UNASSIGNED:NCT02655016 (PRIMA study) (ClinicalTrials.gov).
PMID: 38501262
ISSN: 1744-8301
CID: 5640342

Guideline concordant care for patients with locally advanced cervical cancer by disaggregated Asian American and Native Hawaiian/Pacific Islander groups: A National Cancer Database Analysis

Lee, Sarah S.; Gold, Heather T.; Kwon, Simona C.; Pothuri, Bhavana; Lightfoot, Michelle D.S.
Objective: Despite the within-group heterogeneity, Asian American (AA) and Native Hawaiian and Pacific Islander (NH/PI) patients are often grouped together. We compared the patterns of guideline-concordant care for locally advanced cervical cancer for disaggregated AA and NH/PI patients. Methods: Patients with stage II-IVA cervical cancer between 2004 and 2020 were identified from the National Cancer Database. AA patients were disaggregated as East Asian (EA), South Asian (SA), and Southeast Asian (SEA). NH/PI patients were classified as a distinct racial subgroup. The primary outcome was the proportion undergoing guideline-concordant care, defined by radiation therapy with concurrent chemotherapy, brachytherapy, and completion of treatment within eight weeks. Results: Of 48,116 patients, 2107 (4%) were AA and 171 (<1%) were NH/PI. Of the AA patients, 36% were SEA, 31% were EA, 12% were SA, and 21% could not be further disaggregated due to missing or unknown data. NH/PI patients were more likely to be diagnosed at an early age (53% NH/PI vs. 30% AA, p < 0.001) and have higher rates of comorbidities (18% NH/PI vs. 14% AA, p < 0.001). Within the AA subgroups, only 82% of SEA patients received concurrent chemotherapy compared to 91% of SA patients (p = 0.026). SA patients had the longest median OS (158 months) within the AA subgroups compared to SEA patients (113 months, p < 0.001). Conclusion: Disparities exist in the receipt of standard of care treatment for cervical cancer by racial and ethnic subgroups. It is imperative to disaggregate race and ethnicity data to understand potential differences in care and tailor interventions to achieve health equity.
SCOPUS:85183202826
ISSN: 0090-8258
CID: 5628962

Health-related quality of life in patients with newly diagnosed advanced ovarian cancer treated with niraparib vs placebo: Results from the phase 3 randomized PRIMA/ENGOT-OV26/GOG-3012 trial

Pothuri, Bhavana; Han, Sileny; Chase, Dana M; Heitz, Florian; Burger, Robert A; Gaba, Lydia; Van Le, Linda; Guerra, Eva; Bender, David; Korach, Jacob; Cloven, Noelle; Churruca, Cristina; Follana, Philippe; DiSilvestro, Paul; Baurain, Jean-François; Jardon, Kris; Pisano, Carmela; Peen, Ulla; Mäenpää, Johanna; Gupta, Divya; Bacqué, Emeline; Li, Yong; Compton, Natalie; Antonova, Jenya; Monk, Bradley J; González-Martín, Antonio
OBJECTIVE:To assess patient-reported health-related quality of life (HRQoL) in patients with ovarian cancer (OC) who received niraparib as first-line maintenance therapy. METHODS:PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) enrolled patients with newly diagnosed advanced OC who responded to first-line platinum-based chemotherapy. Patients were randomized (2:1) to niraparib or placebo once daily in 28-day cycles until disease progression, intolerable toxicity, or death. HRQoL was assessed as a prespecified secondary end point using patient-reported responses to the European Organisation for Research and Treatment of Cancer QOL Questionnaire (EORTC QLQ-C30), the EORTC QLQ Ovarian Cancer Module (EORTC QLQ-OV28), the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), and EQ-5D-5L questionnaires. Assessments were collected at baseline and every 8 weeks (±7 days) for 56 weeks, beginning on cycle 1/day 1, then every 12 weeks (±7 days) thereafter while the patient received study treatment. RESULTS:Among trial participants (niraparib, n = 487; placebo, n = 246), PRO adherence exceeded 80% for all instruments across all cycles. Patients reported no decline over time in HRQoL measured via EORTC QLQ-C30 Global Health Status/QoL and FOSI overall scores. Scores for abdominal/gastrointestinal symptoms (EORTC QLQ-OV28) and nausea and vomiting, appetite loss, and constipation (EORTC QLQ-C30) were higher (worse symptoms) in niraparib-treated patients than placebo-treated patients; except for constipation, these differences resolved over time. Patients did not self-report any worsening from baseline of fatigue, headache, insomnia, or abdominal pain on questionnaires. CONCLUSIONS:Despite some early, largely transient increases in gastrointestinal symptoms, patients with OC treated with niraparib first-line maintenance therapy reported no worsening in overall HRQoL.
PMID: 38325276
ISSN: 1095-6859
CID: 5632222

