tbuckley/cabot-search huggingface dataset:
Characteristics and treatment (Tx) patterns (TxP) of high-risk biochemically recurrent (HR-BCR) non-metastatic castration-sensitive prostate cancer in the real-world by race, age, and prostate-specific antigen (PSA) doubling time (PSADT).
Authors: Alicia K. Morgans, Lisa Mucha, Nader N. El-Chaar, Dina Elsouda, Krishnan Ramaswamy, Tammy Schuler, Bruce A. Feinberg, Prathamesh Pathak, Parisa Asgarisabet, Danielle Gentile, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2024)

e17071 Background: The optimal approach to manage HR-BCR is undefined. Recent trials examined early intensified androgen-deprivation therapy (ADT), but its alignment with current practice is unclear. We describe real-world characteristics and TxP in patients (pts) with HR-BCR, and how age, race, and PSADT impact them. Methods: This physician-abstracted chart review used de-identified data from the Cardinal Health’s Urology and Oncology Provider Extended Network 2018-2022 in the US. HR-BCR was defined as in EMBARK: PSADT ≤9 months (m) and PSA ≥1 ng/mL for pts with prior radical prostatectomy (RP) or ≥2 ng/mL above nadir PSA for pts with radiotherapy (RT) without prior RP. Data were collected from index date (PSADT ≤9 m observed) until disease progression/last follow-up/death. PSADT was reported by physician (rwPSADT) or calculated (cPSADT) retrospectively. First-line (1L) Tx was that received ≤60 days post-index; no Tx received was defined as observation. Pt characteristics and TxP were analyzed descriptively in the overall cohort and by age ( &lt; 65 or ≥65 years [yrs]), race (White [W]/Black [B]), and PSADT (≤3 m, &gt; 3─9 m). Results: Of 284 pts with HR-BCR (mean [SD] age, 67 [7.5] yrs), most had Gleason ≥8. While one-third received 1L Tx (mainly systemic Tx ± RT [Table]), during a median follow-up of 1193 days, 75% of pts on 1L observation received systemic Tx (median time to Tx, 162 days), mostly ADT alone. Observation was used as 1L more often in the &lt; 65 yrs, W, and PSADT ≤3 m groups, but few pts in these groups, especially in PSADT ≤3 m and &lt; 65 yrs, had rwPSADT. At follow-up, over 70% pts received systemic Tx in all subgroups. Conclusions: During a short follow-up period, most pts with HR-BCR received systemic Tx suggesting that current practice includes Tx with systemic therapy rather than surveillance alone. Notably, pts &lt; 65 yrs and PSADT ≤3 m, those who perhaps stand the most to benefit, had lower rates of 1L systemic Tx, likely because many lacked rwPSADT (i.e., physician didn`t know PSADT). Our data support that lack of knowing PSADT in real-time may be associated with delayed Tx, which may warrant further research. [Table: see text]
Willingness of patients with biochemically recurrent prostate cancer (BCR) with positive 18F-dcfpyl PET/CT PSMA to monitor without treatment.
