tbuckley/cabot-search huggingface dataset:
Efficacy and safety of PARP inhibitors (PARPi) with immune checkpoint inhibitors (ICI) in metastatic castration-resistant prostate cancer (mCRPC): A systematic review and single-arm meta-analysis.
Authors: Gabriela Gazzoni, João Pedro Oliveira, Pedro Cotta Abrahão Reis, Vinicius Bittar, Bruno Murad Carvalho, Maysa Vilbert, Carlos Eduardo Stecca
Journal: Journal of Clinical Oncology (2024)

e17053 Background: Recent therapeutic advances in prostate cancer have allowed patients with metastatic disease to live longer and better, especially in the castration sensitive setting. Although improvements have been observed in the castration resistant space, survival in this setting remains suboptimal. Early-phase clinical trials suggest the combination of PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICI) have synergistic effect by modulating the tumor microenvironment. In this systematic review and meta-analysis, we assessed the efficacy and safety of PARPi and ICI in the metastatic castration-resistant prostate cancer (mCRCP) setting. Methods: Pubmed, Cochrane and EMBASE were systematically searched from inception through December 10, 2023. Randomized and non-randomized clinical trials evaluating PARPi + ICI in mCRPC were included. PSA response rate (PSArr), radiographic progression-free survival (rPFS), objective response rate (ORR) and overall survival (OS) were analyzed. Subgroups according to (HRR) were assessed. We also pooled the prevalence of immune-related adverse events (irAE) and their corresponding 95% confidence intervals (95% CI). Statistical analysis was performed using R software version 4.3.2 and heterogeneity was evaluated through I 2 statistics. Results: We screened 1070 reports, and six trials met the inclusion criteria (one phase III RCT and 5 phase I/II non-RCT), involving 799 participants. The overall ORR was 8.48% (95% CI 6.48-10.86 I 2 0%). About 19% of patients achieved an PSArr (95% CI 9.51-32.50 I 2 75%). Median OS was 15.8 months (95% IC 13.9-15.8), and rFPS was 4.5 months (95% IC 4.4-4.9). In patients harboring HRR mutations, PSArr was 17.53% (95% CI 10.43-27.95 I 2 75), while in HRR non-mutated it was 10.49% (95% CI 5.89-17.99 I2 0%). The frequency of any-grade irAEs was 21.12% (95% CI 12.34-33.74 I2 85%), with 6.70% of grade 3-4 irAEs (95% CI 3.09-13.91 I2 80%). Hypothyroidism rate was 8.53% (95% CI 5.86-12.27 I2 29%) and adrenal insufficiency was 2.80% (95% CI 1.81-4.30 I2 0%). Conclusions: This meta-analysis results suggest that the combination of PARPi plus ICI in patients with mCRPC is safe and may benefit mainly patients with HRR mutations. Further studies in biomarker selected patients are needed. [Table: see text]
Circulating tumour DNA fraction as a predictor of treatment efficacy in a randomized phase 2 trial of [<sup>177</sup>Lu]Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603).
Authors: Edmond Michael Kwan, Michael S Hofman, Sarah WS Ng, Louise Emmett, Shahneen Sandhu, James Patrick Buteau, Amir Iravani, Anthony M. Joshua, Roslyn J. Francis, Vinod Subhash, Sze Ting Lee, Andrew Mark Scott, Andrew James Martin, Martin R. Stockler, Gráinne Donnellan, Matti Annala, Sofie H. Tolmeijer, Arun Azad, Ian D. Davis, Alexander William Wyatt
Journal: Journal of Clinical Oncology (2024)

