bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing the efficacy of abiraterone and enzalutamide in United States veterans with metastatic castration-sensitive prostate cancer (mCSPC) by estimating rates of tumor growth (g-rate).
Authors: Leuva Harshraj , Zhou Mengxi , Stamatov Rumen , Teply Benjamin A. , Rosenberg Ta-Chueh Melody , Luhrs Carol A. , Mundi Prabhjot Singh , Park Yeun-Hee Anna , Bates Susan Elaine , Faiena Izak , Fojo Antonio Tito
Published: June 2023

5076

Background: The choice of 1st line novel hormonal therapy in mCSPC is often based on comorbidities/physician preference due to the lack of data comparing abiraterone (Abi) and enzalutamide (Enza) in clinical trials and in real-world settings; especially in Black American (BA) patients. We have developed a novel method to estimate rates of tumor growth ( g-rate) and have shown that the g-rate is a robust biomarker of drug efficacy and overall survival in prostate cancer (Wilkerson, 2017; Leuva, 2019). We performed a 1:1 matched analysis to compare Abi and Enza outcomes in 1st line mCSPC, using g-rate and median overall survival (mOS) estimates. Methods: All patients with mCSPC diagnosis in national VA Corporate Data Warehouse were eligible for comparison. The cohort date range was from 7/2017 to 6/2022. Drug efficacy was established by estimating g-rates using PSA values while on therapy via the TUMGr package for R. For the matched analyses, we created 1:1 comparison cohorts for Abi and Enza, matched on age (±10 years), race, total number of therapies received (1/≥2), drug start year (<2020/≥2020), PSA at diagnosis (<20/≥20), Gleason score (GS) (<8/≥8), Charlson comorbidity index excluding cancer diagnosis (<5/≥5) and therapy setting (urban/rural). Results: We identified a total of 1712 and 464 Veterans with mCSPC who received Abi and Enza as 1st line, with median follow-ups of 19 and 12 mo, respectively. Fewer Veterans and shorter duration of follow up with Enza than Abi reflect Abi’s earlier approval in mCSPC. The Abi and Enza cohorts had similar median g-rates 0.000114/d and 0.000110/d, respectively (p=0.76). The mOS was 43 mo for Abi versus not reached (NR) for Enza (p=0.33). Our cohort had 425(25%) and 119(26%) BA veterans who received Abi and Enza, respectively. Compared to Caucasians, mOS was similar with Abi (42.7 vs 41.9 mo, HR-0.96, p=0.6) and Enza (NR, HR-0.85, p=0.4) for BA. In 1:1 matched analysis, the Abi and Enza arms had 391 patients and both had median follow-ups of 13 mo. We did not observe a statistically significant difference in median g-rate and mOS for either the whole matched cohort or BA subgroup when comparing Abi to Enza. The matched cohort had 203 (52%) with GS ≥8 and 228 (58%) Veterans with PSA ≥20 at diagnosis; there was no significant mOS difference in these subgroups. Conclusions: Real-world data from 2176 Veterans show comparable efficacy for Abi and Enza as 1st line for mCSPC, with similar g-rates and mOS, even when matched on various factors, including comorbidities, and in aggressive/high volume matched cohorts. BA patients also had similar g-rates and mOS. [Table: see text]
Phase 2 study of olaparib (without ADT) in men with biochemically recurrent prostate cancer (BCR) after prostatectomy.
Authors: Marshall Catherine Handy , Teply Benjamin A. , Lim Su Jin , Wang Hao , Mao Shifeng S. , Kelly William Kevin , Paller Channing Judith , Markowski Mark Christopher , Denmeade Samuel R. , Carducci Michael Anthony , Eisenberger Mario A. , King Serina , Sullivan Rana , Lotan Tamara L. , Antonarakis Emmanuel S.
Published: June 2023

5087

Background: The natural history of BCR after prostatectomy is variable and current treatment approaches include observation, salvage radiation, or androgen deprivation therapy (ADT), although many men wish to defer such therapy. We hypothesized that olaparib, now approved for use in certain men with metastatic castration resistant prostate cancer, might be an alternative option for men with high-risk BCR. Methods: This was a single arm, phase 2 trial (NCT03047135) conducted at 4 US sites. Subjects with biochemically recurrent (M0) prostate cancer, post prostatectomy, with a PSA doubling time of ≤6 months and an absolute PSA of ≥1.0 ng/mL were eligible. Patients were NOT selected based on the presence of homologous recombination repair (HRR) mutations. 51 patients were treated with olaparib 300mg twice per day, until radiographic or symptomatic progression, PSA doubling from baseline value, or drug-related toxicity. The primary endpoint was PSA50 response (50% PSA decline from baseline). Secondary endpoint was PSA progression free survival (PFS). Patients were required to undergo tissue-based next generation sequencing on the radical prostatectomy specimen to determine the presence of mutations in HRR genes ( ATM, BARD1, BRCA1/2, BRIP1, CDK12, CHEK1/2, FANCA/E/L, PALB2, RAD51B/C/D). A prespecified endpoint was to assess PSA responses in HRR[+] and HRR[–] cohorts separately. Results: Mean age was 64 years (SD 7), and 92% (47/51) of patients were White. Mean baseline PSA doubling time was 2.9 (SD 1.5) months. 55% (28/51) of pts had Gleason 6-7, 14% (7/51) had Gleason 8, and 31% (16/51) had Gleason 9-10. 86% (44/51) of patients had previously received salvage radiation. 27 patients harbored HRR mutations, the most common of which were BRCA2 (n=11), CHEK2 (n=6), and ATM (n=6). The overall PSA50 response rate was 24% (12 of 51)(95% CI 0.13, 0.38), with no responses in the HRR[–] group and 44% (12/27) PSA50 responses in the HRR[+] group (95%CI 0.26, 0.65). All 11 of the participants with a BRCA2 mutation achieved a PSA50 response. The median PSA PFS was 22 months in the HRR[+] group and 13 months in the HRR[–] group (HR 0.71; 95% CI 0.31, 1.63). Most AEs were low grade. The most common all-grade AEs were fatigue, nausea, leukopenia, anemia, and dysgeusia. Grade-3 AEs were leukopenia (9.8%), ALT/AST increase (3.9%), and anemia (2.0%). There were no grade 4–5 AEs. Conclusions: Olaparib, in the absence of ADT, can be safely administered and demonstrated activity in men with BCR prostate cancer and HRR mutations, especially for BRCA2 mutations. Additional studies to further evaluate olaparib in these patients are indicated. Clinical trial information: NCT03047135 .
Assessment of risk of overall and late distant recurrence by Breast Cancer Index in postmenopausal women with early-stage, HR+ breast cancer in the TEAM trial.
Authors: Bartlett John MS , Xu Keying , Wong Jenna , Pond Gregory Russell , Zhang Yi , Spears Melanie , Salunga Ranelle C. , Mallon Elizabeth , Taylor Karen J , Hasenburg Annette , Markopoulos Christos , Dirix Luc Yves , Seynaeve Caroline M. , Van De Velde Cornelis J.H. , Rea Daniel William , Schnabel Catherine A , Treuner Kai , Bayani Jane
Published: June 2023