Authors: Monique Williams, Amy Hankin, Megan Hausler, Esther Mena Gonzalez, Liza Lindenberg, Jeanny B. Aragon-Ching, Laura Sena, Philip M. Arlen, Fatima Karzai, Peter L Choyke, Ravi Amrit Madan
Journal: Journal of Clinical Oncology (2024)

5104 Background: For patients that have a rising PSA and negative CT and bone scan after surgery or radiation, there are no therapies that have been shown to improve survival. This fact has not been changed by the approval of DCFPyL PET/CT PSMA, which can now define subclinical disease in patients with bone and CT scans that are otherwise negative. Treatment and outcome data in BCR is not equivalent to metastatic castration sensitive prostate cancer (mCSPC). Despite the lack of data for the optimal management for prostate cancer that is PSMA positive (ppBCR), many providers feel they must treat patients because patients are unwilling to monitor ppBCR over time. Methods: The NCI is currently accruing to a study (NCT05588128; goal n=250) designed to monitor patients with BCR to understand the evolution of PSMA imaging over time. Eligible patients have BCR and underwent definitive treatment (surgery and/or radiation therapy) &gt; 6 months prior to enrollment. Required PSA minimum 0.5 ng/mL; Testosterone minimum 100 ng/dL. Baseline CT and Tc-99m bone scans must be negative. Initial PSMA assessments occur within 8 weeks of confirmed eligibility. Positive PSMAs will be repeated every 6 months and negative PSMAs are repeated every 12 months for up to 5 years. PSAs are collected every 3 months. Following each PSMA scan, patients are counseled on the results. Radiation and intermittent systemic therapies (for 6 months or less) are allowed on this trial. Results: 57 patients have enrolled on the study and have been evaluated with PSMA PET thus far. Median PSA value at enrollment is 3.65 ng/mL (range, 0.5-71.6 ng/mL). Median PSA doubling time is 11.3 months (range, 1.2-132.4 months). Median patient age is 71 years (range, 54-92 years old). Self-reported race/ethnicity as follows: 75% White, non-Hispanic, 12% Black, non-Hispanic, 3.5% White, Hispanic, 3.5% Other, Hispanic, 2% Asian, 4% Unknown. Of the first 57 patients enrolled who have had PSMA PET scans, 52 patients (91%) were found to have positive findings. Among these, 49 patients (94%) with ppBCR elected to monitor their disease until the next scan. Conclusions: This study (NCT05588128) is the first prospective trial to monitor ppBCR patients to better define the natural history of BCR in the PSMA era. This preliminary data from the ongoing study thus far suggests that with appropriate counseling and a follow-up plan, the majority of patients are willing to monitor ppBCR. Given that no data has demonstrated a survival advantage for BCR or ppBCR, it is important for providers to have balanced conversations with patients about the implications of ppBCR, which often results in an indolent disease course. Clinical trial information: NCT05588128 .
Efficacy and toxicity of [<sup>177</sup>Lu]Lu-PSMA-617 for metastatic castration-resistant prostate cancer in a real-world setting: Results from the U.S. Expanded Access Program and comparisons with phase 3 VISION data.
Authors: Jeremie Calais, Vishnu Murthy, Andrew Voter, Kathleen Nguyen, Martin S. Allen-Auerbach, Sydney Caputo, Elisa M. Ledet, Opeoluwa Akerele, Abuzar Moradi Tuchayi, Courtney Lawhn Heath, Michael Anthony Carducci, Martin Pomper, Channing Judith Paller, Johannes Czernin, Lilja Solnes, Thomas A. Hope, Oliver Sartor, Andrei Gafita
Journal: Journal of Clinical Oncology (2024)

e17061 Background: ThePhase 3 VISION trial demonstrated that [ 177 Lu]Lu-PSMA-617 prolonged overall survival (OS) in metastatic-castration resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSi). The expanded access program (EAP) (NCT04825652) was opened to provide access to [ 177 Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. The VISION trial required strict inclusion and exclusion criteria, which may not represent the patient population encountered in clinical practice. This study aimed to evaluate the efficacy and safety profile of [ 177 Lu]Lu-PSMA-617 in a real-world setting within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP between May 2021 and March 2022 at four institutions in the United States with available toxicity and outcome data were included. Outcome measures included overall survival (OS), ≥50% PSA decline rates (PSA-RR), and incidences of toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Differences in baseline characteristics, toxicity, and PSA-RR between the EAP and VISION were evaluated using a t-test of proportions. Results: 117 patients with mCRPC were eligible and included. Patients enrolled in the EAP were similarly pretreated with taxane-based chemotherapy regimens (&gt;1 taxane: 47% vs 40%; p=0.16) and more heavily pretreated with ARSi (&gt;1 ARSi: 70% vs 46%; p&lt;0.001). EAP patients had similar levels of ≥3 grade anemia (18% vs 13%; p=0.15), thrombocytopenia (13% vs 8%; p=0.13), and neutropenia (3% vs 3%; p=0.85) and higher levels of ≥3 grade lymphopenia (34% vs 8%; p&lt;0.001). Patients treated within the EAP experienced numerically shorter OS (median OS: 13.7 vs 15.3 months) and similar PSA-RR (40% vs 46%; p=0.29). Median follow-up was numerically shorter in the EAP compared with VISION (14.7 mo vs 20.3 mo). Conclusions: mCRPC patients treated with [ 177 Lu]Lu-PSMA-617 in a real-world setting were more heavily pretreated with ARSi, had a similar safety profile, and experienced numerically shorter OS and similar PSA-RR compared with VISION trial patients. A major limitation of this study is that we did not have access to individual patient data from the VISION trial, so we were not able to assess whether differences in OS between VISION and the EAP were statistically significant.
