tbuckley/cabot-search huggingface dataset:
A phase II trial of enzalutamide (Enz) with 5-alpha reductase inhibitors (5-ARI) as an androgen deprivation therapy (ADT)–sparing approach for older men with castration-sensitive prostate cancer (CSPC).
Authors: Deepak Kilari, Sindhuja G Kadambi, Andrea M. Baran, Jason Zittel, John D. Burfeind, Edward M. Messing, Peter J. Van Veldhuizen, Kathryn A. Bylow, Deepak M. Sahasrabudhe, Supriya Gupta Mohile, Chunkit Fung
Journal: Journal of Clinical Oncology (2024)

5089 Background: Older men with prostate cancer who have aging-related conditions are at high risk for adverse events (AEs) from ADT. 5-ARI inhibit the conversion of testosterone to dihydrotesterone and could be synergistic with Enz. In this phase II study, we evaluated Enz and Dutasteride (Dut) or Finasteride (Fin) in lieu of ADT for older men with CSPC who are at risk of AEs from ADT. Methods: Eligible patients were ≥65 years (y); deemed “not fit” by geriatric assessment (GA) or at high risk for side effects from ADT as determined by the treating physician; had metastatic (M1) or non-metastatic (M0) CSPC with a PSA doubling time ≤9 months and testosterone &gt;50ng/dl. Enz 160 mg daily and Dut 0.5mg daily or Fin 5mg daily were administered until disease progression per Prostate Cancer Clinical Trials Working Group 2 guidelines. The primary study endpoint is PSA progression free survival (PFS). Key secondary endpoints include time to PSA nadir, absolute PSA nadir and evaluation of safety and toxicity of study treatments per CTCAE V4.0. Results: 43 men enrolled in the study. At study entry, subjects had the following baseline characteristics: median age was 78 y (range 66-94); 93% had ECOG 0-1; 63% had M1 CSPC with 30% of them having high volume disease per CHAARTED criteria; 23% had Gleason ≥ 8 CSPC; median PSA was 11.4 ng/ml (2-145), and median testosterone level was 342 ng/dl (56-639). Baseline GA at study entry showed that 18.6% had Instrumental Activity of Daily Living impairment; 9.8% had recent falls; 52.4% had Short Physical Performance Battery impairment; 40.5% had Older American Resources and Services (OARS) physical health and 31% had OARS medical social support impairments; 11.6% had Geriatric Depression Scale impairments; 65.9% had either Blessed Orientation-Memory-Concentration or Montreal Cognitive Assessment impairments; and 34.9% had Vulnerable Elders Survey-13 impairments. At a median follow-up of 5.9 y, 23 pts (53%) remained on study treatment and the median PSA PFS has not been reached for the entire group. The median time to PSA nadir was 8.1 months, with median PSA nadir at 0.02 ng/ml (range 0-2.75) and 98% having ≥90% PSA decline. The five most common any grade AE was fatigue (88%), gynecomastia (72%), hot flashes (42%), hypertension (40%), and falls (37%). No subject had treatment-related Grade 4 or 5 AEs. Four (9.3%) subjects withdrew treatment, 21% held treatments and 30.2% reduced dose of treatment due to AEs. Conclusions: The combination treatment with Enz and Dut/Fin appears to have clinical efficacy for older patients with CSPC who are at high risk for AEs from ADT. Clinical trial information: NCT02213107 .
Implications of HPV infection on survival outcomes in patients with penile squamous cell carcinoma: Insights from a nationwide study.
Authors: Rohan Garje, Mohammad Arfat Ganiyani, Atulya Aman Khosla, Shahzaib Ahmad, Vivek Podder, Shreyas S Bellur, Diya Jayram, Karan Jatwani, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2024)