5055 Background: The TheraP trial showed that for patients with PSMA-positive, non-FDG-discordant mCRPC progressing after docetaxel, LuPSMA significantly improved biochemical and objective response rates, progression-free survival (PFS), and quality of life compared to cabazitaxel. While subsequent studies nominated high PSMA SUVmean to inform patient prioritization for LuPSMA, limited genomic data exists to guide optimal selection of these two life-prolonging therapies. We present an exploratory analysis of ctDNA fraction (ctDNA%) in baseline samples from the TheraP trial. Methods: We analyzed 180 baseline blood samples from participants who received ≥1 cycle of protocol-assigned treatment. Plasma cell-free DNA and matched white blood cell DNA underwent targeted sequencing to estimate ctDNA%. Prespecified ctDNA% categories (&lt;2%, 2-30%, and &gt;30%) were associated with previously validated imaging thresholds (PSMA SUVmean ≥10 and FDG metabolic tumor volume [MTV] ≥200mL), rate of PSA reduction ≥50% (PSA50-RR), and PFS, using chi-square test, logistic regression and Cox regression, respectively. Results: ctDNA% was evaluable in 178 (99%) participants, with ctDNA ≥2% in 85%. Median ctDNA% was 28% in ctDNA≥2% samples, and balanced across treatment arms. The odds of a PSA50 response to LuPSMA vs cabazitaxel were significantly higher for men with ctDNA &lt;2% (OR infinite, p=0.0067; PSA50-RR 100% vs 58%), with no difference at ctDNA &gt;30% (OR 1.1, p=1.0; PSA50-RR 46% vs 44%). Higher ctDNA% was associated with shorter PFS in LuPSMA- but not cabazitaxel-treated patients (LuPSMA: HR 5.0, p&lt;0.001 for ctDNA &lt;2% vs &gt;30%; cabazitaxel: HR 1.4, p=0.35 for ctDNA &lt;2% vs &gt;30%; interaction p=0.035). The predictive potential of ctDNA% was additive to PSMA SUVmean in LuPSMA-treated patients. Higher ctDNA% categories were enriched for patients with high FDG MTV and low PSMA SUVmean disease (Table). Conclusions: ctDNA% is a candidate predictive and prognostic biomarker for differential response to LuPSMA versus taxane chemotherapy in patients with molecular imaging-selected mCRPC progressing after docetaxel. Clinical trial information: NCT03392428 . [Table: see text]
Addition of MRI or DRE to clinical data and risk prediction for clinically significant prostate cancer.
Authors: Christopher J.D. Wallis, Robert J Paproski, M Eric Hyndman, Adrian S. Fairey, Leonard Marks, Christian P. Pavlovich, Sean Fletcher, Roman Zachoval, Vanda Adamcova, Jiri Stejskal, Armen G. Aprikian, Adam Kinnaird, Desmond Pink, Catalina Vasquez, Perrin H Beatty, John D Lewis
Journal: Journal of Clinical Oncology (2024)

e17105 Background: In patients suspected of prostate cancer, the decision to perform a biopsy hinges on available clinical data. Magnetic resonance imaging (MRI) and digital rectal exam (DRE) data are informative but may not be available. We created accurate models for clinically significant prostate cancer (csPCa), flexible to MRI and DRE data availability. Methods: Optimized ensembles of calibrated random forest models predicting csPCa (Grade Group ≥2) used total PSA, free PSA, prior negative biopsy status, and age, with or without DRE and MRI data (prostate volume and PI-RADS score). Risk models were derived (training cohorts n=1257 to 2191) and validated (validation cohorts n=317 to 1257) from different clinical sites. Models were evaluated by the area under the receiver operating characteristic curve (ROC AUC), sensitivity, specificity, positive predictive value, and negative predictive value, using thresholds providing ~ 95% sensitivity. Feature importance was determined by SHAP analysis. Results: All models had an AUC of at least 0.80, showing that predicting csPCa can be accurate without MRI or DRE data. Including MRI data significantly increased the AUC in the validation cohort (ClarityDX Prostate 0.80 vs ClarityDX Prostate +MRI 0.87). DRE had moderate value for models without MRI data (ClarityDX Prostate 0.80 vs ClarityDX Prostate +DRE 0.82) and minor value with MRI data (ClarityDX Prostate +MRI vs ClarityDX Prostate +DRE+MRI; AUC 0.87 vs 0.87; specificity 45% vs 47%, Table). Mean absolute SHAP values were highest for PI-RADS and prostate volume. Conclusions: These optimized risk models provide high accuracy for predicting csPCa in various clinical settings. Including MRI data greatly increases model accuracy, while DRE has a smaller effect on model accuracy. [Table: see text]
Prevalence of HER3 expression in prostate adenocarcinoma and its clinicopathological characteristics.
Authors: Rithika Rajendran, Coen Johannes Gerardus Lap, Fayez Estephan, Shanshan Liu, Ramesh Subrahmanyam, Guoqing Diao, Victor Nava, Maneesh Rajiv Jain
Journal: Journal of Clinical Oncology (2024)