Rapid and deep prostate-specific antigen (PSA) response to apalutamide plus ADT and survival in metastatic castration-sensitive prostate cancer (mCSPC) in real world practice in the US (OASIS Project).
Authors: Benjamin L. Maughan, Yanfang Liu, Suneel Mundle, Xiayi Wang, Lawrence Ivan Karsh
Journal: Journal of Clinical Oncology (2024)

5076 Background: Apalutamide (APA) in combination with androgen-deprivation therapy (ADT) is an effective life-prolonging treatment option for mCSPC. Early and deep PSA responses are response indicators in metastatic castration-resistant PC that have been associated with improved clinical outcomes in patients with PC. APA+ADT has been shown to induce early and deep PSA responses. We evaluated correlations between PSA and long term clinical outcomes in adults with mCSPC in real world practice. Methods: This retrospective, observational cohort study used the ConcertAI RWD 360 prostate cancer dataset to evaluate correlations between PSA and long term clinical outcomes in adults with mCSPC who initiated treatment with APA+ADT. All patients with newly diagnosed mCSPC from 1 Jan 2018 to 30 Sept 2022 were enrolled and followed up until 31 Mar 2023. Correlations between time to 50% and 90% declines in PSA (PSA50 and PSA90), and time to undetectable PSA (≤0.2 ng/mL) and 24-month OS were evaluated. Adjusted Hazard ratios (aHRs) were estimated using multivariate Cox proportional hazard models adjusted for age, comorbidities, BMI, baseline PSA. Results: 183patients with mCSPC who initiated APA+ADT treatment and had monthly PSA testing were included in the analysis; mean (SD) age 73 years (8), baseline PSA 34 (81). Mean (SD) duration of follow up was 18 m (10). Overall, 116 patients (63%) reached undetectable PSA over the follow-up period and 24-month OS was 68%. OS was significantly higher when patients achieved undetectable PSA, PSA90 and PSA50 within 3 months after initiating APA+ADT (24-month survival rate, 87%, 84% and 80%, respectively) compared with patients who did not reach these levels during the follow-up period (Table). The aHR was 0.15 (95% CI 0.05–0.47; p&lt;0.001) in patients who reached undetectable PSA within 3 months compared with not yet reached. The aHR was 0.27 (0.12–0.65; p&lt;0.01) in patients with onset of undetectable PSA beyond 3 months compared to not reached. Conclusions: Rapid and deep PSA decline was strongly associated with better overall survivalin patients with mCSPC initiated on APA+ADT.[Table: see text]
Real-world intensification beyond androgen deprivation therapy (ADT) in metastatic hormone sensitive prostate cancer (mHSPC) in the United States 2017-2023: An administrative claims database study.
Authors: Amit D Raval, Orsolya Lunacsek, Matthew J. Korn, Natasha Littleton, Niculae Constantinovici, Daniel J. George
Journal: Journal of Clinical Oncology (2024)

e17082 Background: Severalguidelines recommended the use of androgen receptor pathway inhibitors (ARPIs) and/or docetaxel along with ADT for mHSPC based on improved clinical outcomes demonstrated in clinical trials. Given the evolving treatment landscape since 2016, there is a need to understand the translation of clinical evidence and guidelines into clinical practice. Therefore, we examined the use of, and factors associated with intensification beyond ADT in men with mHSPC. Methods: A retrospective cohort of men treated for mHSPC was selected from private insurance claims of the Komodo Research Dataset (Jan 2017-Sep 2023). Men with mHSPC were identified based on their earliest claim for metastasis on or after prostate cancer diagnosis date without evidence of castration resistance. Index date was the earliest claim of ADT following mHSPC. Continuous insurance coverage for ≥ 12 months pre- (baseline) and ≥ 4 months post-index was required. Intensification beyond ADT was defined as the addition of ARPIs, docetaxel or both within ±4 months of the index date. Multinomial regression was conducted to examine factors associated with ADT intensification. Results: The study cohort comprised of 10,717 men with mHSPC with a median age of 65 years. Most had de novo mHSPC (62%), bone-only metastases (49%), hypertension (68%), diabetes (29%), and received opioids (59%) at