tbuckley/cabot-search huggingface dataset:
Debunking the frailty-sarcopenia-ADT axis in metastatic prostate cancer with multicomponent exercise: The FIERCE trial.
Authors: Christina Marie Dieli-Conwright, Alicia K. Morgans, Paola Gonzalo-Encabo, Dong-Woo Kang, Michael Hayden Rosenthal, Matthew Vander Heiden, Hajime Uno, Rebekah L Wilson
Journal: Journal of Clinical Oncology (2024)

TPS5124 Background: Metastatic prostate cancer (mPCa) incidence is growing despite a decrease in the prevalence of prostate cancer (PCa). Androgen deprivation therapy (ADT), the mainstay treatment for mPCa, is accompanied by a number of side effects, such as decline in muscle mass and physical function, leading to the exacerbation of age-related conditions including frailty and sarcopenia. Frailty is characterized by a loss of functional reserve, where frail men with mPCa have a worse prognosis. Sarcopenia refers to a decrease in muscle mass, strength, and function, and is associated with increased mortality in men with mPCa. Notably, PCa patients who received ADT are 3 times more likely to develop frailty compared to patients who never received ADT and 2 times more likely to develop sarcopenia compared to men without cancer. Exercise plays a key role in ameliorating or preventing further deterioration of ADT-related side effects and improving muscle mass, fitness, and strength. However, while there is a number of exercise studies in men with PCa, those with mPCa have been vastly understudied, with a lack of studies focusing on frailty and sarcopenia and the mechanisms of how exercise could address such outcomes. Thus, we have designed the FIERCE Trial to assess the effects of a 16-week multicomponent exercise intervention, encompassing resistance, aerobic, and functional training on frailty and sarcopenic status and their potential mechanistic biomarkers, and disease progression. Methods: The FIERCE trial is a prospective study aiming to recruit eighty pre-frail/frail men with mPCa receiving ADT who will be randomized to an exercise or attention control group. The 16-week exercise intervention will include thrice weekly clinic supervised, resistance and functional exercise circuit training, and self-directed home-based aerobic exercise. The attention control group will receive a stretching program and will be offered the exercise program following the study period. The primary outcome will be frailty, measured by the Fried Frailty phenotype (i.e., muscle loss, exhaustion, physical activity, gait speed, and strength) and frailty associated biomarkers (IL-6, TNF-α, CRP). Secondary outcomes include sarcopenia, measured using computerized tomography scans and sarcopenia associated muscle biopsy-driven biomarkers (myokines and insulin pathway markers). An exploratory outcome will assess the effect of exercise on cancer cell line growth (LNCaP cell line). To date, eight out of planned 80 patients have been enrolled. This trial is registered in clinicaltrials.gov (NCT06040125). Clinical trial information: NCT06040125 .
Survival outcomes for metastatic castration sensitive prostate cancer: Real world data from a Danish cohort 2016-2022.
Authors: Ahmed H. Zedan, Torben Hansen, Signe Timm
Journal: Journal of Clinical Oncology (2024)