5019 Background: Human epidermal growth factor receptor 3 (HER3) has been found upregulated in a wide variety of cancers and has been associated with disease progression and resistance to EGFR-targeted therapies in HER2-positive malignancies. Several studies have reported expression of HER3 in prostate cancer (PCa). Furthermore, concurrent expression of HER2 and HER3 in PCa has been associated with androgen resistance, development of metastatic disease, and less favorable outcomes. However, due to conflicting results, the exact nature of the relationship between HER2 and HER3 in PCa requires further investigation. Methods: 194 patients diagnosed with PCa between 2000-2021 at the Washington DC Veterans Affairs Medical Center who had adequate formalin-fixed paraffin embedded prostate tissue available were selected from our previously published cohort of patients. HER3 immunostaining was performed and independently scored by two pathologists as 0 (absent), 1+ (weak), 2+ (moderate), or 3+ (marked). HER2 immunostaining data and clinical information was retrieved. Statistical analysis included Fisher’s exact test and linear regression models. Results: In our self-identified predominantly African American (85%) patient cohort, a 94% overall prevalence of HER3 positivity (1+, 2+, or 3+) was observed. Notably, the majority of positive patients was found to have HER3 expression of either 2+ (~60%; 116/194) or 3+ (~17%; 33/194). HER3 positivity was associated with a higher PSA ( p=0.023), a higher Grade Group (GG) ( p=0.017), and a higher AJCC disease stage ( p=0.006) at time of diagnosis (Table 1). A significant association was observed between positivity for both HER2 and HER3 ( p=0.031). HER3 positivity independently predicted GG ( p=0.02) and AJCC disease stage ( p=0.01) when adjusted for HER2 positivity. Conclusions: In this predominantly African American cohort, a high prevalence of HER3 positivity was observed across PCa disease stages. Higher expression levels of HER3 were observed in more advanced stages of the disease. Because of the observed efficacy of HER3-antibody drug conjugates in other HER3-expressing malignancies, the high prevalence of HER3 in PCa makes it an attractive therapeutic target that warrants further evaluation.[Table: see text]
Socio-economic disparities in prostate cancer hospitalizations and outcomes across the United States.
Authors: Michael Imeh, Ani Gvajaia, Lemchukwu Amaeshi, Ali Raza, Fidelis Uwumiro
Journal: Journal of Clinical Oncology (2024)

5103 Background: Socioeconomic class (SEC), measured by educational attainment, is recognized as a notable factor influencing outcomes in prostate cancer. This study evaluated the effects of income status on the prevalence, treatment, and hospitalization outcomes among men diagnosed with prostate cancer. Methods: The combined 2016–2020 nationwide inpatient sample database was queried for all hospitalizations for a primary diagnosis of prostate cancer using ICD-10-CM codes. Socioeconomic status was defined based on the Agency for Healthcare Research and Quality (AHRQ) median annual income index into the lowest SEC ($1–$49,999), the lower SEC ($50,000–$64,999), the high SEC ($65,000–$85,999), and the highest SEC ($≥86,000). Baseline characteristics were compared using Pearson’s χ2 tests and the Kruskal-Wallis test for nominal and continuous variables. Outcomes of interest were hospitalization rates, treatment, and outcomes (including mortality, complications, and resource utilization). The adjusted odds ratios of the outcomes were assessed using a stepwise multivariable logistic regression, adjusted for age, sex, race, insurance status, illness severity, risk of mortality, and comorbidity burden. This was done using the All Patient Refined Diagnosis Related Groups (APR-DRG) metrics and the Charlson comorbidity index. Results: The study analyzed 244,520 hospitalizations for prostate cancer. The median age of the cohort was 64 years (interquartile range: 59–69 years). Most were white Americans (69.9%) and blacks (16.3%). Approximately 53,550 (21.9%) were in the lowest SEC, 58,196 (23.8%) were in the lower SEC, 61,619 (25.2%) in the high SEC, and 66,803 (27.3%) in the highest SEC. Hospitalizations in the highest SEC were younger than those in the lowest SEC (63.7 vs. 66.5; P&lt;0.001). Hospitalizations in the lowest SEC were correlated with greater mortality (655, 1.2%; AOR: 1.43; 95% CI: 1.22-1.56; P=0.011) compared with those in the highest SEC (475, 0.7%; AOR: 0.86; 95% CI: 0.65-0.97; P&lt;0.001). The highest SEC correlated with higher rates of prostatectomy (2,995, 4.5%; AOR: 1.29; 95% CI: 1.08-1.10; P&lt;0.001), whereas the lowest SEC had lower rates (1,810, 3.4%; AOR: 0.52-0.98; P=0.008). The lower and lowest SECs had higher frequencies of chemotherapy (8.1% and 7.4%, respectively; P for all &lt;0.001). SEC did not correlate with the likelihood of immunotherapy (P = 0.738), radiotherapy (P = 0.073), length of hospital stays (P = 0.283), or mean hospital costs (P = 0.582). Hospitalizations in the higher SECs had lower odds of erectile dysfunction (highest SEC, AOR: 0.83; 95% CI: 0.74-0.93; P = 0.001; and high SEC, AOR: 1.13; 95% CI: 1.02-1.24). Conclusions: Prostate cancer affects the younger demographics of patients with higher SECs. However, hospitalizations in patients with lower SECs present with more advanced disease and result in poorer mortality outcomes than those in patients with higher SECs.
Metastatic pure seminomas with early relapse: Prognostic roles of high dose chemotherapy and surgery of residual disease.
Authors: Lucile Duval, Benoît Allignet, Christine Chevreau, Gwenaelle Gravis, Camille Mazza, Marine Gross-Goupil, Brigitte Laguerre, Patrice Peyrat, Floriane Izarn, Anna Patrikidou, Aude Flechon
Journal: Journal of Clinical Oncology (2024)