509

Background: Individual risk assessment of distant recurrence (DR) is particularly relevant for early-stage HR+ breast cancer patients, as they face a prolonged risk of recurrence even after adjuvant endocrine therapy. Previously, we have shown that the Breast Cancer Index (BCI) and BCIN+ risk groups are significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence in N0 and N1 breast cancer patients, respectively, enrolled in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Here, the prognostic performance of BCI and BCIN+ as a continuous risk score for overall and late distant recurrence was evaluated in the TEAM trial. Methods: BCI testing was performed blinded to clinical outcome with BCI/BCIN+ risk scores calculated as previously described. Cox proportional hazard models adjusted for age, tumor size, grade and treatments were used to estimate hazard ratios (HRs) and the associated 95% confidence intervals (CIs) for BCI/ BCIN+ continuous risk scores. The 10y risk of overall and late DR were estimated as a function of risk scores from the Cox models using Breslow estimates. Results: Continuous risk curves for overall and late DR were obtained in patients who did not receive adjuvant chemotherapy and those who remained DR-free at 5 years regardless of chemotherapy, respectively, to reflect the two key time points for breast cancer treatment decision-making. InN0 patients not treated with chemotherapy (N = 1197), BCI was significantly prognostic for overall DR with a HR of 1.39 (95% CI 1.25-1.54; p < 0.001), while BCIN+ was significantly prognostic in N1 patients who did not receive chemotherapy (N = 1319) with a HR of 4.29 (95% CI 2.93-6.28; p < 0.001). Among patients who remained DR-free at 5 years, in the N0 subset (N = 1285), BCI was significantly prognostic for late DR with a HR of 1.23 (95% CI 1.07-1.42; p < 0.001), while BCIN+ remained to be significantly prognostic in the N1 subset (N = 1762) with a HR of 2.78 (95% CI 1.75-4.43; p < 0.001). Similar results were observed in the HER2- subset for both overall and late DR. Continuous risk curves for BCI and BCIN+ for overall and late DR showed an increasing risk of DR with higher BCI/BCIN+ scores. Conclusions: Results from this largest BCI study to date further support the use of BCI to provide individualized risk estimates for both overall and late DR in women with HR+ breast cancer to aid in personalized decision-making for adjuvant therapy. [Table: see text]
Racial differences in the utilization of MRI-guided biopsy before prostate cancer diagnosis.
Authors: Lu-Yao Grace L. , Gandhi Krupa , Nikita Nikita , Shaver Amy L , Sharma Swapnil , Keith Scott W. , Freedland Stephen J.
Published: June 2023

5093

Background: Most low-risk prostate cancer (PCa) patients undergo active surveillance (AS). Compared with Whites, Blacks are more likely to opt for AS and suffer a higher risk of cancer progression while on AS. A primary concern of AS is the likelihood of missing clinically significant cancer. Transrectal ultrasound-guided biopsy is the most common method for diagnosing and grading PCa; however, this method often misses anterior PCa. Magnetic resonance imaging (MRI) allows clinicians to identify better and detect PCa; however, current guidelines on MRI-guided biopsy (MRI-GB) are inconsistent. This population-based study aimed to examine the utilization of MRI-GB 6 months before PCA diagnosis over time by race in the US. Methods: We used SEER-Medicare data to identify men diagnosed with PCa between January 1, 2012, to December 31, 2017, and excluded patients missing the date of diagnosis, being diagnosed at death, enrolled in HMO, or having no continuous A and B coverage six months before diagnosis. We used the CPT codes to identify prostate biopsy and MRI use. Multivariable logistic regression was used to evaluate racial disparity in MRI use six months before PCa. The model included covariates age, race, SEER region, marital status, state buy-in for Medicare (a poverty indicator), education, income, Charlson comorbidity index, and procedure (MRI) year. Results: Among 38,612 eligible men, MRI use six months before PCa diagnosis increased from 2012 to 2017 (3.2% to 24.3% among Whites, 1.8% to 14.2% among Blacks). Compared with Whites, Blacks were 38% less likely to receive pre-diagnosis MRI (OR=0.62, 95% CI 0.52-0.74). Besides race, having state buy-in for Medicare (OR=0.44; 95% CI 0.30-0.65) and geographic regions (Central vs. West OR=0.40; 95% CI 0.34-0.45) were strong predictors of lower utilization of MRI. Conclusions: The gap in the utilization of MRI may exacerbate racial disparities in PCa. Future studies are needed to identify potential barriers to adopting MRI for PCa workups.
Post radical prostatectomy (RP) PSA outcomes following 6 vs 18 months of perioperative androgen deprivation therapy (ADT) in men with localized high risk prostate cancer (LHRPC): Results of Part 2 of a randomized phase 2 trial.
Authors: McKay Rana R. , Xie Wanling , Yang Xiaoyu , Rathkopf Dana E. , Laudone Vincent Paul , Bubley Glenn , Einstein David Johnson , Chang Peter , Wagner Andrew , Kane Christopher J. , Parsons J. Kellogg , Preston Mark A. , Kilbridge Kerry L. , Chang Steven Lee , Choudhury Atish Dipankar , Trinh Quoc-Dien , Pomerantz Mark , Kibel Adam S. , Taplin Mary Ellen
Published: June 2023

