tbuckley/cabot-search huggingface dataset:
<sup>68</sup>Ga-PSMA PET/CT response and clinical outcomes in patients treated with enzalutamide as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC): Results of a prospective study.
Authors: Emilio Francesco Giunta, Paola Caroli, Emanuela Scarpi, Amelia Altavilla, Irene Marini, Monica Celli, Chiara Casadei, Cristian Lolli, Giuseppe Schepisi, Sara Bleve, Nicole Brighi, Maria Concetta Cursano, Giovanni Martinelli, Federica Matteucci, Ugo De Giorgi
Journal: Journal of Clinical Oncology (2024)

5018 Background: 68 Ga prostate specific membrane antigen positron emission tomography/computed tomography ( 6 8 Ga-PSMA PET/CT) is a highly sensitive diagnostic tool whose adoption is constantly increasing in prostate cancer patients, also for monitoring response to therapies. We evaluated the impact of 68 Ga-PSMA PET/CT response, as compared to prostate-specific antigen (PSA) response, in patients treated with enzalutamide as first-line therapy (1L) for mCRPC. Methods: From Oct 2017 to May 2022, in an observational prospective study, 70 consecutive mCRPC patients were treated with 1L enzalutamide 160 mg QD and underwent 68Ga-PSMA PET/CT within 3 weeks before (baseline) and 12 weeks (SD: ±4 weeks) after treatment initiation. We measured at both the timepoints the sum of metabolic total volume (sMTV), mean and maximum standardized uptake volume (sSUVmean and sSUVmax, respectively) and total lesion activity (sTLA), which is the product of MTV and SUVmean, for a maximum of 20 lesions. On the basis of EAU/EANM criteria, patients were categorized as PSMA responders (PET-R, in case of complete/partial response or stable disease) or PSMA non-responders (PET-NR, in case of progressive disease). Based on prostate-specific antigen (PSA), patients were classified as biochemical responders (PSA-R, in case of PSA decrease ≥ 50%) or non-responders (PSA-NR in all other cases). Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. Results: At the data cut-off (31 st Dec 2023), 69 mCRPC patients were considered fully evaluable. The median age was 75 years (range: 47-91), GS was &lt;8 in 24 (35%) and ≥8 in 37 (53%), the median baseline PSA was 2.57 µg/L (range: 0.09-197). We observed a median sSUVmax of 41.6, median SSUVmean of 28.2 and median sTLA of 44.8. The median follow-up was 57 months. In the Table, we reported survival results according to PSA and PET response. Differences between the discordant groups were not statistically significant for both median progression-free survival (mPFS) and median overall survival (mOS) (p=0.09 and 0.41, respectively), even if a positive trend for PET was shown. At multivariate analysis, only sTLA at 12 weeks was significantly associated with both mPFS (p=0.0004) and mOS (p=0.0006). Conclusions: 68Ga-PSMA PET/CT response appeared more accurate than PSA monitoring to predict survival to enzalutamide initiation in mCRPC. Some PET parameters may better predict survival benefit and need future validation. [Table: see text]
Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Secondary analysis of the SPARTAN trial.