5045 Background: Human Papilloma Virus (HPV) infection is a favorable prognostic marker in certain cancers, particularly oropharyngeal and vulvar (SCC). Patients with pSCC have risk profile and clinical course like pSCC. However, the impact of HPV status on survival in pSCC remains uncertain. Methods: We conducted a retrospective study using the National Cancer Database and included patients with pSCC tested for HPV between 2004-2021. Survival outcomes were analyzed and reported as median overall survival (mOS, 95% CI). Multivariate analysis adjusting for age, disease stage, treatment modalities, and comorbidities, was performed using Cox proportional hazards models and reported as hazard ratios (HR, 95% CI). Results: Out of 1371 men with pSCC, 539 (39.3%) were HPV positive (HPV +ve). At diagnosis, most HPV +ve men with pSCC presented with early-stage cancer(I-III), and 6% were stage IV. The mOS for HPV +ve patients was 123.96 months (98.96 - 148.40) vs. 104.38 months (89.13 - 115.98) in HPV negative patients with pSCC (P=0.01). In the adjusted analysis, the presence of HPV infection was associated with HR for death of 0.79 (0.65-0.98; P = 0.03) compared to patients without HPV (table). Conclusions: HPV infection in patients with pSCC is associated with improved survival. These findings highlight HPV status as a prognostic Indicator in pSCC irrespective of clinical profile. Therefore, testing for HPV at the time of diagnosis should be performed routinely in patients with pSCC. [Table: see text]
EMBARK post hoc analysis of sexual activity (SA) patient-reported outcomes (PROs) in patients (pts) who were sexually active or interested in sex at baseline (BL).
Authors: Stephen J. Freedland, John Mulhall, Martin Gleave, Ugo De Giorgi, Antti Rannikko, Fred Saad, Miguel Ramirez-Backhaus, Jasmina I. Ivanova, Anchen F. Nasr, Arijit Ganguli, Pavol Kral, Arlene Reisman, Neal D. Shore
Journal: Journal of Clinical Oncology (2024)

5084 Background: In EMBARK (NCT02319837), enzalutamide (ENZ) + leuprolide (L) or ENZ (ENZ mono) delayed metastasis-free survival vs placebo (P) + L while maintaining high quality of life (QoL) in high-risk biochemically recurrent nonmetastatic hormone-sensitive prostate cancer. SA (a composite score from European Organization for Research and Treatment [Tx] of Cancer QoL Questionnaire-Prostate 25 [QLQ-PR25]) was better preserved with ENZ mono vs P + L with no difference between ENZ + L vs P + L. To better understand effect on SA in relevant subgroups, we examined SA in pts who were sexually active or interested in sex at BL. Methods: QoL was assessed (BL, every 12 weeks) until metastasis/death. Cox regression was used to examine time to confirmed deterioration (TTCD) (confirmed at next visit) defined by one category change for sexual interest, activity, satisfaction, erectile function, and feeling like a man using QLQ-PR25 and FACT-P items (Table).Intent-to-treat analysis was applied. Results: Among pts interested in sex (n=694) or sexually active (n=437) at BL, TTCD in QLQ-PR25 SA domain, items 50 (interest), 51 (activity), GS7 (satisfaction), and BL5 (erectile function) were significantly delayed with ENZ mono vs P + L. In contrast, TTCD in BL5 (erectile function) was shorter with ENZ + L vs. P + L (Table). Conclusions: Among pts who were interested in sex or sexually active at BL, ENZ mono better preserved SA vs P + L in terms of SA domain, interest, activity, satisfaction, and maintaining erection. Adding ENZ to L had no impact on interest, activity, or satisfaction but may adversely affect erectile function, though differences in the median TTCD were clinically non-significant (0.06 months [1.8 days] and 0.09 months [2.7 days] in pts interested in sex and sexually active at BL, respectively). Clinical trial information: NCT02319837 . [Table: see text]
Descriptive analysis of patients on active surveillance escalating to treatment for localized prostate cancer.
Authors: Young Son, Edward Wu, Shawon Akanda, Katelyn Klimowich, Thomas Mueller, Gordon Andrew Brown
Journal: Journal of Clinical Oncology (2024)

e17092 Background: It is predicted that 1 in 8 men will be diagnosed with prostate cancer and 1 in 41 men will die of prostate cancer, making it the second leading cause of death in men. However, not all diagnosis of prostate cancer is clinically significant and active surveillance (AS) can be an option. Although AS is an option, an estimated 50% of patients will progress to treatment within 5-10 years. In this study, we aim to characterize those patients that required escalation to treatment from AS. Methods: A multicenter retrospective review was performed of patients that were had biopsy proven prostate cancer that elected to undergo AS. The cohort was subdivided into those that progressed to treatment (radiation, surgery, or hormonal therapy) and those that continued AS. Patient demographics, prostate biopsy characteristics, and biomarker usage was analyzed between the two groups. Descriptive analysis was performed and a multivariate logistic regression was performed. Results: A total of 158 patients were reviewed from 2021-2023. Among the cohort, 55 (34.2%) progressed to treatment while 106 (65.8%) remained on AS. The treated cohort were younger (63.2 vs. 68.6), had lower initial PSA (1.6 vs. 4.7), lower % free PSA (10.5 vs. 20.6), and higher number of cores positive (3.9 vs. 2.7) on biopsy. There was no difference in biomarker testing including Prolaris, Decipher, and Oncotype Dx between the treated and AS group. On adjusted analysis, age (OR 0.9, 0.81 – 0.99, P=0.035) and initial PSA (OR 0.38, 0.22 – 0.59, P&lt;0.001) were predictive covariates into treatment (Table). Conclusions: AS is an option for favorable prostate cancer. We show that there was no difference in Biomarkers, PIRADS, and PSAD between the treated and the AS group. Escalation to treatment from AS should be a shared decision making between provider and patient. Our multicenter, real-world analysis shows that younger patients and lower initial PSA were factors that were associated with escalation to treatment. [Table: see text]
Antimicrobial stewardship
Authors: John H Powers
Journal: BMJ (2024)