e17088 Background: Metastatic castration sensitive prostate cancer (mCSPC) has the worst prognosis in the whole disease spectrum of prostate cancers. However, the therapeutic armamentarium has dramatically evolved during the last decade leading to a marked improvement in survival outcomes for this population. The main aim of this study is to investigate the impact of treatment options for mCSPC derived from real world data (RWD). Methods: This is a single retrospective observational study performed at Department of Oncology, Vejle Hospital, Denmark. Eligible patients (men aged ≥18 years) had newly diagnosed, histologically confirmed mCSPC, and were treated with androgen deprivation therapy (ADT) plus either docetaxel (DOC) or novel androgen receptor axis-targeted agents (ARATA) such as abiraterone (ABI) or enzalutamide (ENZ). Endpoints included overall survival (OS), both Radiological- and Biochemical progression free survival (rPFS and bPFS) and time to next treatment (TTNT). Subgroup analysis was done for those whose inclusion criteria were matching to those in the randomized controlled trails (RCTs); both CHAARTED and LATITUDE. Results: In total, 259 patients diagnosed with mCSPC from January 2016 until January 2022 have been included in the study. Patients treated with DOC were 224 (87%), while ABI and ENZ were used in 32 (12%), and 3 (1%) patients, respectively. Data analysis was done after a median follow-up of 39.9 months (range 11.4-85.1). Median OS, rPFS and bPFS were not reached during the follow-up period, while median TTNT was 26.7 months (95% CI 23.8-31.2). For the above defined subgroup (233 patients) median TTNT was 26.2 months (95% CI 23.2-29.7). Conclusions: Observations from this study emphasizes the remarkable benefits for treatment intensification for mCSPC population, and inclusion of RWD resulted in outcomes comparable with RCTs.
PLATIPARP: A phase 2 study of induction docetaxel and carboplatin followed by maintenance rucaparib in treatment of patients with mCRPC with homologous recombination DNA repair deficiency.
Authors: Ruben Raychaudhuri, Roman Gulati, Michael Thomas Schweizer, Todd Yezefski, Hiba M Khan, Evan Y. Yu, Peter Nelson, Colin C. Pritchard, Robert Bruce Montgomery, Heather H. Cheng
Journal: Journal of Clinical Oncology (2024)

5052 Background: Genes involved in homologous recombination DNA repair (HR) are inactivated in ~25% of patients with metastatic castration-resistant prostate cancer (mCRPC). Inactivation of HR has been associated with sensitivity to DNA damage by platinum chemotherapy and PARP inhibitors (PARPi). While both drug classes have shown efficacy, resistance and/or cumulative dose-limiting toxicities are inevitably observed. Here, we report results from a single-center phase 2 study investigating whether induction chemotherapy (IC) with docetaxel and carboplatin followed by maintenance PARPi would provide prolonged disease control. Methods: Patients with mCRPC tumors harboring a pathogenic alteration in an HR gene, who had received prior taxane and/or androgen receptor pathway inhibitor (ARPI), but not prior PARPi were eligible. Patients received IC with 4 cycles of docetaxel 60mg/m 2 with carboplatin AUC 5 IV q21 days, followed by the PARPi rucaparib 600mg BID continuously as maintenance therapy until disease progression or unacceptable toxicity. The primary endpoint was clinical/radiographic progression free survival (PFS) compared to a historical control of 9.1 months with PARPi alone without prior platinum. 20 patients provided ~90% power to determine whether this treatment lowered risk of progression with a hazard ratio of 0.5 (implying PFS of 18.2 months), based on a 1-sided 1-sample log-rank test. Secondary endpoints included PSA 50 response rate, safety, and overall survival. Post-hoc subgroup analysis was performed for the BRCA complex group (alterations in BRCA1, BRCA2, and PALB2) and for those refractory to IC. Results: 18 patients were enrolled between 2018 and 2021. Under-enrollment occurred due to loss of manufacturer support for rucaparib prior to study completion. 11/18 (61%) of patients had ≥2 prior ARPI, and 9/18 (50%) had previously received docetaxel. HR genes included on study were ATM (7), BRCA1 (3), BRCA2 (8), PALB2 (1), FANCA (1) and CHD1/ SPOP (1) with three tumors harboring two alterations. Clinical outcomes for the overall cohort and key sub-groups are reported in the table. 6/18 (33%) patients experienced grade ≥3 adverse events, including one patient with grade 4 thrombocytopenia. Conclusions: IC followed by maintenance rucaparib did not significantly increase PFS in patients with HR alterations compared to historical control. Results were more encouraging in the BRCA complex group. IC refractory patients were not rescued by subsequent PARPi, suggesting overlapping mechanisms of resistance when platinum is used prior to PARPi. Clinical trial information: NCT03442556 . [Table: see text]
Race and association between ADT and adverse events.
Authors: Nadine Friedrich, Jessica L. Janes, Joshua Parrish, Amanda Marie De Hoedt, Nicholas Tatonetti, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2024)