5031 Background: Metastatic seminomatous germ cell tumors (mSGCT) are a rare form of cancer. Few studies focused on early relapse (&lt; 12 months) after first-line chemotherapy (ChT). We aimed to evaluate the impact of salvage retroperitoneal lymph node dissection (RPLND), and high-dose ChT with hematopoietic stem cell transplantation (HDCT-HSCT) in mSGCT patients in a situation of early relapse. Methods: Ninety-one mSGCT patients treated between 2005 and 2022 in 7 French expert centers for an early recurrence after an initial favorable response to 1st-line ChT were retrospectively included. Patient clinical characteristics, progression-free survival after first relapse (PFS) and overall survival (OS) were evaluated. We also assessed the role of HDCT-HSCT as first salvage treatment, and the impact of complementary RPLND after salvage ChT. Results: After a median follow-up of 56 months, 3-year PFS and OS rates were 77.6% (95%CI, 68.3-88.1) and 88.4% (95%CI, 81.0-96.4), respectively. HDCT-HSCT was not associated with longer PFS or OS compared to standard-dose 2 nd -line ChT. In contrast, patients who underwent RPLND after salvage ChT demonstrated significantly longer PFS (at 3-years: 97.1% vs 63%; HR 0.15; 95%CI 0.03-0.65; p=0.012) and a notable trend towards improved OS (at 3-years: 97.0% vs 81.8%; HR 0.15; 95%CI 0.02-1.23; p=0.078). Conclusions: In mSGCT patients with first-year relapse, RPLND after salvage treatment is correlated with longer PFS and tends to be associated with longer OS. Identification of a subpopulation that might benefit from HDCT-HSCT ought to be performed since it did not confer survival benefits in the overall population.
Myocardial Inflammation in Heart Failure With Reduced and Preserved Ejection Fraction
Authors: Pilar Alcaide, Marinos Kallikourdis, Ramona Emig, Sumanth D. Prabhu
Journal: Circulation Research (2024)

Heart failure (HF) is characterized by a progressive decline in cardiac function and represents one of the largest health burdens worldwide. Clinically, 2 major types of HF are distinguished based on the left ventricular ejection fraction (EF): HF with reduced EF and HF with preserved EF. While both types share several risk factors and features of adverse cardiac remodeling, unique hallmarks beyond ejection fraction that distinguish these etiologies also exist. These differences may explain the fact that approved therapies for HF with reduced EF are largely ineffective in patients suffering from HF with preserved EF. Improving our understanding of the distinct cellular and molecular mechanisms is crucial for the development of better treatment strategies. This article reviews the knowledge of the immunologic mechanisms underlying HF with reduced and preserved EF and discusses how the different immune profiles elicited may identify attractive therapeutic targets for these conditions. We review the literature on the reported mechanisms of adverse cardiac remodeling in HF with reduced and preserved EF, as well as the immune mechanisms involved. We discuss how the knowledge gained from preclinical models of the complex syndrome of HF as well as from clinical data obtained from patients may translate to a better understanding of HF and result in specific treatments for these conditions in humans.
Correlation of body mass index (BMI) with survival outcomes in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): Analysis of patient (pt)-level data from SWOG 1216 study.
Authors: Umang Swami, Yeonjung Jo, Arshit Narang, Melissa Plets, Chadi Hage Chehade, Georges Gebrael, Shilpa Gupta, Zin Myint, Catherine Tangen, Primo N Lara, Ian M. Thompson, Maha H. A. Hussain, Tanya B. Dorff, Seth P. Lerner, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2024)