5095

Background: Patients with LHRPC have an increased risk of relapse following RP. We previously reported on Part 1 of a phase 2 trial testing neoadjuvant apalutamide, leuprolide, and abiraterone acetate plus prednisone (ALAAP) or leuprolide and abiraterone plus prednisone (LAP) for 6 months followed by RP (McKay, J Urol, 2021). We demonstrated favorable pathologic responses (tumor <5 mm) at RP in 20.3% of patients (n=24/118). Herein, we report the results of Part 2 testing adjuvant ALAAP (NCT02903368). Methods: Eligible patients had a Gleason score ≥4+3, PSA >20 ng/mL, or T3 disease (by DRE or MRI) and lymph nodes <20 mm. At Part 2, patients were randomized 1:1 to ALAAP for 12 months (Arm 2A) or observation (Arm 2B), stratified by neoadjuvant therapy and pathologic T stage (<ypT3 or ≥ypT3). The primary endpoint was biochemical progression-free survival (bPFS) at 3 years post-RP. bPFS was defined as the time from randomization to progression (PSA ≥ 0.2 ng/mL, local/distant disease on CT/MRI or bone scan, or receipt of post-RP therapy or radiation for rising PSA) or death. The Kaplan-Meier estimate of bPFS at 3 years was compared between arms using a Chi-square test (Klein, Stat Med, 2007). Secondary endpoints included safety and time to testosterone recovery (>200 ng/dL). Results: Overall, 82/118 (69%) of patients enrolled to Part 1 were randomized to Part 2. Median follow-up was 47 months post-RP. Patient preference was the main reason for non-randomization in Part 2. In the intent-to-treat analysis, the 3-year bPFS estimate was 80% (95% CI:65-90%) for Arm 2A and 72% (95% CI:56-84%) for Arm 2B, which was not statistically significant (2-sided p=0.39). Patients who achieved pathologic responses (n=14) had longer bPFS than non-responders (log-rank test two-sided p=0.03; 3-year bPFS 100% vs 72%). In per-protocol population, of 36 patients receiving Arm 2A treatment with available data, 83% had testosterone recovery and median time to recovery from therapy end was 8.7 months. For patients on observation (n=42), 95% had testosterone recovery, and median time to recovery from RP was 4.0 months. No new safety signals were observed. Conclusions: Neoadjuvant ADT in LHRPC resulted in favorable pathologic responses and 3-year bPFS in a subset of patients. As 30% of patients declined an additional 12 months of adjuvant treatment, the study was underpowered to detect a difference between 6 months vs. 18 months of treatment. Subsequent analyses will evaluate predictors of improved bPFS. Clinical trial information: NCT02903368 . [Table: see text]
ECOG-ACRIN E2197: Comparison of HER2 gene expression by RT-PCR across all HER2 immunohistochemistry groups with recurrence analysis.
Authors: Can Nhu Thuy , Bennett John , Flannery Cynthia A. , Bailey Helen , Goldstein Lori J. , Davidson Nancy E. , Sparano Joseph A. , Baehner Frederick L. , Badve Sunil S.
Published: June 2023

515

Background: Accurate assessment of HER2-low [immunohistochemical (IHC) score of 1+ or 2+ and in-situ hybridization negative] breast cancer is clinically relevant following DESTINY-Breast04. In hormone receptor positive breast cancers, Oncotype DX assay Recurrence Score results are widely used to guide adjuvant chemotherapy selection, and standardized quantitative HER2 mRNA reference-normalized expression levels by RT-PCR are included in patient reports. Previously, a high degree of concordance between central IHC and quantitative HER2 by RT-PCR was demonstrated in E2197. Here, we compare quantitative HER2 gene expression using Oncotype DX assay within all IHC subgroups and risk of recurrence in E2197. Methods: Data analyzed were from a case-control sample from E2197 (no adjuvant anti-HER2 therapy) of 755 patients. Central IHC for HER2 used duplicate 1.0 mm microarrays (HercepTest, Dako) and scored per 2007 ASCO/CAP guidelines. Based on quantitative reference-normalized RT-PCR measures of HER2 expression, cases were assigned: positive ≥11.5 units, equivocal ≥10.7 to <11.5 units, and negative <10.7 units (1 unit increase represents ~2-fold increase in RNA). Spearman’s rank correlation was used to measure strength of association between the 2 methods. Cox proportional hazards regression was used to evaluate the association between quantitative HER2 expression and recurrence (defined as invasive breast cancer in local, regional, or distant sites). Analyses were weighted to account for study design. Results: 48% were IHC 0, 11% were IHC 1+, 23% were IHC 2+, and 18% were IHC 3+. 85% were HER2 negative, 3% equivocal, and 11% positive by RT-PCR. While there was moderately strong correlation between HER2 IHC and HER2 gene expression by RT-PCR [Spearman’s rho: 0.63 (95% CI: 0.59, 0.67); p<0.001], there were wide and overlapping ranges of HER2 gene expression across all IHC categories with almost identical medians and inter-quartile ranges for HER2 IHC 1+ and 2+ (n=248; see table). An exploratory analysis showed 86% of IHC 0, 97% of IHC 1+, and 99% of IHC 2+ had HER2 >8 units. After controlling for baseline clinicopathologic features (age, hormone receptor status, grade, size, and nodal status), continuous quantitative HER2 expression was associated with time to recurrence in HER2 IHC 0 to 2+ [HR 1.17 per 1-unit increase in HER2 (95% CI 1.01, 1.35; p=0.036)]. Conclusions: There was a wide range of quantitative HER2 gene expression using Oncotype DX assay across all IHC categories; continuous HER2 expression is independently associated with recurrence. Quantitative HER2 expression may be useful for identification of HER2-low breast cancer. Further studies are needed. [Table: see text]
Differential benefit of capecitabine-based chemotherapy among TNBC subtypes in the context of the CBCSG010 study.
Authors: Li Junjie , Wu Wenya , Yang Yunsong , Yang Wentao , Zhimin Shao
Published: June 2023