Authors: Soumyajit Roy, Fred Saad, Shawn Malone, Yilun Sun, Daniel Eidelberg Spratt, Amar Upadhyaya Kishan, Christopher J.D. Wallis, Angela Jia, Osama Mohamad, Umang Swami, Michael Ong, Neeraj Agarwal, Simon Chowdhury, Scott C. Morgan
Journal: Journal of Clinical Oncology (2024)

5046 Background: While exposure to concomitant medications (conmeds) have been found to influence survival and treatment response in patients with metastatic prostate cancer, it is unclear if exposure to these medications affect treatment response and survival in men with non-metastatic castrate resistant prostate cancer (nmCRPC) treated with androgen receptor signaling inhibitors (ARSI). We performed an exploratory analysis of the SPARTAN trial to determine whether receipt of conmeds influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with nmCRPC. Methods: SPARTAN is a phase III randomized controlled trial in which nmCRPC patients were randomly assigned 2:1 to receive apalutamide or placebo in addition to androgen deprivation therapy (ADT). We focused on 5 groups of commonly prescribed classes of conmeds: biguanides (metformin), HMG-CoA reductase inhibitors (statins), angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid derivatives (ASA), and proton pump inhibitors (PPI) given their plausible biologic and clinical rationale. To determine the potential effect-modification, we applied Cox regression models with interaction term between the conmed class, the randomized treatment in addition to a minimally sufficient set of confounders. To determine the independent association of each class of conmeds with outcome, we applied IPTW-based survival analysis and log-rank test. Results: Overall, 1152 patients (772 and 380 in the apalutamide and placebo arm, respectively) were eligible for this secondary analysis. For OS, we did not find any statistically significant heterogeneity of treatment effect from ADT plus apalutamide across subgroups stratified by concomitant exposure to the conmeds listed above. We noted a significant difference (p=0.01) in treatment effect from apalutamide on MFS between patients with concomitant receipt of statins (adjusted hazard ratio [aHR]: 0.20; 95% CI: 0.15-0.28) vs without statins (aHR: 0.31 [0.24-0.39]). On IPTW-based analysis, patients with concomitant metformin (median: NR vs 31 months (mos); p=0.002) and concomitant ACEI (median: 37 vs 29 mos; p=0.006) had significantly superior MFS. Patients with exposure to all of metformin, ACEI, and statin had significantly improved MFS (median: NR vs 31 mos; p&lt;0.001). Conclusions: In this post-hoc exploratory analysis, treatment effects from apalutamide on MFS and OS were consistent across subgroups stratified by exposure to conmeds. Exposure to concomitant metformin or ACEI was associated with a significant improvement in MFS.
Association of very deep prostate-specific antigen (PSA) decline with longer radiologic-progression-free survival (rPFS) in patients with metastatic castration-sensitive prostate cancer.
Authors: Caner Kapar, Volkan Tuğcu, Selçuk Şahin, Haydar Güler, Saadettin Kilickap, Deniz Tural
Journal: Journal of Clinical Oncology (2024)

e17074 Background: Previous studies have shown rare PSA and rapid reduction in PSA to be associated with survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with ADT, docetaxel, abiraterone, or enzalutamide. The ability to accurately rate nadir PSA level may help inform treatment intensification or de-escalation decisions. PSA nadir level was determined as 0.2 ng/mL for mCSPC in previously reported. However, the deeper the reduction in PSA level, the better the survival outcomes in prostate cancer may be. In the current study, we evaluated the association between a very deep PSA decline and rPFS in patients treated with mCSPC. Methods: Patients with mCSPC treated with ADT, Abiraterone acetate, Enzalutamide, or Docetaxel in the first line setting were included in the study. Serum PSA values were recorded at baseline, 1st, 3rd, and 6th months (mo ). Based on the lowest reached PSA level, patients were divided into four subgroups (PSA &lt;=0.02 ng/mL, PSA 0.02–0.2ng/mL, PSA 0.2-4ng/mL, PSA &gt;4 ng/mL). Median follow-up and rPFS were estimated using the Kaplan-Meier method. Results: Data from 151 patients were analyzed. 