5081 Background: Obesity has been associated with improved survival outcomes in metastatic castration-resistant prostate cancer (PMID: 34226662). However, association of obesity with survival has not been reported in mHSPC setting. Herein we report the correlation of BMI with survival outcomes from patient level data from phase III study, SWOG 1216 which randomized pts with mHSPC in 1:1 to ADT + bicalutamide or ADT + orteronel. Methods: Inclusion: all pts treated on SWOG 1216 study with available BMI. Overall survival (OS) was summarized by median survival and its 95% confidence interval (CI). Multivariate analysis for OS was conducted using Cox proportional hazard model with categorized BMI as a continuous variable, and adjusted for treatment arm, disease burden, Gleason score, log 2 PSA, age and Zubrod performance status. All analysis was conducted using R v4.2.1. Results: Of 1279 pts, 12 were underweight, 252 had normal BMI, 958 were overweight and 57 were obese. Median age was 67.8 (IQR: 61.9, 73.9) years, no visceral metastases (88%) and baseline log2 median PSA of 4.89 (IQR: 3.27, 6.76). All four BMI cohorts had similar age, Gleason score, extensive disease burden, liver metastases and treatment allocation (p&gt;0.05). Differences in baseline PSA and Zubrod performance status were observed between BMI cohorts (p&lt;0.05). The OS (in years) in underweight, normal, overweight and obese cohorts was 1.8, 4.4, 6.5 and 4.8 for bicalutamide arm and 2.8, 5.7, not reached (NR) and NR for orteronel arm, respectively. After adjusting for prognostic variables, multivariate analysis confirmed that high BMI is associated with better OS (HR=0.82, 95% CI: 0.68-0.98; p=0.029) (Table). Conclusions: Our results show that as categorized BMI increased, the risk of death decreased in pts with mHSPC. These data warrant external validation in other randomized phase III studies and can help counseling and prognostication of patients with mHSPC in the clinic. Funding: NIH/NCI grants CA180888, CA180819, and in part by Millennium Pharmaceuticals (Takeda Oncology Company). Clinical trial information: NCT01809691 . [Table: see text]
Clinico-molecular predictors of exceptional response to immune checkpoint inhibitors (ICI) in metastatic cervical cancer (mCC).
Authors: Solenn Barraud, Cyril Roussel-Simonin, Alexandra Leary
Journal: Journal of Clinical Oncology (2024)

5539 Background: Metastatic cervical cancer (mCC) constitutes a global health challenge, despite preventive efforts like HPV vaccination, with imputable 342,000 deaths in 2020. Immunotherapies with Immune checkpoint inhibitors (ICI) have been assessed in the context of recurrent or mCC. Only 15% of patients with PDL1+ mCC respond to ICI, however responses can be prolonged. We aimed to describe outcomes for long-term responders (LTR) versus non long-term responders (NLTR) to ICI, and identify clinico-molecular predictors for LTR. Methods: We conducted a retrospective review of all patients with mCC treated with an ICI at Institut Gustave Roussy (IGR). Patients were classified as LTR if they had a complete response (CR) / partial response (PR) / stable disease (SD) maintained for ≥12 months (mo) and as NLTR if progressed &lt;12mo after ICI initiation. Cox regression analysis was performed to identify factors significantly associated with LTR (vs NLTR) and expressed as an odds ratio (OR). For a subset (43/106 patients), genomic analyses were performed using large panel next generation sequencing done at IGR within specific trials: STARTRK (NCT02097810) and STING (NCT04932525) on a tumor sample. Results: Between 01/2015 and 09/2023, 106 patients with mCC were treated with an ICI at the IGR. 20 patients (19%) were classified as LTR and 86 as NLTR (81%). 93% of patients received ICI without chemotherapy (2 LTR and 6 NLTR). After a median follow-up of 42mo, median PFS was not-reached in LTR versus 3.5mo for NLTR. Among the 20 LTR, 11 pts were in sustained complete response with a median of 22mo (range 2-55mo) since ICI discontinuation. Neither body mass index, performance status, LDH, neutrophil/lymphocyte ratio nor number of prior lines were predictive of LTR vs NLTR. A multivariate regression analysis identified 3 clinical factors significantly associated with LTR: oligo-metastatic (OR=11.4; p 0.006), lymph node metastases only (OR=8.2; p 0.02) and progression outside of irradiated fields (OR=5.9; p 0.03). With regards to molecular features, neither TMB nor MMR status were predictive, however PIK3CA mutations were significantly more frequent in LTR, found in 90% (vs 27% of NLTR) and PBMR1 mutations found exclusively in LTR, while NLTR presented with higher rates of STK11 alterations. Conclusions: Although responses to ICI in mCC remain rare (&lt;20% patients), they are associated with impressive outcomes (median PFS&gt;3.5 years) with a significant proportion disease-free months to years after ICI discontinuation suggesting some may be cured. Certain clinico-molecular features are strongly associated with LTR and may allow the selection of patients for ICI.