Guideline concordant care for patients with locally advanced cervical cancer by disaggregated Asian American and Native Hawaiian/Pacific Islander groups: A National Cancer Database Analysis

Lee, Sarah S; Gold, Heather T; Kwon, Simona C; Pothuri, Bhavana; Lightfoot, Michelle D S
OBJECTIVE:Despite the within-group heterogeneity, Asian American (AA) and Native Hawaiian and Pacific Islander (NH/PI) patients are often grouped together. We compared the patterns of guideline-concordant care for locally advanced cervical cancer for disaggregated AA and NH/PI patients. METHODS:Patients with stage II-IVA cervical cancer between 2004 and 2020 were identified from the National Cancer Database. AA patients were disaggregated as East Asian (EA), South Asian (SA), and Southeast Asian (SEA). NH/PI patients were classified as a distinct racial subgroup. The primary outcome was the proportion undergoing guideline-concordant care, defined by radiation therapy with concurrent chemotherapy, brachytherapy, and completion of treatment within eight weeks. RESULTS:Of 48,116 patients, 2107 (4%) were AA and 171 (<1%) were NH/PI. Of the AA patients, 36% were SEA, 31% were EA, 12% were SA, and 21% could not be further disaggregated due to missing or unknown data. NH/PI patients were more likely to be diagnosed at an early age (53% NH/PI vs. 30% AA, p < 0.001) and have higher rates of comorbidities (18% NH/PI vs. 14% AA, p < 0.001). Within the AA subgroups, only 82% of SEA patients received concurrent chemotherapy compared to 91% of SA patients (p = 0.026). SA patients had the longest median OS (158 months) within the AA subgroups compared to SEA patients (113 months, p < 0.001). CONCLUSION/CONCLUSIONS:Disparities exist in the receipt of standard of care treatment for cervical cancer by racial and ethnic subgroups. It is imperative to disaggregate race and ethnicity data to understand potential differences in care and tailor interventions to achieve health equity.
PMID: 38262236
ISSN: 1095-6859
CID: 5624882

Demographic reporting and language exclusion in gynecologic oncology clinical trials

Lee, Sarah S; Dinicu, Andreea I; Arthurs, Likolani; Shields, Danielle; Pothuri, Bhavana; Lightfoot, Michelle D S
BACKGROUND:Participation in clinical trials may help mitigate disparate cancer outcomes. Thus, ensuring equitable access to clinical trials is a major priority for national cancer organizations. OBJECTIVE:This study aimed to examine clinical trial eligibility criteria that may adversely affect the enrollment of underrepresented groups and assess the availability of demographic information in published gynecologic oncology studies. STUDY DESIGN/METHODS:ClinicalTrials.gov was searched for gynecologic oncology studies conducted between 1997 and 2021. Each study's inclusion and exclusion criteria were reviewed to determine whether demographic factors were used for enrollment screening. For published studies, demographic variables that were reported were identified. The expected clinical trial enrollment based on disease incidence and mortality was compared with the observed trial enrollment based on race. RESULTS:There were 1597 gynecologic oncology studies: 883 (55%) from ovarian cancer studies, 336 (21%) from cervical cancer studies, 262 (17%) from uterine cancer studies, and 116 (7%) from multisite gynecologic oncology studies. Of the 581 published studies, 554 (95%) reported age, 363 (63%) reported race, and 171 (29%) reported ethnicities. Cervical cancer studies were most likely to report demographic information, including race (P=.026) and ethnicity (P<.001). During the study period, 189 studies (12%) excluded patients based on the language spoken. Industry-sponsored trials (odds ratio, 0.07; 95% confidence interval, 0.02-0.30) and organization-sponsored trials (odds ratio, 0.40; 95% confidence interval, 0.22-0.73) were less likely to exclude patients because of language than investigator-initiated trials. A minority of patients (37%) in cervical cancer trials were of White race, compared with 85% of patients in uterine cancer trials and 82% of patients in ovarian cancer trials. CONCLUSION/CONCLUSIONS:Over the last 3 decades, 1 in 10 gynecologic oncology trials excluded patients because of language. Race and ethnicity were reported in more than half of the available studies. Initiatives to increase transparency in recruiting underrepresented patients and reporting demographic data are urgently needed.
PMID: 37751830
ISSN: 1097-6868
CID: 5614112