11 patients were excluded due to insufficient data, and 7 patients were not included due to inadequate follow-up. The median age was 68 (38–91) years, and the majority of patients (51.1%) had Eastern Cooperative Oncology Group performance status (ECOG PS) scores of 1≥. Of the patients, 54.1% had high-volume disease, and 65.4% had synchronous metastasis. Additionally, 82% of the patients had bone metastasis, 15% had lung metastasis, and 7% had liver metastasis. When patients were stratified into 4 subgroups based on their lowest PSA levels, the distribution was as follows: PSA&lt;=0.02 ng/mL, 15% (n=20); PSA 0.02–0.2 ng/mL, 20.3% (n=27); PSA 0.2–4 ng/mL, 48.9% (n=65); PSA &gt;4 ng/mL, 15.8% (n=21). The median follow-up time was 32.3 (3–86) mo. The median rPFS for all populations was calculated as 18.1 mo [15.1–20.9 mo, 95% CI]. In the PSA&lt;=0.02 ng/mL group, the median rPFS was 49.8 mo [38–61.6 mo, 95% CI]; PSA 0.02–0.2 ng/mL group, 27 mo [16.8–37.2 mo, 95% CI]; PSA 0.2–4 ng/mL group, 16 mo [13.5–18.8 mo, 95% CI]; PSA &gt;4 ng/mL group, 8 mo [1.4-14.6 mo, 95% CI]. The statistical analysis revealed a significant relationship between very deep PSA levels and rPFS [p&lt;0.01]. 5-year rPFS were %78, %16, %8 and %0 for each group, respectively(p&lt;0.01). Conclusions: Very deep prostate-specific antigen decline is associated with longer rPFS in patients with mCSPC. Very deep prostate-specific antigen decline is a more potent surrogate marker for longer rPFS and it can be used new primary endpoint for clinical trials.
Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities
Authors: Ingo Hilgendorf, Stefan Frantz, Nikolaos G. Frangogiannis
Journal: Circulation Research (2024)

The adult mammalian heart has limited endogenous regenerative capacity and heals through the activation of inflammatory and fibrogenic cascades that ultimately result in the formation of a scar. After infarction, massive cardiomyocyte death releases a broad range of damage-associated molecular patterns that initiate both myocardial and systemic inflammatory responses. TLRs (toll-like receptors) and NLRs (NOD-like receptors) recognize damage-associated molecular patterns (DAMPs) and transduce downstream proinflammatory signals, leading to upregulation of cytokines (such as interleukin-1, TNF-α [tumor necrosis factor-α], and interleukin-6) and chemokines (such as CCL2 [CC chemokine ligand 2]) and recruitment of neutrophils, monocytes, and lymphocytes. Expansion and diversification of cardiac macrophages in the infarcted heart play a major role in the clearance of the infarct from dead cells and the subsequent stimulation of reparative pathways. Efferocytosis triggers the induction and release of anti-inflammatory mediators that restrain the inflammatory reaction and set the stage for the activation of reparative fibroblasts and vascular cells. Growth factor–mediated pathways, neurohumoral cascades, and matricellular proteins deposited in the provisional matrix stimulate fibroblast activation and proliferation and myofibroblast conversion. Deposition of a well-organized collagen-based extracellular matrix network protects the heart from catastrophic rupture and attenuates ventricular dilation. Scar maturation requires stimulation of endogenous signals that inhibit fibroblast activity and prevent excessive fibrosis. Moreover, in the mature scar, infarct neovessels acquire a mural cell coat that contributes to the stabilization of the microvascular network. Excessive, prolonged, or dysregulated inflammatory or fibrogenic cascades accentuate adverse remodeling and dysfunction. Moreover, inflammatory leukocytes and fibroblasts can contribute to arrhythmogenesis. Inflammatory and fibrogenic pathways may be promising therapeutic targets to attenuate heart failure progression and inhibit arrhythmia generation in patients surviving myocardial infarction.
Real-world baseline treatment patterns and overall survival (rwOS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with olaparib in the United States.