528

Background: Our previous study classified TNBCs into four mRNA subtypes, provided additional insights into TNBC heterogeneity and potential therapeutic options. Then we conducted a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial (FUTURE, NCT03805399 ), demonstrated the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC. Here, we further evaluate the prognosis and predictive value of molecular classification in early TNBC in CBCSG010 trial (NCT01642771), which is a prospective, randomized phase III trial confirmed adding capecitabine to anthracycline-taxane-based adjuvant chemotherapy significantly improved survival in TNBC. Methods: Tumor tissues and pathological sections were retrospectively collected. Immunohistochemical (IHC) staining and hematoxylin and eosin (HE) staining were performed on paraffin-embedded sections to conduct TNBC IHC subtype staining. RNA-sequencing were performed to characterize the intrinsic molecular features of TNBC microenvironment. Results: 585 patients enrolled in the CBCSG010 trial, 450 patients had pathological sections, among which 207 patients achieved successfully stained sections. PDL1, CD8 and stromal tumor infiltrating lymphocytes (sTILs) were chosen for identified TNBC Immune enriched phenotype. Patients with ≥20% positive tumor cell proportion score (TPS) of PDL1, ≥10% positive cells of CD8, and ≥10% positive sTILs were significantly associated with better 5y-DFS (disease-free survival). Among Immune enriched TNBC, kaplan-Meier curves showed that DFS rates were 96.4% and 73.7% in the capecitabine and control groups. Transcriptome data was used to picture the immune microenvironment landscape, showed that “immune-hot” patients (immune cells or immune genes enriched) were more likely to benefit from capecitabine treatment. Conclusions: TNBC subtypes is significantly associated with DFS, with Immune enriched phenotype achieving the best outcome, and “immune-hot” patients are more likely to benefit from adjuvant capecitabine. Designing future clinical trials adding immunotherapy in adjuvant treatment of TNBC might base on molecular features.
Disease-free survival (DFS) as a surrogate for overall survival (OS) in patients (pts) with HR+/HER2− early breast cancer (EBC): A correlation analysis.
Authors: Untch Michael , Pérol David , Mayer Erica L. , Cortes Javier , Nusch Arnd , Cameron David A. , Barrios Carlos , Delea Thomas E. , Romero Salas Tonatiuh , Kalra Manik , Gupta Rhea , Pathak Purnima , Fasching Peter A.
Published: June 2023

535

Background: DFS has been widely adopted as a clinically meaningful primary endpoint in EBC trials in place of OS, which needs extensive follow-up to observe sufficient events and fails to assess survival benefit early. However, a rigorous validation of DFS as a surrogate endpoint for OS is required for each given setting. The objective of this analysis was to evaluate DFS as surrogate for OS in the adjuvant treatment of HR+/HER2− EBC. Methods: A systematic literature review (SLR) was conducted using biomedical literature databases (ie, Embase, PubMed, and Medline [from database inception to January 2023]) and key conferences to identify published studies in EBC. The eligibility criteria for the SLR were RCTs that included ≥80% of adult pts with HR+/HER2− EBC and assessing different treatment options (ie, cyclin-dependent kinase 4/6 inhibitors [CDK4/6i], endocrine therapies [ET], and chemotherapies [CT]). Studies were considered for correlation analysis if hazard ratios (HRs) were reported for both DFS and OS. The analysis excluded observational studies and trials with immature OS data. Spearman rank correlation (rs) and weighted linear regression analyses (measured by coefficient of determination [R2]) were performed to evaluate the correlation between HRs for OS and DFS. Considering heterogeneity, multiple scenario analyses were conducted. Surrogate threshold effect (STE) was also estimated; STE is defined as the maximum value of the HR for DFS that needs to be observed in a trial to ensure the possibility of concluding that a significant effect on OS occurred. Correlation was also assessed using pt-level data from the FACE trial (letrozole vs anastrozole in postmenopausal pts with HR+/HER2− EBC) to validate findings of the trial-level analysis. Results: A total of 14 RCTs (N = 31,668) were included (CDK4/6, 2; ET, 7; CT, 5). Trial-level analysis showed that rs between OS and DFS was 0.81 (95% CI, 0.56-0.94), which when weighted by variance was 0.81. Regression analysis showed that 84% of the variability in OS was explained by DFS (R2 = 0.84). A meta-regression model estimated an STE of 0.82 for HR of DFS, which can be leveraged to validate the surrogacy based on the DFS estimated from a future trial. Analysis of pt-level data from the FACE trial demonstrated a correlation between DFS and OS (rs = 0.75). Additionally, correlation coefficients estimated by the Pearson method and iterative imputation were 0.83 and 0.89, respectively. Conclusions: Both trial-level and pt-level analyses demonstrate a positive correlation between DFS and OS. These results support the use of DFS as a reliable surrogate endpoint for OS in HR+/HER2− EBC trials to give an early access to innovative therapies.
Real-world outcomes with adjuvant nonsteroidal aromatase inhibitors (NSAIs) vs tamoxifen (TAM) in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative (HR+/HER2−) early breast cancer (EBC): A US database analysis.
Authors: Graff Stephanie L. , Tolaney Sara M. , Hart Lowell L. , Razavi Pedram , Fasching Peter A. , Janni Wolfgang , Schwartzberg Lee S. , Lanoue Brad , Romero Salas Tonatiuh , Khakwani Aamir , McDermott Courtney , Pathak Purnima , O'Shaughnessy Joyce
Published: June 2023