5073 Background: Many prior studies have linked androgen deprivation therapy (ADT) for prostate cancer (PC) with adverse events such as cardiac events and osteoporosis. Whether these associations differ by race is unknown. Methods: We performed a retrospective population-level analysis to assess the association between ADT (specifically GnRH agonist) use and time to cardiovascular events, bone fracture, new osteoporosis diagnosis, or time to composite event (i.e., the first of any of cardiovascular, bone fracture, or osteoporosis events) in the Veterans Affairs Health Care System (VA) as a function of race. We identified 790,916 patients from 2001-2021 who were diagnosed with PC and treated with ADT or no ADT. Given small numbers, patients treated with other forms of ADT including bilateral orchiectomy or GnRH antagonists were excluded. Patients were also excluded if they were missing race/ethnicity. Data were stratified by race/ethnicity including: Non-Hispanic White (White) 598,574, Non-Hispanic Black (Black) 145,267, Hispanic 30,139 and Other 16,936. Univariable and multivariable Cox proportional hazards models were used to test the association between ADT as a time-dependent covariate and time to the given event across all patients and as a function of race. Results: On multivariable analysis among all patients, ADT was associated with increased risk of cardiovascular events (HR 1.16, 95% CI 1.15- 1.17, p&lt;0.001), bone fractures (HR 1.59, 95% CI 1.55-1.62, p&lt;0.001), osteoporosis (HR 2.73, 95% CI 2.65-2.80, p&lt;0.001), and composite event (HR 1.29, 95% CI 1.27-1.30, p &lt;0.001). When stratified by race, ADT remained significantly associated with all outcomes in all races (all p&lt;0.001). Compared to White men, among Black men, the HRs for ADT were slightly lower for cardiovascular events (1.09 vs. 1.18), bone fracture (1.35 vs 1.65), and composite event (1.19 vs 1.31), but slightly higher for osteoporosis (3.16 vs 2.64). HRs in Hispanics and Other races were very similar to those in White men. Conclusions: Consistent with many prior studies, we found that ADT was associated with increased risk of cardiovascular events and bone complications. Though risks differed slightly among Black men, overall differences were small. These findings demonstrate that ADT is associated with adverse cardiovascular and bone complications regardless of race. Better means to reduce ADT-associated risks are needed across all races.
EMBARK post hoc analysis of impact of treatment suspension (TxS) on health-related quality of life (HRQoL).
Authors: Stephen J. Freedland, Martin Gleave, Ugo De Giorgi, Antti Rannikko, Fred Saad, Miguel Ramirez-Backhaus, Anchen F. Nasr, Jasmina I. Ivanova, Arijit Ganguli, Pavol Kral, Arlene Reisman, Neal D. Shore
Journal: Journal of Clinical Oncology (2024)

5005 Background: EMBARK (NCT02319837) showed enzalutamide (ENZ) + leuprolide (L) and ENZ mono delayed metastasis-free survival vs placebo (P) + L while maintaining high global HRQoL in high-risk biochemically recurrent nonmetastatic hormone-sensitive prostate cancer. Treatment was suspended (TxS) at week 37 if PSA &lt;0.2 ng/mL; reinstated if PSA rose to ≥2.0 ng/mL with radical prostatectomy (RP) or ≥5.0 ng/mL without RP. This analysis examined HRQoL after TxS. Methods: Longitudinal change in HRQoL from new baseline, week 37 (time of TxS), to subsequent assessments until week 205 were assessed via mixed model repeated measures using separate models for each instrument. Intention to treat analysis was used. Results: Treatment was suspended in 90.9% (321/353), 85.9% (304/354), and 67.8% (240/354) of patients treated with ENZ + L, ENZ mono, and P + L, respectively. A numerical trend inHRQoL improvement after week 37 TxS was seen in all 3 arms, which often reached clinically meaningful threshold at week 205 (Table). Post TxS, all arms reached clinically meaningful improvement in hormonal treatment side effects at the subsequent assessments of week 49 to week 97; however, patients slowly deteriorated, with clinically meaningful deterioration at week 205 relative to week 37 with ENZ + L and P + L. No statistically significant differences were observed between arms in change from week 37 to week 205. Conclusions: This post hoc analysis confirmed that TxS, as expected, leads to clinically meaningful improvements in HRQoL. Clinical trial information: NCT02319837 . [Table: see text]
Mutational burden among patients with metastatic prostate cancer differs by race in 3 key genes: An analysis of genomic and clinical data from the AACR Project GENIE biopharma collaborative in cBioPortal.
Authors: Olumide M. Arigbede, David Gbogbo, Sarah Buxbaum
Journal: Journal of Clinical Oncology (2024)