baseline. Overall, in addition to ADT, 28% received ARPI (abiraterone: 18%, androgen receptor inhibitors: 10%), 9% docetaxel and 2.5% ARPI + docetaxel. From 2017 to 2023, there has been an increase in the intensification of ADT with ARPI from 13% to 47% and with docetaxel + ARPI from 0.8% to 15%, while the use of ADT + docetaxel declined from 12% to 3% and ADT alone from 74% to 36%. Key factors (age, comorbidity, de novo mHSPC, bone metastases) associated with intensification with either docetaxel or ARPI are listed in Table. Conclusions: There was a linear increase in intensification with ARPI and/or docetaxel in mHSPC between 2017-2023 in the US. Findings highlight a gradual uptake of guideline-recommended treatment for men with mHSPC, while over a third are still receiving ADT alone. [Table: see text]
Intersection of Immunology and Metabolism in Myocardial Disease
Authors: Edward B. Thorp, Anja Karlstaedt
Journal: Circulation Research (2024)

Immunometabolism is an emerging field at the intersection of immunology and metabolism. Immune cell activation plays a critical role in the pathogenesis of cardiovascular diseases and is integral for regeneration during cardiac injury. We currently possess a limited understanding of the processes governing metabolic interactions between immune cells and cardiomyocytes. The impact of this intercellular crosstalk can manifest as alterations to the steady state flux of metabolites and impact cardiac contractile function. Although much of our knowledge is derived from acute inflammatory response, recent work emphasizes heterogeneity and flexibility in metabolism between cardiomyocytes and immune cells during pathological states, including ischemic, cardiometabolic, and cancer-associated disease. Metabolic adaptation is crucial because it influences immune cell activation, cytokine release, and potential therapeutic vulnerabilities. This review describes current concepts about immunometabolic regulation in the heart, focusing on intercellular crosstalk and intrinsic factors driving cellular regulation. We discuss experimental approaches to measure the cardio-immunologic crosstalk, which are necessary to uncover unknown mechanisms underlying the immune and cardiac interface. Deeper insight into these axes holds promise for therapeutic strategies that optimize cardioimmunology crosstalk for cardiac health.
Association of genomic alterations with clinical outcomes following lutetium-177-PSMA vipivotide tetraxetan in men with metastatic castrate-resistant prostate cancer.
Authors: Timothy Gauntner, Jinesh S. Gheeya, Adam Khorasanchi, Menglin Xu, Elshad Hasanov, Katharine A. Collier, Lingbin Meng, Danielle Elise Zimmerman, Peng Wang, Edmund Folefac, Paul Monk, Amir Mortazavi, Steven K. Clinton, Yuanquan (Aaron) Yang
Journal: Journal of Clinical Oncology (2024)

5057 Background: Lutetium-177-PSMA vipivotide tetraxetan (Lu177) is approved for men with PSMA-positive metastatic castrate-resistant prostate cancer (mCRPC) previously treated with androgen receptor signaling inhibitors and taxane chemotherapy. The tumor genomic alterations conferring sensitivity or resistance to Lu177 are unknown. We investigated the association of genomic variants with clinical outcomes in men with mCRPC treated with Lu177. Methods: Somatic &amp; germline DNA sequencing data were examined from men treated with ≥1 cycle Lu177 at The James Cancer Hospital of The Ohio State University from 3/2022 – 10/2023. Pathogenic variants from tissue or blood testing were identified. Sets of genes with similar biological function were annotated, including homologous recombination repair (HRR) genes ( BRCA1, BRCA2, ATM, CDK12, CHEK1, CHEK2, PALB2, RAD51B, RAD51C, RAD51D, RAD54L), established tumor suppressor genes ( TP53, RB1, PTEN) and cell cycle genes ( CCND1, CCND3, CDK4, CDK6, CDK12, CDKN1B, CDKN2B) associated with prostate cancer. The impact of genomic variants on PSA50 response (Chi-Square &amp; Fisher’s exact test), median overall survival (OS) and median progression-free survival (PFS) (Kaplan-Meier method) and OS or PFS (Cox proportional hazards model) was assessed. Results: Of 153 patients treated with Lu177, 120 underwent genomic sequencing: 109 had somatic testing (76 tissue-based, 