542

Background: Randomized controlled trial (RCT) meta-analysis data have shown a significantly greater disease-free survival (DFS) benefit with aromatase inhibitors than TAM in patients with HR+/HER2− EBC. Here we compare real-world outcomes in patients with HR+/HER2− EBC who received adjuvant endocrine therapy (ET) with NSAIs or TAM. Methods: This was a retrospective analysis of ConcertAI’s deidentified electronic medical records data set of patients treated at US academic and community oncology clinics from January 1, 1995 to April 30, 2021. The cohort included patients with stage II-III (if IIIB or IIIC, confirmation was required on residual tumor status) HR+/HER2− EBC who underwent surgery and initiated adjuvant ET (excluding those who switched classes of ET); ovarian function suppression (OFS) was permitted. Menopausal status was determined using age (≥ 50 years) as a proxy for undocumented status. Invasive DFS (IDFS; risk of disease recurrence, death, or second primary tumor), distant DFS (DDFS; risk of distant recurrence, death, or second primary tumor), and overall survival (OS; risk of death) were assessed and defined as the time interval between start of ET and first event. Multivariate Cox regression analyses were performed, adjusting for age, stage, Charlson Comorbidity Index, and prior adjuvant or neoadjuvant chemotherapy for the ET cohort. Results: Of the total 3133 patients analyzed, 2507 were included in this analysis (NSAI ± OFS, n = 1854; TAM ± OFS, n = 653). Among these patients, the median (range) age was 59.5 (22.8-86.6) years, 25.4% were premenopausal, and 56.2% had tumor node involvement. The mean (SD) time to ET discontinuation was 46.2 (35.9) months overall and was similar between the NSAI and TAM cohorts. Reasons for ET discontinuation were undocumented or missing from the database for 76.8% of patients. Multivariate Cox regression analyses suggested a significant risk reduction with NSAIs vs TAM, with a 17% reduction in risk of an IDFS event (hazard ratio [HR], 0.83 [95% CI, 0.69-0.98]) and an 18% reduction in risk of a DDFS event (HR, 0.82 [95% CI, 0.69-0.98]). Although there were few events, OS analysis suggested a numerical trend favoring NSAIs over TAM, with a 12% reduction in risk of death (HR, 0.88 [95% CI, 0.69-1.13]). Conclusions: This real-world data analysis revealed a reduction in risk of IDFS and DDFS events with adjuvant NSAIs vs TAM in patients with HR+/HER2− EBC. Collectively, RCT and real-world data demonstrate greater benefit with adjuvant NSAIs vs TAM with respect to risk of recurrence in this patient population.
The worldwide impact of HER2-targeted treatments in women with breast cancer: An epidemiological modeling study.
Authors: Press David J. , Arnold Melina , Hansen Svenn
Published: June 2023

543

Background: HER2-targeted therapies (trastuzumab, pertuzumab, and T-DM1) have revolutionized the treatment and epidemiological landscape of HER2+ breast cancer, resulting in population-level increases in survival and decreases in disease recurrence. The aim of this epidemiological modeling study was to quantify the estimated global impact of HER2-targeted therapies, by estimating the number of women diagnosed with HER2+ early breast cancer (eBC) who have avoided (or will avoid) metastatic disease recurrence following treatment. Methods: We used data and projections from cancer registries, observational studies, clinical trials, and drug sales volumes (ie, utilization) to create annual country-level synthetic cohorts of patients diagnosed with HER2+ eBC, for the years 2004-2033 in 185 countries. The real-world uptake of HER2-targeted treatments and treatment flow was estimated in the main scenario. The impact of chemotherapy alone was estimated in the counterfactual scenario, assuming 100% chemotherapy worldwide. The occurrence of distant recurrences was modeled in both scenarios using weighted transitional probability averages based on invasive disease-free survival curves from clinical trials. Results: In total, during the 3-decade study period, we predicted that 11.9 million (M) women would be diagnosed with HER2+ eBC, out of which 7.5M were estimated to be treated with HER2-targeted therapies in a real-world uptake scenario. In the counterfactual scenario with only chemotherapy available, a total of 2.9M women were estimated to experience a metastatic disease recurrence, compared to only 2.1M women in the base scenario of predicted real-world uptake of HER2+ targeted therapies. This corresponds to a reduction of 26% or 768,000 women who may avoid metastatic recurrence since the introduction of HER2-targeted therapies (Table). Conclusions: HER2+ targeted therapies have substantially improved breast cancer outcomes and continue to contribute to the reduction in breast cancer recurrence rates. Further research may elucidate treatment-related reductions in costs to society as a result of population-level improvements in disease outcomes for breast cancer survivors. Given the expected rise in the burden of breast cancer globally, therapeutic advances and increased treatment utilization may further accelerate global patient benefit. [Table: see text]
Additional prognostic value of the BCT score in patients with ER+HER2- breast cancer receiving 21-gene assay–guided adjuvant treatments.
Authors: Ahn Sung Gwe , Kook Yoonwon , Lee Sae Byul , Lee Eun-Gyeong , Yu Jonghan , Lee Young-Won , Kim Yeon Jin , Woo Sang Uk
Published: June 2023