5106 Background: Prostate cancer exhibits a range of aggressive oncological traits due to its genomic heterogeneity. The extent to which clinical and demographic variables affect cancer behaviors and increase disparities is a complex and open question. Objective: We aim to comprehensively explore the genomic and epigenetic characteristics of metastatic prostate cancer (PCa) across different racial groups to elucidate potential molecular and immune mechanisms underlying disparities in disease progression and treatment response. Methods: Data from the Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (AACR-GENIE) registry to study men diagnosed with PCa was queried. Patients with metastatic disease (n = 1,684) were stratified into three racial groups: White (80.5%), Black (8.1%), and Asian (3.1%). cBioPortal was used to analyze the differences in genetic mutation frequencies by race and to determine the importance of these mutations. The relationships between mutation frequencies and race were examined using chi-squared test. Results: In our study, among patients with metastatic prostate cancer, the following three genes demonstrated the highest differences in frequencies of mutation: TP53, ATR, and PTEN. The most significant differences in mutation frequencies by race in metastatic PCa patients were found in TP53 (White: 3.1%; Black: 16.7%; Asian: 11.8%; P &lt;0.005) and ATR (White: 2.39%; Black: 3.58%; Asian: 4.87%; P = 0.035). PTEN has a metastatic tumor frequency of 6.5% in Asians, 4.2% in Black men, and 7.1% in White men (P = 0.0434). Conclusions: Consistent with previous literature, our study provides new insight into the complex interplay between PCa pathogenesis and progression, paving the way for precision. In the TP53 gene, Black men were more likely than their counterparts to have a higher mutational burden. This research has significant implications for improving health equity in PCa.
Site versus central read discrepancy rates in PCWG3 evaluation for progression.
Authors: Danielle Phillippi, Matthew Marini, Erin Bowman
Journal: Journal of Clinical Oncology (2024)

5067 Background: Prostate Cancer Working Group-3 Criteria (PCWG3) is the standard for determining radiographic response assessments in Prostate Cancer (PC) Clinical Trials. PCWG3 accounts for soft tissue and bone responses by following RECIST and evaluation of metastatic bone disease, respectively. In PC, the determination of progressive disease (PD) by bone metastases is often challenging due to increased osteoblastic activity during drug treatment known as flare phenomenon. To account for this, PCWG3 uses the 2+2 rule during the flare window and requires persistence of bone lesions over a specified period. Protocols often require blinded independent central review (BICR) verification of PD (VOP) where sites request BICR confirm site suspected radiographic PD (rPD). This is often a challenge as BICR radiologists are required to follow the strict PCWG3 requirements for PD. Previous studies have shown a 32% site vs. central discordance in RECIST trials, yet there is limited data for PCWG3. Due to the complexity of PCWG3, we hypothesized that site vs central discordance is greater than that of RECIST. Thus, we aimed to examine site vs central discordance for PD by PCWG3 by analyzing archived data on site requested radiographic VOP. Methods: Aggregate data from metastatic PC trials requiring BICR VOP by PCWG3 was collected and retrospectively analyzed. Of the 6537 patient data reviewed, 3685 patients had at least one site requested VOP. For these patients with site suspected progression, a comparison between site submitted VOP requests and the BICR outcome of PD or non-PD was used for determination of discordance. The data was further categorized based on the number of times the site submitted a request and when BICR verified PD. Results: Analyses showed 50.91% of patients had BICR verified PD at the time of initial site request. The remaining 49.09% of patients had at least one instance of non-PD before PD was determined by BICR. For 33.3% of patients, central PD was never verified by BICR. In the remaining patients with VOP requests, 11.78% had verified PD following one Non-PD result, 4.03% had verified PD following two or more non-PD results. Conclusions: BICR verified rPD serves as an important endpoint in PC trials yet our analysis shows almost half of initial patient VOP requests from the site were not verified centrally. This is greater than the established discordance in RECIST trials and warrants further investigation. For over 15% of patients who did not have verified PD by BICR on the first request, PD was verified in a subsequent request. We postulate that these discrepancies are due site misinterpretation of PCWG3 or sites requesting VOP when insufficient time has passed to meet the persistence requirements. In addition, PCWG3s requirement for lesion persistence may differ from clinical practice in the assessment of PD. This preliminary analysis provides vital insight into site vs central discordance in BICR confirmation of PD in PC trials.
SAVE: A prospective, single-arm, single-center clinical study of disitamab vedotin in combination with toripalimab in patients with advanced penile cancer that has progressed or is intolerant to cisplatin chemotherapy.
Authors: Fang Yuan
Journal: Journal of Clinical Oncology (2024)