33 blood-based), 50 had germline and 39 had both somatic &amp; germline testing. Patients with amplification of cell cycle genes (n=8) had poorer OS of 5.1 months (mos.) vs 13.4 mos. for those without amplification (p=0.001, HR 4.26, 95% CI 1.79-10.11), and shorter PFS of 4.3 vs 7.4 mos. (p=0.027, HR 2.40, 95% CI 1.10-5.22). Patients with loss or mutation of HRR genes (n=32) had OS of 13.7 vs 12.2 mos. for those with no HRR alterations, but this was not significant (p=0.101, HR 0.57, 95% CI 0.29-1.12). No other genomic alterations were significantly associated with OS or PFS and none were associated with PSA50 response. The table lists the most frequently altered genes in PSA50 responders vs non-responders (differences not significant by Fisher’s exact test). Conclusions: Genomic alterations warrant investigation in larger cohorts as prognostic and predictive biomarkers for Lu177 therapeutic response. Our data suggest that amplification of genes impacting cell cycle regulatory pathways may be of particular interest. Our findings support continued efforts to determine the impact of cyclin dependent kinase (CDK) 4/6 inhibitors for high-risk and metastatic prostate cancer, either alone or in combination with agents such as Lu177.[Table: see text]
The effect of ACEi/ARB on survival outcome of patients with mCRPC treated with abiraterone.
Authors: Junliang Zhao, Xinyang Cai, Zhenyu Yang, Xingbo Long, Tianyou Zhang, Diwei Zhao, Yuanwei Li, Fangjian Zhou, Jun Wang, Yonghong Li
Journal: Journal of Clinical Oncology (2024)

5071 Background: Androgen deprivation therapy (ADT), such as Abiraterone Acetate (AA), has emerged as a standard treatment for metastatic prostate cancer (mPCa). However, long-term ADT treatment may increase the incidence of cardiovascular adverse events, such as hypertension, which are a common cause of death in patients receiving ADT. Therefore, it is crucial to select appropriate antihypertensive drugs that effectively manage blood pressure and improve overall survival (OS) in these patients. Methods: This study conducted a secondary analysis of the COU-AA-301 and COU-AA-302 trials, which were multicenter double-blind randomized controlled trials (RCTs) to evaluate the efficacy of AA in combination with prednisone and ADT compared to prednisone plus ADT alone in patients with metastatic castration-resistant prostate cancer (mCRPC). Patients were retrospectively assessed and stratified based on the concurrent medication including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB) or not. OS and progression-free survival (PFS) were assessed using the Kaplan-Meier method and log-rank test. Multivariable Cox regression analysis was performed to determine the independent correlation of ACEi/ARBs with OS and PFS. Statistical significance was defined as P&lt;0.05. Results: In COU-AA-301, the use of ACEi/ARB medications showed a significant association with improved OS (16.4 vs. 14.2 months, p&lt;0.001) and PFS (3.1 vs. 2.9 months, p=0.002) in AA arm. After adjusting for baseline factors, ACEi/ARB medications were still found to reduce the risk of death (HR 0.72, 95% CI 0.56-0.91) and disease progression (HR 0.81, 95% CI 0.69-0.96). Similarly, in COU-AA-302, ACEi/ARB medications were associated with prolonged OS (37.4 vs. 31.9 months, p=0.003) and PFS (20.3 vs. 14.7 months, p=0.002) in AA arm. By adjusting for baseline factors, ACEi/ARB medications remained significantly associated with lower risk of death (HR 0.70, 95% CI 0.56-0.88) and disease progression (HR 0.70, 95% CI 0.55-0.88). In the placebo group, ACEi/ARB medications demonstrated improved OS only in COU-AA-301 (13.7 vs. 10.6 months, p=0.021). However, this trend did not reach statistical significance after adjusting for baseline factors (HR 0.76, 95% CI 0.55-1.03). Furthermore, the use of ACEi/ARB medications did not confer any PFS benefits in COU-AA-301 and failed to show both PFS and OS benefits in COU-AA-302. Conclusions: The use of ACEi/ARB medications has shown promise in improving OS and PFS in mCRPC patients treated with AAP. However, it is important to acknowledge the inherent limitations of post-hoc analysis, and therefore, further validation through prospective clinical trials is warranted.