Oral Selinexor as Maintenance Therapy After First-Line Chemotherapy for Advanced or Recurrent Endometrial Cancer

Vergote, Ignace; Pérez-Fidalgo, Jose Alejandro; Hamilton, Erika Paige; Valabrega, Giorgio; Van Gorp, Toon; Sehouli, Jalid; Cibula, David; Levy, Tally; Welch, Stephen; Richardson, Debra L; Guerra, Eva M; Scambia, Giovanni; Henry, Stéphanie; Wimberger, Pauline; Miller, David S; Klat, Jaroslav; Martínez-Garcia, Jerónimo; Raspagliesi, Francesco; Pothuri, Bhavana; Romero, Ignacio; Bergamini, Alice; Slomovitz, Brian; Schochter, Fabienne; Høgdall, Estrid; Fariñas-Madrid, Lorena; Monk, Bradley J; Michel, Dayana; Kauffman, Michael G; Shacham, Sharon; Mirza, Mansoor Raza; Makker, Vicky; ,
PURPOSE/OBJECTIVE:Selinexor inhibits exportin-1 (XPO1) resulting in nuclear accumulation of tumor suppressor proteins including p53 and has clinical activity in endometrial cancer (EC). The primary end point was to assess progression-free survival (PFS) with once-weekly oral selinexor in patients with advanced or recurrent EC. PATIENTS AND METHODS/METHODS:ENGOT-EN5/GOG-3055/SIENDO was a randomized, prospective, multicenter, double-blind, placebo-controlled, phase III study at 107 sites in 10 countries. Patients 18 years or older with histologically confirmed EC were enrolled. All had completed a single line of at least 12 weeks of taxane-platinum combination chemotherapy and achieved partial or complete response. Patients were assigned to receive 80 mg oral selinexor once weekly or placebo with 2:1 random assignment (ClinicalTrials.gov identifier: NCT03555422). RESULTS:wild-type (wt) EC had a median PFS of 13.7 and 3.7 months with selinexor and placebo. The most common grade 3 treatment-related adverse events were nausea (9%), neutropenia (9%), and thrombocytopenia (7%). CONCLUSION/CONCLUSIONS:wt EC showed promising results with selinexor maintenance therapy.
PMID: 37669480
ISSN: 1527-7755
CID: 5589672

Concurrent uterine surgery and uptake of hormone therapy in patients undergoing bilateral salpingo-oophorectomy for risk-reducing or therapeutic indications

Sasse, Simone A; Lee, Sarah S; Rajeev, Pournami; Sharma, Sneha R; Kahan, Tamara; Pothuri, Bhavana
OBJECTIVE:This study aimed to analyze factors associated with concurrent uterine surgery in patients undergoing bilateral salpingo-oophorectomy (BSO) for risk reducing or therapeutic purposes. Additionally, trends in surgical choice and uptake of post-operative hormone therapy (HT) were examined. METHODS:A 10-year retrospective study was conducted on patients who underwent risk-reducing or therapeutic BSO at one institution. Multinomial regression analysis of patient and case characteristics was performed evaluating associations with surgery type (BSO, BSO and hysterectomy, or BSO and endometrial sampling). Trends in surgery type and uptake of HT post operatively are described. RESULTS:Among the study sample of 643 patients, 140 (22%) patients underwent therapeutic BSO for a history of hormone receptor (HR) positive breast cancer, while the remainder underwent risk-reducing BSO due to a pathogenic variant and/or family history. Pathogenic variants included BRCA1 (141, 40%) BRCA2 (173, 49%), and Lynch syndrome genes (15, 4%). Regression analysis revealed significant associations between concurrent hysterectomy and Black race (RR = 3.55, CI = 1.51-8.38, p = 0.004), history of HR positive breast cancer (RR = 1.88, CI = 1.03-3.42, p = 0.04), and surgeon (Surgeon 1, RR = 2.43, CI = 1.36-4.35, p = 0.003). Among eligible patients under age 51, 36% initiated HT. Over the study period, concurrent hysterectomy rates declined while endometrial sampling increased. CONCLUSIONS:Rates of hysterectomy declined over the study period and slightly more than one-third of eligible patients utilized post-operative HT. Further research on concurrent uterine surgery is needed to establish standardized treatment recommendations in the risk-reducing and therapeutic BSO population. Additionally, education regarding the benefits of postoperative HT in eligible patients is warranted.
PMID: 37988946
ISSN: 1095-6859
CID: 5608502