548

Background: In early estrogen receptor (ER)+HER2- breast cancer, a 21-gene expression assay-guided decision-making for adjuvant treatments has been widely utilized as a standard-of-care. The GenesWell BCT is a multigene assay that is designed to predict the risk of distant recurrence (DR) in patients with ER+HER2- breast cancer. This assay consists of nine genes, which are used to generate a risk score that can help guide treatment decisions. We addressed an additional value of the GenesWell Breast Cancer Test (BCT) score using the cohort of ER+HER2- breast cancer patients receiving a 21-gene assay-guided adjuvant treatments, focusing the chemotherapy untreated subset with low 21-gene recurrence score (RS). Methods: This multicentre, observational follow-up study was done in 4 academic institutions in South Korea. Patients with ER+HER2- breast cancer who received RS-guided adjuvant treatments were enrolled. A total of 705 patients were included. Of these, the rate of women with node-positive disease was 21.6% (152/705), and the rate of women with younger than 50 years old was 61.4% (433/705). The BCT score was obtained using the specimens which were previously analyzed for RS. The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was distant recurrence-free survival (DRFS). Results: Among the 705 patients, the RS assigned 110 (15.6%) as high risk (≥26), whereas the BCT score assigned 239 (33.9%) as high risk (≥4). The agreement between two tests was noted in 494 (70.1%); concordances were made in 69 for high and in 425 for low, respectively. At a median follow up of 85 months, 80 had tumor recurrences, 38 had distant recurrences, and the 7-year RFS was 90.0% (95% CI, 87.6%-92.5%). In the 595 patients with low RS, 556 (93.4%) did not receive adjuvant chemotherapy. Within the 556 chemotherapy-untreated patients with low RS, the RFS differed significantly according to the BCT score ( p= .014); the 7-year RFS was 92.9% in the BCT-low, while it was 85.7% in the BCT-high. Within the group, the BCT score was demonstrated as an independent prognostic factor for both RFS and DRFS adjustment of tumor size, nodal stage, and histologic grade. In addition, the RFS of the low-BCT score group was superior to that of the high-BCT group in either women younger than 50 years of age with an RS of 21 to 25 or all women with an RS of 21 to 25. Conclusions: We found that the BCT score was useful in stratifying the risk of relapse in chemotherapy-untreated patients with a low recurrence score (RS). This indicates that the BCT score could provide additional clinical value in identifying patients with a long-term risk of relapse, particularly in young women with an RS of 21 to 25.
KEYNOTE-826: Final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer.
Authors: Monk Bradley J. , Colombo Nicoletta , Tewari Krishnansu Sujata , Dubot Coraline , Caceres M. Valeria , Hasegawa Kosei , Shapira-Frommer Ronnie , Salman Pamela , Yañez Eduardo , Gumus Mahmut , Olivera Hurtado de Mendoza Mivael , Samouëlian Vanessa , Castonguay Vincent , Arkhipov Alexander , Tekin Cumhur , Li Kan , Keefe Stephen Michael , Lorusso Domenica
Published: June 2023

5500

Background: The first interim analysis of KEYNOTE-826 (NCT03635567) showed that first-line pembrolizumab (pembro) + chemotherapy (chemo) provided statistically significant and clinically meaningful improvements in OS and PFS vs placebo (pbo) + chemo in patients (pts) with recurrent, persistent, or metastatic cervical cancer across all prespecified populations (PD-L1 combined positive score [CPS] ≥1, all-comer, and CPS ≥10). Here, we present the protocol-specified final OS analysis results of KEYNOTE-826. Methods: Eligible adults with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemo (prior radiosensitizing chemo allowed) and not amenable to curative treatment (surgery or radiation) were randomized 1:1 to pembro 200 mg or placebo Q3W for up to 35 cycles + chemo (paclitaxel 175 mg/m2 + cisplatin 50 mg/m2 or carboplatin AUC 5), ± bev 15 mg/kg. Pts were stratified by metastatic status at diagnosis (yes/no), planned bev use (yes/no), and PD-L1 CPS (<1, 1 to <10, or ≥10). Dual primary end points were OS and PFS per RECIST v1.1 assessed by investigator review, each tested sequentially in the PD-L1 CPS ≥1, all-comer, and CPS ≥10 populations. Results: From Nov 2018 to Jan 2020, 617 patients were randomized (pembro + chemo, n = 308 [63.6% with bev]; pbo + chemo, n = 309 [62.5% with bev]); 548 (88.8%) pts had PD-L1 CPS ≥1 and 317 (51.4%) had CPS ≥10. At the Oct 3, 2022 data cutoff, median follow-up was 39.1 mo. Pembro + chemo significantly improved OS and PFS in the CPS ≥1, all-comer, and CPS ≥10 populations (Table). The pembro + chemo benefit was seen regardless of bev use. Grade ≥3 AE incidence was 82.4% in the pembro + chemo arm and 75.4% in the placebo + chemo arm. The most common grade ≥3 AEs were anemia (30.3% vs 27.8%), neutropenia (12.4% vs 9.7%), and hypertension (10.4% vs 11.7%). Conclusions: The addition of pembro to chemo ± bev significantly reduced the risk of death by 40% in the PD-L1 CPS ≥1 population, by 37% in the all-comer population, and by 42% in the CPS ≥10 population, and had a manageable safety profile. These data are consistent with the earlier results and provide further support for pembro + chemo ± bev as a new standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Clinical trial information: NCT03635567 . [Table: see text]
Dostarlimab for primary advanced or recurrent (A/R) endometrial cancer (EC): Outcomes by blinded independent central review (BICR) of the RUBY trial (ENGOT-EN6-NSGO/GOG-3031/RUBY).
Authors: Powell Matthew A. , Hietanen Sakari , Coleman Robert L. , Monk Bradley J. , Zub Oleksandr , O'Malley David M. , Gilbert Lucy , Podzielinski Iwona , Angioli Roberto , Chase Dana Meredith , Bauerschlag Dirk , Black Destin , Thijs Annemarie , Sharma Sudarshan , Gold Michael A. , Ring Kari L , He Zangdong , Stevens Shadi , Slomovitz Brian M. , Mirza Mansoor R.
Published: June 2023