related admissions for children to emergency departments. 17Studies raise the possibility that the antimicrobial effects on the host microbiome may decrease the efficacy of immunotherapies for cancer. 18 The priority for appropriate prescribing and the outcomes measured in future stewardship studies should be direct patient outcomes.Showing direct benefits for patients would justify the cost and implementation of such programmes before they are routinely recommended.
PHAROS, a real-world multi-country European study on patients with high-risk localised and locally advanced prostate cancer receiving radical treatment.
Authors: Matthias Eiber, Daniel M. Aebersold, Alfonso Valcarcel diaz, Christian Wetterauer, Michael Bach, Flavio Camarrone, Kathleen Herkommer, Honghao Li, Fernando Lopez Campos, Thomas Mathieu, Jonathan Olivier, Geneviève Pissart, Paul Robinson, Mohamed Shelan, Hind Stitou, Céline Thiriez, Maxime Touzot, Arnauld Villers
Journal: Journal of Clinical Oncology (2024)

5027 Background: Primary radical therapy with curative intent is standard of care for patients diagnosed with high risk (HR) localised (LPC) and locally advanced prostate cancer (LAPC). However, many patients relapse and detailed epidemiological data on natural history, routine management, and clinical outcomes in this setting are sparse. We aimed to explore real world data (RWD) to gain insights into the understanding of the disease pathway. Methods: PHAROS is a retrospective, observational study conducted in five academic centres across four European countries from 1989 to 2022 (France, Germany, Switzerland, Spain). All patients with HR LPC and LAPC, according to EAU guidelines, and treated by primary radical prostatectomy (RP) or radiotherapy (RT) (alone or with ADT) were eligible. Data were structured and analysed to describe the patient characteristics at the time of radical therapy, subsequent treatment patterns and clinical events including biochemical recurrence (BCR), event-free survival (EFS) [defined by loco-regional relapse, BCR, metastasis or death] and overall survival (OS) that were estimated by Kaplan-Meier method. Results: The table summarizes baseline characteristics and intermediate endpoints for a total of 2303 patients, mostly diagnosed between 2005 and 2020, with a mean follow-up of 6.8 years. RP patients were younger and more likely to be node-positive (N+) as compared to RT patients. EFS at 5 years was 48 % [0.43-0.54] in the RP cohort (N=1539), and 74% [0.66-0.81] in the RT cohort (N=764). At 5 years after radical treatment, 21% of the RP cohort developed distant metastases and rates were higher (30%) in centres with routine access to PSMA PET. The rate was lower (12%) in the RT cohort potentially because of extended hormonal treatment. The principal reported treatment after the first BCR in the RP cohort was salvage RT ±ADT and ADT for the RT cohort. Only 249 and 311 deaths were observed in the RP and RT cohort with an estimated 10-year OS of 73 % [0.66-0.80] and 69% [0.57-0.80], respectively. Conclusions: In this large RWD cohort of HR LPC &amp; LAPC, initial results suggest that a significant proportion of patients fail after primary curative treatment within 5 years, indicating an unmet medical need to improve outcomes. Further analysis of the PHAROS dataset will bring better understanding of the real-world patient pathway in this setting and the role of intermediate endpoints. [Table: see text]
Evaluation of persistence and adherence for oral and injectable androgen deprivation therapies (ADT) in United States (US) patients with prostate cancer (PC).
Authors: Jason Hafron, Agnes Hong, Simon DePaauw-Holt, Hela Romdhani, Frédéric Kinkead, Scott C Flanders, Michael J. Ryan, Rana R. McKay
Journal: Journal of Clinical Oncology (2024)