Authors: Furaha Kariburyo-Yay, Daniel J. George, Himani Aggarwal, Jon G. Tepsick, Rebekah Yu, Weiyan Li, Chinelo Orji, Lincy S. Lal, Sameer R. Ghate
Journal: Journal of Clinical Oncology (2024)

5054 Background: Olaparib is one of the first targeted therapies for pts with mCRPC. Real-world data on treatment patterns prior to receiving olaparib are limited in mCRPC pts with homologous recombination repair gene mutation (HRRm). This study describes real-world novel hormonal agent (NHA) use by clinical setting prior to receiving olaparib in mCRPC and rwOS in pts with HRRm mCRPC treated with olaparib monotherapy. Methods: HRRm+ pts with confirmed mCRPC diagnosis, age ≥21 years, treated with olaparib monotherapy (post May 19, 2020) and prior to abiraterone or enzalutamide were abstracted from electronic medical records in the ConcertAI Oncology Dataset with PC diagnosis between 1990 and 2023. HRR genes of interest were ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L. Frequency of pts who progressed from metastatic hormone-sensitive PC (mHSPC) and from non-metastatic CRPC (nmCRPC) to mCRPC and treatment patterns prior to mCRPC were summarized. Kaplan-Meier analysis was used to describe the rwOS from the start date of earliest olaparib monotherapy treatment (index date). Results: A total of 144 mCRPC olaparib treated pts were identified [median age 73 years; any BRCAm including co-occurring HRRm 56.3%; White 73.6%; ECOG 0-1 at index 78.4%; Gleason ≥8 at index 66.7%]. Of the 144 pts, 80.5% of pts progressed from mHSPC, 11.8% of pts progressed from nmCRPC, and 7.6% of pts were identified in mCRPC setting. For pts who progressed from mHSPC, 62.1% were NHA-treated in the mHSPC setting. Overall, 43.8% initiated olaparib monotherapy in the first 2 lines of therapy after mCRPC diagnosis while 15.3% initiated olaparib in 5L+ (Table). Among pts diagnosed with mHSPC before mCRPC, olaparib was most frequently received in 2L (26.7%) and in 3L (22.4%). For mHSPC pts treated with NHA, olaparib was most frequently received in 2L (31.9%); in contrast, for mHSPC pts that were NHA-naïve, olaparib was most frequently received in the 5L+ (29.5%). The overall median rwOS from olaparib initiation was 16.5 (95% CI: 12.4, 21.1) months; and 20.3 (95% CI: 14.7, 26.8) and 12.9 (95% CI: 10.9, 16.9) months, respectively, for pts with and without any BRCA mutations. Conclusions: This real-world analysis indicates many mCRPC pts with HRRm are receiving several lines of therapy prior to olaparib, even when NHA are used prior to mCRPC. Earlier treatment with olaparib monotherapy may improve duration of therapy and overall survival. [Table: see text]
Resources to address challenges in first-line treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC): A discrete choice experiment.
Authors: Stacy Loeb, Neeraj Agarwal, Nader N. El-Chaar, Laura de Ruiter, Janet Kim, Jessica Mack, Christopher S Bland, Sarah Rich-Zendel, Jay Sheldon, Jin Su Joo, Judith Dyson
Journal: Journal of Clinical Oncology (2024)

5087 Background: Althoughfirst-line treatment intensification (TI) (i.e., androgen-deprivation therapy with chemotherapy, novel hormonal therapies, or both) is recommended in mCSPC guidelines, it is used in &lt;1/3 of patients. Phase 1 of the IMPLEMENT study used an implementation science approach to identify barriers to and facilitators of TI. Phase 2 of IMPLEMENT aimed to prioritize these factors and identify resources to increase TI. Methods: A discrete choice experiment was developed for 300 US-based physicians (150 oncologists, 150 urologists) who manage mCSPC. It included 6 descriptions of potential resources to help with TI decisions, based on results from Phase 1. Respondents selected from pairs of resource sets the set they perceived as most helpful across 12 scenarios. We analyzed responses using a mixed-effects logistic regression model and calculated a coefficient of helpfulness for each resource to identify those with the strongest impact on physicians’ decisions. Coefficients were required to have a minimum value of zero, as resources would be optional. Results: Overall, physicians preferred decision support tools and databases of post-treatment options. Urologists found decision support tools most beneficial (coefficient of helpfulness 3.27; 95% CI 2.90-3.64), while oncologists preferred post-treatment databases (2.58; 95% CI 2.29-2.89) and clinical trial summaries (2.41; 95% CI 2.13-2.69). Tools to reduce administrative burden and information on outcomes of earlier vs later TI were not considered as helpful compared to other resources and across specialties. Conclusions: There were key differences between specialties in the helpfulness of resources, indicating substantial variability in clinical practice needs. These findings provide a clear path to develop concrete, specialty-tailored tools to increase guideline-concordant treatment of mCSPC. [Table: see text]
Genetic analysis of metastatic castration resistant prostate cancer patients treated with Lu-177 PSMA radioligand therapy.