5503

Background: RUBY (NCT03981796) evaluated the efficacy and safety of the anti–programmed death 1 (PD-1) dostarlimab + standard of care (SOC) carboplatin paclitaxel (CP) versus CP alone in A/R EC. The primary endpoint of PFS by investigator assessment (INV) per RECIST v1.1 was significantly longer with dostarlimab+CP than placebo (PBO)+CP in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H; HR 0.28; 95% CI 0.162–0.495) and overall populations (HR 0.64, 95% CI 0.507–0.800). Here we present secondary efficacy endpoints by BICR. Methods: RUBY is a phase 3, global, randomized, double-blind, multicenter, PBO-controlled study. Patients (pts) with primary advanced stage III or IV or first recurrent EC were randomized 1:1 to receive dostarlimab 500 mg, or PBO, plus carboplatin AUC 5 and paclitaxel 175 mg/m2 Q3W (6 cycles), followed by dostarlimab 1000 mg, or PBO, monotherapy Q6W for up to 3 y. Secondary endpoints by BICR assessment per RECIST v1.1 were PFS, ORR, DOR, and DCR in the overall and dMMR/MSI-H populations. Results: 494 pts were randomized (245:dostarlimab+CP; 249:PBO+CP); 47.8% had recurrent disease, 18.6% and 33.6% had primary stage III and IV disease, respectively. PFS by BICR was longer with dostarlimab+CP than PBO+CP in the dMMR/MSI-H (HR 0.29; 95% CI 0.158–0.543) and overall populations (HR 0.66; 95% CI 0.517–0.853; Table). Consistent benefits were seen with dostarlimab+CP for ORR, DCR, and DOR by BICR in the dMMR/MSI-H and overall populations (Table). Safety was previously reported. Conclusions: Dostarlimab+CP showed clinically meaningful improvement in BICR-assessed PFS in the dMMR/MSI-H and overall populations compared with CP alone. The HRs for PFS per BICR and per INV were consistent, which supports the reliability of PFS by INV in EC trials. Benefits were seen in all BICR-assessed endpoints, which were consistent with INV. Dostarlimab+CP represents a new SOC for pts with primary A/R EC. Clinical trial information: NCT03981796 . [Table: see text]
Randomized controlled phase III trial of weekly paclitaxel ± ofranergene obadenovec (VB-111) for platinum-resistant ovarian cancer (OVAL Study/GOG 3018).
Authors: Arend Rebecca Christian , Monk Bradley J. , Shapira-Frommer Ronnie , Secord Angeles Alvarez , Herzog Thomas J. , Tewari Krishnansu Sujata , Ledermann Jonathan A. , Rachmilewitz Minei Tamar , Buyse Marc E. , Haggerty Ashley , Alvarez Edwin A , Amit Amnon , Muller Carolyn , Casado Herraez Antonio , Holman Laura L. , Cohen Joshua , Huang Marilyn , Yachnin Adelya , Harats Dror , Penson Richard T.
Published: June 2023

5505

Background: Ofranergene obadenovec (ofra-vec, VB-111) is a nonreplicating adenoviral vector with a murine pro-endothelin 1 (PPE-1-3X) promoter and pro-apoptotic Fas-tumor necrosis factor receptor 1 (TNFR1) chimeric transgene thought to have a dual mechanism of action: vascular disruption and immune activation. Methods: This is a randomized, placebo-controlled, double-blind, multi-center randomized phase III trial (ClinicalTrials.gov identifier: NCT03398655) of ofranergene obadenovec combined with paclitaxel vs paclitaxel with placebo for the treatment of patients with recurrent platinum resistant ovarian cancer (PROC). Patients were randomly assigned 1:1 to receive IV VB-111 1x1013 viral particles (VPs) every 8 weeks with weekly IV paclitaxel 80 mg/m2 or placebo with paclitaxel until disease progression. The dual primary endpoints were overall survival (OS) and progression free survival (PFS) as assessed by Blinded Independent Central Review (BICR). Results: Between December 2017 and March 2022, 409 patients were randomized at 86 clinical sites in US, Israel, Spain, Poland and Japan. The median PFS was 5.29 months in the VB-111 arm and 5.36 months in the control arm; hazard ratio (HR) 1.03 (CI: 0.83-1.29, p = 0.7823), and median OS with was 13.37 months vs. 13.14 months HR 0.97 (CI: 0.75–1.27 p = 0.8440). Objective response rates (ORR) were similar in both arms: RECIST 1.1 ORR was 28.9% with VB-111 vs. 29.6% with control (CA-125 ORR 41.1% vs 49.4%). In both treatment arms response to CA-125 was a substantial prognostic factor for both PFS and OS. In the VB-111 arm, the HR in CA-125 responders compared to non-responders was for PFS HR 0.2428 (CI: 0.1642-0.3588), and for OS HR 0.3343 (CI: 0.2134-0.5238). Safety profile was consistent with the known safety profile of ofra-vec and was characterized by common transient flu like symptoms such as fever and chills. Conclusions: The addition of ofranergene obadenovec to paclitaxel did not improve PFS or OS. Clinical trial information: NCT03398655 .
Luveltamab tazevibulin (STRO-002), an anti-folate receptor alpha (FolRα) antibody drug conjugate (ADC), safety and efficacy in a broad distribution of FolRα expression in patients with recurrent epithelial ovarian cancer (OC): Update of STRO-002-GM1 phase 1 dose expansion cohort.
Authors: Oaknin Ana , Fariñas-Madrid Lorena , García-Duran Carmen , Martin Lainie P. , O'Malley David M. , Schilder Russell J. , Uyar Denise , Moroney John William , Diaz John Paul , Spira Alexander I. , Garcia-Donas Jesus , Palumbo Michael , Dokainish Hatem , Liu Lin , Berman Craig Jerome , Naumann R. Wendel
Published: June 2023