e17110 Background: Relugolix (REL) is the only oral gonadotropin-releasing hormone (GnRH) antagonist available for patients (pts) with advanced PC. Other ADT options for these pts include the injectable GnRH antagonist degarelix (DEG) or injections or implants of GnRH agonists (i.e., leuprolide, goserelin, triptorelin, or histrelin). This study assessed persistence and adherence for REL, DEG, and GnRH agonists in US pts with PC. Methods: This retrospective study used the Merative MarketScan Research Claims Database (Commercial Claims and Medicare Supplemental; 01/2017–12/2022). Eligible pts were adult men with ≥1 claim with PC diagnosis who initiated REL, DEG, or a GnRH agonist (first claim was the index date) between 01/01/2021 and 06/30/2022. Pts were classified into these 3 mutually exclusive cohorts based on the index ADT. Kaplan–Meier (KM) analysis was used to assess persistence (i.e., time from index to treatment discontinuation defined as a gap in treatment of ≥60 days after the last day of supply, or switch to a new ADT). Treatment adherence was assessed at 6 and 12 months (mo) using proportion of days covered (PDC) defined as the sum of non-overlapping days of supply divided by the time period. Results: In total, 173 REL, 266 DEG, and 2,955 GnRH agonist pts were included. Median age was similar across cohorts and the proportion of pts with metastatic disease was slightly lower in GnRH agonist pts (Table). Median time on index ADT was 13.5 (REL), 3.1 (DEG), and 8.8 (GnRH agonist) mo. At 6 mo, persistence was 72.9% (REL), 24.2% (DEG), and 57.3% (GnRH agonist); and the proportion of pts with PDC ≥0.80 was numerically highest in REL and GnRH agonist pts and lowest in DEG. At 12 mo, persistence was 54.8% (REL), 9.9% (DEG), and 39.9% (GnRH agonist); and the proportion of pts with PDC ≥0.80 was also numerically highest in REL and GnRH agonist pts and lowest in DEG (Table). Conclusions: Despite differences in mode of administration, findings indicate that persistence and adherence are similar in pts with PC treated with REL and GnRH agonists while higher than those treated with DEG. Future research is needed to understand the factors associated with persistence and adherence. [Table: see text]
Association of tumor genetics with outcomes in patients (pts) with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) treated with <sup>177</sup>Lu-PSMA-617.
Authors: Justine Panian, Nicholas Henderson, Pedro C. Barata, Mehmet Asim Bilen, Laura Graham, Elisabeth I. Heath, Daniel Herchenhorn, Clara Hwang, Deepak Kilari, Vadim S Koshkin, Jones T. Nauseef, Alexandra Sokolova, Yousef Zakharia, Michael Thomas Schweizer, Tanya B. Dorff, Andrew J. Armstrong, Ajjai Shivaram Alva, Rana R. McKay
Journal: Journal of Clinical Oncology (2024)

5050 Background: 177 Lu-PSMA-617 is approved for the treatment (tx) of mCRPC. Though tx is associated with improved survival, not all pts experience a benefit. Acquired resistance is common and some pts have intrinsic resistance. There is a lack of data on genomic markers that could aid in selecting pts for tx. In this study, we aim to characterize molecular predictors of benefit to 177 Lu-PSMA-617. Methods: We used the retrospective Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) clinical-genomic database (n=2100). The primary endpoint was to investigate the association of genomic alterations with a ≥50% PSA decline (PSA50) from baseline following 177 Lu-PSMA-617. Associations were assessed using Wald-chi square test and Cox regression in multivariable analysis. Secondary endpoints included clinical progression-free survival (PFS) and overall survival (OS). Results: We identified 115 pts with PSMA PET+ mCRPC treated with 177 Lu-PSMA-617 who had commercial genetic sequencing prior to tx (median age 72 yrs, 25% non-white). Median number of prior lines for mCRPC was 3 with 71 pts (62%) receiving &gt;1 androgen receptor signaling inhibitor (ARSI) and 55 pts (48%) receiving &gt;1 taxane; 11 pts (9%) received ARSI with 177 Lu-PSMA-617. Overall, the PSA50 was 49% with median OS and PFS of 14.0 and 7.6 months (mos), respectively. In pts with a PSA50, median OS and PFS were 22.6 and 11.6 mos, respectively, vs 11.2 and 5.6 mos for those without a PSA50. Genetic alterations associated with PSA50 are in the table. PSA50 was 48% in pts with (n=32) vs 49% in pts without DDR alterations (n=83). PSA50 was 44% in pts with tumor suppressor gene alterations (TSGa) ( PTEN, p53, RB1) (n=68) vs 56% in pts without (n=47). Median PFS was 7.6 vs 7.3 mos for pts with and without any TSGa (p=0.90), and median OS was 12.2 mos vs 22.6 mos for pts with and without TSGa (p=0.004). Of the 43 pts with AR alterations, 8/15 (53%) with LBD mutations, 10/27 (37%) with AR amplification, and 0/1 with AR-V7 had a PSA50. FGFR, CDK12 and MYC alterations were enriched in individuals without a PSA50 (75-83%). Conclusions: We demonstrate that CDK12, MYC and FGFR alterations were associated with a lower PSA50 with 177 Lu-PSMA-617. Larger cohorts should be investigated for confirmation, as biomarkers to inform relative benefit of tx could be useful in prioritizing options for mCRPC. [Table: see text]
Cardiac Fibroblastic Niches in Homeostasis and Inflammation
Authors: Nadine Cadosch, Cristina Gil-Cruz, Christian Perez-Shibayama, Burkhard Ludewig
Journal: Circulation Research (2024)