Authors: Burcak Yilmaz, Cameron Chalker, Yun Yu, Andy Kaempf, Erik Mittra, Nadine Mallak, Alexandra Sokolova
Journal: Journal of Clinical Oncology (2024)

e17063 Background: We aim to elucidate associations between mutations, treatment response, and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients undergoing Lu-177 PSMA radioligand therapy (PSMA-RLT). Methods: We reviewed mCRPC patients who received at least 1 cycle of PSMA-RLT between May 2022 and October 2023, assessing mutations that included ATM, ATR, BRCA1/2, BRIP1, CHEK2, EPCAM, FANCA, GEN1, HOXB13, MLH1, MSH2/6, NBN, PALB2, PMS2, RAD51C, RAD51D, and TP53. Clinical variables were collected. Biochemical response (BR) was defined as PSA reduction ≥ 50% over the complete course of PSMA-RLT. PSMA PET segmentation was performed with MIM PUR PSMA (version 7.2.9). OS was measured from start of PSMA-RLT, estimated by the Kaplan-Meier method, and modeled with Cox regression; BR was modeled with logistic regression. Results:71 mCRPC patients with median age of 72 (range: 48-90) were included. 47 (66%) patients completed ≥ 4 PSMA-RLT cycles with 30% receiving all 6 cycles. 35 (49%) had a GS ≥ 8 (11 unknown) and 33 (46%) had metastases at diagnosis. 25 patients had somatic testing, 29 had germline testing, 16 had both, and 1 was unknown. All tumors were microsatellite stable. 6 had a BRCA 1/2 mutation, of which 3 were in the germline; 9 carried a non- BRCA homologous recombination deficiency (HRD) mutation. 17 had a mutation in p53, RB1, or PTEN. There was no correlation between mutation status and any pretreatment PET parameters, BR, or OS. BR was achieved in 48%. At median follow-up of one year, 41% of patients died; median OS was 12 months (95%CI: 10 – NA). No significant correlation was found when comparing prior therapy, mutation status, and any pretreatment PET parameter with BR or OS. Patients receiving all 6 cycles were 7 times more likely to achieve BR (p = 0.002). Conclusions: There was no significant association between PSMA-RLT outcomes and either mutation status or pretreatment PET parameters. This study is limited by the low number of patients with genomic alterations. [Table: see text]
Fractionated docetaxel (D) and radium 223 (Ra223) in metastatic castration-resistant prostate cancer (CRPC): A modular phase I trial.