Safety, Efficacy, and Biomarker Analyses of Dostarlimab in Patients with Endometrial Cancer: Interim Results of the Phase I GARNET Study

Oaknin, Ana; Pothuri, Bhavana; Gilbert, Lucy; Sabatier, Renaud; Brown, Jubilee; Ghamande, Sharad; Mathews, Cara; O'Malley, David M; Kristeleit, Rebecca; Boni, Valentina; Gravina, Adriano; Banerjee, Susana; Miller, Rowan; Pikiel, Joanna; Mirza, Mansoor R; Dewal, Ninad; Antony, Grace; Dong, Yuping; Zografos, Eleftherios; Veneris, Jennifer; Tinker, Anna V
PURPOSE/OBJECTIVE:This interim report of the GARNET phase I trial presents efficacy and safety of dostarlimab in patients with advanced or recurrent endometrial cancer (EC), with an analysis of tumor biomarkers as prognostic indicators. PATIENTS AND METHODS/METHODS:A total of 153 patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) and 161 patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) EC were enrolled and dosed. Patients received 500 mg dostarlimab every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until progression. Primary endpoints were objective response rate (ORR) and duration of response (DOR). RESULTS:A total of 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC were evaluated for efficacy. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. Median DOR for dMMR/MSI-H EC was not met (median follow-up, 27.6 months); median DOR for MMRp/MSS EC was 19.4 months. The ORRs by combined positive score (CPS) ≥1 status were 54.9% and 21.7% for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORRs by high tumor mutational burden (≥10 mutations/Mb) were 47.8% (43/90) and 45.5% (5/11) for dMMR/MSI-H EC and MMRp/MSS EC, respectively. ORR in TP53mut or POLεmut molecular subgroups was 18.1% (17/94) and 40.0% (2/5), respectively. The safety profile of dostarlimab was consistent with previous reports. CONCLUSIONS:Dostarlimab demonstrated durable antitumor activity and safety in patients with dMMR/MSI-H EC. Biomarkers associated with EC may identify patients likely to respond to dostarlimab. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT02715284.
PMID: 37363992
ISSN: 1557-3265
CID: 5540132

Optimizing disease progression assessment using blinded central independent review and comparing it with investigator assessment in the PRIMA/ENGOT-ov26/GOG-3012 trial: challenges and solutions

Herzog, Thomas J; Wahab, Shaun A; Mirza, Mansoor R; Pothuri, Bhavana; Vergote, Ignace; Graybill, Whitney S; Malinowska, Izabela A; York, Whitney; Hurteau, Jean A; Gupta, Divya; González-Martin, Antonio; Monk, Bradley J
OBJECTIVE:Progression-free survival is an established clinically meaningful endpoint in ovarian cancer trials, but it may be susceptible to bias; therefore, blinded independent centralized radiological review is often included in trial designs. We compared blinded independent centralized review and investigator-assessed progressive disease performance in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy. METHODS:PRIMA/ENGOT-ov26/GOG-3012 was a randomized, double-blind phase 3 trial; patients with newly diagnosed stage III/IV ovarian cancer received niraparib or placebo. The primary endpoint was progression-free survival (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), determined by two independent radiologists, an arbiter if required, and by blinded central clinician review. Discordance rates between blinded independent centralized review and investigator assessment of progressive disease and non-progressive disease were routinely assessed. To optimize disease assessment, a training intervention was developed for blinded independent centralized radiological reviewers, and RECIST refresher training was provided for investigators. Discordance rates were determined post-intervention. RESULTS:There was a 39% discordance rate between blinded independent centralized review and investigator-assessed progressive disease/non-progressive disease in an initial patient subset (n=80); peritoneal carcinomatosis was the most common source of discordance. All reviewers underwent training, and as a result, changes were implemented, including removal of two original reviewers and identification of 10 best practices for reading imaging data. Post-hoc analysis indicated final discordance rates between blinded independent centralized review and investigator improved to 12% in the overall population. Median progression-free survival and hazard ratios were similar between blinded independent centralized review and investigators in the overall population and across subgroups. CONCLUSION:PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize blinded independent centralized review and investigator concordance using early, specialized, ovarian-cancer-specific radiology training to maximize validity of outcome data.
PMCID:10646892
PMID: 37931976
ISSN: 1525-1438
CID: 5609792