Fibroblasts are essential for building and maintaining the structural integrity of all organs. Moreover, fibroblasts can acquire an inflammatory phenotype to accommodate immune cells in specific niches and to provide migration, differentiation, and growth factors. In the heart, balancing of fibroblast activity is critical for cardiac homeostasis and optimal organ function during inflammation. Fibroblasts sustain cardiac homeostasis by generating local niche environments that support housekeeping functions and by actively engaging in intercellular cross talk. During inflammatory perturbations, cardiac fibroblasts rapidly switch to an inflammatory state and actively communicate with infiltrating immune cells to orchestrate immune cell migration and activity. Here, we summarize the current knowledge on the molecular landscape of cardiac fibroblasts, focusing on their dual role in promoting tissue homeostasis and modulating immune cell–cardiomyocyte interaction. In addition, we discuss potential future avenues for manipulating cardiac fibroblast activity during myocardial inflammation.
Real-world comparative effectiveness and cardiovascular safety of enzalutamide versus abiraterone amongst older men diagnosed with metastatic castration-resistant prostate cancer.
Authors: Charles Gaber, Ebere Okpara, Abdullah Abdelaziz, Jyotirmoy Sarker, Kent Hanson, Lubna Hassan, Fang-Ju Lin, Todd Lee, Natalie Marie Reizine
Journal: Journal of Clinical Oncology (2024)

5053 Background: Abiraterone and enzalutamide are frequently used in treating metastatic castration-resistant prostate cancer (mCRPC), and their use has expanded to castration-sensitive and non-metastatic settings. The objective of this study was to compare real-world overall survival and risk of major adverse cardiovascular events (MACE) between initiators of abiraterone and enzalutamide in a cohort of older adult men with mCRPC. Methods: The Surveillance Epidemiology and End Results-Medicare database was leveraged to design a comparative observational study. Initiators of abiraterone or enzalutamide between 2011-2017 were identified, a period when both drugs were only approved for mCRPC. Propensity scores and inverse-probability-of-treatment weighting were used to balance measured confounders. MACE was defined as a hospitalization for myocardial infarction, heart failure, or ischemic stroke or transient ischemic attack. Hazard ratios were obtained from weighted Cox proportional hazards (mortality) and Fine-and-Gray models (MACE). Results: The study population consisted of 5,633 men 66 years of age and older diagnosed with mCRPC, of which 3,720 initiated abiraterone and 1,913 enzalutamide. The median age at initiation was 77. Compared to enzalutamide initiators, the overall survival was similar in patients initiating abiraterone at both one-year (mortality hazard ratio (HR) = 1.05; 95% CI: 0.95 – 1.17) and five-years of follow up (HR= 1.01; 95% CI: 0.95 – 1.08). The one-year risk of MACE was higher in abiraterone initiators (HR = 1.30; 95% CI: 1.01 – 1.67). The agents displayed similar effects on MACE when considering a five-year follow-up period after therapy initiation (Table). Conclusions: The long-term comparative effectiveness and cardiovascular safety of abiraterone and enzalutamide were similar, though a short-term increase in MACE was seen in abiraterone initiators, highlighting the importance of considering cardiovascular risk and cancer prognosis during therapy selection.[Table: see text]