Authors: Brendan Connell, Clara Hwang, Edmund Folefac, Christian Lawlor, Benjamin Koethe, Paul Mathew
Journal: Journal of Clinical Oncology (2024)

5049 Background: Disease progression following novel hormonal therapy in CRPC remains bone-dominant and D-responsive. D + Ra223 would be a logical combination but myelosuppression is dose-limiting. Prior combinations have required a reduction in dose intensity (DI) in both agents. Fractionated schedules of D Q2weekly (DQ2) have comparable activity to D 75mg/m 2 Q3weekly with mitigated myelosuppression. We hypothesized that a fractionated schedule of DQ2 with standard Ra223 dosing would be feasible while preserving DI. Methods: Subjects had progressive bone-metastatic CRPC, ECOG PS 0-2, and no bulky visceral disease. Design was phase I, 6+6, dose escalation plus expansion with 28-day cycles. DQ2 was given in a 4-week lead-in, then with Ra223 every 4 weeks. Dose-level (DL) 1: D 40mg/m 2 ; if neutropenia, then 1a: D 40mg/m 2 with G-CSF on Day 16, 2a: D 50mg/m 2 with G-CSF on Day 16. Up to 6 cycles of the combination were given. Primary objective was the feasibility and maximum tolerated DL explored (MTD). Secondary objectives included PSA response, ORR, PFS, OS, and quality of life. Results: 43 patients (pts) enrolled including 34.9% non-white pts and 76.7% with ≥ 4 bony mets. 8 dropped out during the D lead in (1 each neutropenia, stroke, failure to thrive, anorexia/fatigue, thrombocytopenia, infusion reaction and 2 hospitalized for other reasons). At DL1, 2 of 3 had DLT (both neutropenia). No DLT occurred at DL1a (n=5) or DL2a (n=5). MTD was DL2a. 22 subjects enrolled to expansion cohort at DL2a. Of the 35 pts treated with D + Ra223, adverse events of interest listed in the table. No febrile neutropenia, fractures, or G5 toxicity were seen. 19/35 completed all 6 cycles of combination therapy. PSA50 response was seen in 18 (51.4%) and PSA90 in 9 (25.7%) pts. Of 31 pts with evaluable data, best response (RECIST 1.1) was 1 CR, 5 PR, 23 SD, 2 PD. Median PFS was 50.0 weeks (95% CI: 37.3-86.1) and OS was 86.1 weeks (95% CI: 60.0-130.9). 10 pts progressed exclusively in nodal/visceral metastases compared to 6 in bone only. Quality of life measures remained stable on study. Conclusions: Utilizing a D lead-in strategy, combination DQ2 and Ra223 was feasible and well tolerated, with a favorable PFS and evidence of preferential control of osseous metastases. Dose-intensity for both docetaxel and Ra223 was preserved and comparable to the FDA-approved dose-schedules for each of the single agents. The lead-in design and use of G-CSF contributes significantly to the feasibility. Clinical trial information: NCT03737370 . [Table: see text]
Fostamatinib effectiveness and safety for immune thrombocytopenia in clinical practice.
Authors: Tomás José González-López, Nuria Bermejo-Vega, Rocío Cardesa-Cabrera, Violeta Martínez-Robles, Gerardo Aguilar-Monserrate, Gloria Pérez-Segura, Abel Domingo, Josefa Luis-Navarro, Sunil Lakhwani, Natalia Acedo, María Luisa Lozano, Silvia Bernat, Ana Torres-Tienza, Ana Ruano, Isidro Jarque, Pilar Galán, Carmen Benet, Shally Marcellini, Reyes Jimenez-Bárcenas, Daniel Martínez-Carballeira, Dunia De Miguel-Llorente, Alvaro Perona-Blázquez, Isabel Gonzalez-Gascón, Elsa Lopez-Ansoar, José María Alonso-Alonso, María Luisa Bengochea-Casado, Francisco Javier Díaz-Gálvez, Ana Moretó, Gemma Moreno-Jiménez, Roberto Hernández-Martin, Erik de Cabo, Julio Dávila-Valls, Amalia Cuesta, Carmen Pastoriza, Gerardo Julio Hermida-Fernández, Covadonga García, Miguel Angel Pozas-Mañas, Carlos Aguilar, Dolores Fernandez-Jimenez, Begoña Navas-Elorza, Carolina López-Santamaría Castro, Alvaro Lorenzo, Xavier Ortín, Marta García, Sonia Piernas, Johana Díaz-Santa, Inmaculada Soto, Drew Provan, Gloria García-Donas Gabaldón
Journal: Blood (2024)