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Background: Luveltamab tazevibulin (luvelta) is a novel FolRα-targeting ADC with a stable cleavable linker and a 3-aminophenyl hemiasterlin warhead (DAR of 4) that induces cytotoxic and immunologic cell death. Using site-specific conjugation technology, luvelta is designed to target a broad range of FolRα expressing OC. STRO-002-GM1 is a global phase 1 study evaluating luvelta in patients with relapsed OC. We provide updated data from the initial ovarian expansion cohort. Methods: The study enrolled advanced OC pts who had progressive platinum resistant (PROC) after 1-3 prior lines or platinum sensitive disease after 2-3 prior lines of platinum chemotherapy. Pts were randomized 1:1 to received luveltamab at 4.3 or 5.2 mg/kg given IV every 3 weeks until disease progression. Prophylactic corticosteroid eyedrops were not required/administered. FolRα expression was not required for study entry but was analyzed retrospectively in archival tissue using the FOLR1 IHC assay (Ventana Medical Systems). The scoring paradigm assessed percentage of cells with any intensity expression (TPS). TPS >25% was selected for further analysis. Results: 44 pts were enrolled (23 pts at 4.3 mg/kg and 21 pts at 5.2 mg/kg). For pts with a TPS >25% (n=35), the median prior lines of therapy was 2.5 (range 1-3), 69% had prior bevacizumab treatment, and 83% prior PARP inhibitor treatment. Investigator assessed efficacy data for pts with a TPS >25% are presented in the table. The most common grade ≥ 3 treatment emergent adverse events (TEAEs) included neutropenia (70.5%), arthralgia (18.2%), and anemia (13.6%). G3/4 neutropenia had a higher incidence at 5.2 mg/kg than 4.3 mg/kg (76% vs 65%); most notable for G4 neutropenia (52% vs 22%). 1 pt at each dose level had febrile neutropenia. TEAEs led to dose delay in 80% of pts with a higher incidence at 5.2 mg/kg (95% vs. 65%). TEAEs led to dose reduction in 61% of pts with a higher incidence at 5.2 mg/kg (76% vs. 48%). 1 pt had a G5 sepsis with G4 neutropenia. Neutropenia, arthralgia and anemia were managed with standard medical treatment and dose reductions. Conclusions: These dose expansion data confirm activity of luvelta at starting doses ranging from 4.3-5.2 mg/kg in recurrent OC with FolRα expression as low as TPS>25% and supports further clinical study in this population. The global phase 2/3 REFRaME registration study will evaluate luvelta in PROC pts with TPS >25%. Clinical trial information: NCT03748186 . [Table: see text]
Final survival analysis of the phase III OVHIPEC-1 trial of hyperthermic intraperitoneal chemotherapy in ovarian cancer after ten year follow-up.
Authors: Aronson Lot , Lopez-Yurda Marta I. , Koole Simone N , Schagen van Leeuwen Jules H , Schreuder Henk , Hermans Ralph , de Hingh Ignace H.J.T. , Van Gent Mignon D.J.M. , Arts Henriëtte J.G. , van Ham Maaike , Van Dam Peter , Vuylsteke Peter , Aalbers Arend , Verwaal Victor , Van de Vijver Koen , Aaronson Neil K , Sonke Gabe S. , Van Driel Willemien
Published: June 2023

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Background: The randomized, phase 3 OVHIPEC-1 trial (NCT00426257) investigated the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery in patients with stage III epithelial ovarian cancer who were ineligible for primary cytoreduction. OVHIPEC-1 previously demonstrated improved recurrence-free and overall survival after 4.7 years of follow-up. Here, we report the final survival outcomes after ten years of follow-up. In addition, we report new data on the subsequent anti-cancer treatments given after disease progression. Methods: Patients were randomized to receive interval cytoreductive surgery with or without HIPEC, after receiving three cycles of neo-adjuvant carboplatin and paclitaxel. Randomization was performed at the time of surgery when either complete (no visible disease) or optimal cytoreduction (residual tumor measuring <10mm in diameter) was anticipated. All patients received an additional three cycles of adjuvant systemic chemotherapy. We analyzed survival according to the intention-to-treat principle using stratified log-rank tests and Kaplan-Meier methods. Subsequent lines of therapy were compared between arms. Results: At a median follow-up of 10.1 years, 114 of 123 patients (92.7%) who underwent surgery alone and 109 of 122 patients (89.3%) who had surgery-plus-HIPEC experienced recurrence, progression, or death from any cause. Median recurrence-free survival was 10.7 months in the surgery group compared to 14.3 months in the surgery-plus-HIPEC group (HR, 0.63; 95% confidence interval [CI], 0.48-0.83; stratified P<0.001). One hundred and eight patients (87.8%) in the surgery group have died as compared to 100 patients (82.0%) in the surgery-plus-HIPEC group. Median overall survival was 33.3 versus 44.9 months (HR, 0.70; 95% CI, 0.53-0.92; stratified P=0.011), respectively. Subsequent anti-cancer therapies, including chemotherapy (platinum and non-platinum based), secondary surgery, poly (ADP-ribose) polymerase (PARP) inhibitors and bevacizumab, were received by 104 patients (84.6%) in the surgery group and 100 patients (82.0%) in the surgery-plus-HIPEC group. The median number of subsequent systemic treatment lines was 2 (IQR 1-3) in both arms. Conclusions: This study provides the first long-term survival analysis of HIPEC in ovarian cancer and confirms the benefit of HIPEC in patients with primary stage III epithelial ovarian cancer undergoing interval cytoreductive surgery. No imbalance in subsequent therapy after disease recurrence was found that could explain the improved overall survival after HIPEC. Clinical trial information: NCT00426257 .