TPS5107 Background: At present, penile cancer patients receiving chemotherapy with paclitaxel, ifosfamide and cisplatin or docetaxel, cisplatin and 5-fluorouracil have a lack of post-progression treatment, and some patients lose the opportunity for effective treatment due to inability to tolerate chemotherapy. Even though the epidermal growth factor receptor (EGFR) is ubiquitously expressed in penile squamous cell carcinoma, anti-EGFR-targeted drugs have not achieved significant survival benefit. Immune checkpoint inhibitors (ICIs) have achieved "de-tumor immune escape", and a small number of penile cancer cases have shown reactivity. However, only patients with high TMB, high PD-L1 expression, or MSI-H have benefited from ICIs. Antibody-drug conjugates (ADCs) have advanced rapidly in recent years, and HER2-targeted ADCs have shown significant efficacy in HER2-overexpressing urothelial carcinoma. HER2 ADC and ICI can simultaneously block HER2 and PD-1/PD-L1 signaling pathways, bridge PD-1-expressing T lymphocytes and HER2-expressing tumor cells, assist T cells to recognize and kill tumor cells, improve immunosuppression in the tumor microenvironment, and enhance the infiltration of immune cells into tumors. Recent cytology and animal studies have also shown that HER2-targeted ADCs exhibit significant anti-tumor activity in both HER2-positive and cisplatin-resistant penile cancers. Therefore, in order to explore the feasible and effective options for patients with advanced penile cancer who have progressed or are intolerant to cisplatin-based chemotherapy, a single-arm, single-center clinical study using Disitamab Vedotin combined with Toripalimab is proposed. Methods: About 20 patients with advanced penile cancer who have progressed or are intolerant to chemotherapy are planned to be enrolled with antibody-drug conjugates (Disitamab Vedotin for injection, 1 time/2 weeks, 2.0 mg/kg) and PD-1 (Toripalimab, 1 time/2 weeks, 3.0 mg/kg; or1 time/3 weeks, 240 mg/kg), regimen until the disease progresses or is intolerant. This study is expected to provide a basis for the treatment of advanced penile cancer using this regimen.
Biomarkers associated with outcomes from KEYLYNK-010: Pembrolizumab (pembro) plus olaparib (ola) versus next-generation hormonal agent (NHA) in previously treated metastatic castration-resistant prostate cancer (mCRPC).
Authors: Evan Y. Yu, Se Hoon Park, Jeffrey C. Goh, Sang Joon Shin, Niven Mehra, Raymond S. McDermott, Peter C.C. Fong, Richard Greil, Juan Pablo Sade, Yi-Hsiu Huang, Gero Kramer, Hiroyoshi Suzuki, Christian Heinrich Poehlein, Ping Qiu, E.J. Dettman, April Wang, Cai Chen, Razvan Cristescu, Matthew J. Marton, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2024)

5064 Background: Pembro + ola did not significantly improve rPFS or OS vs NHA in unselected patients (pts) with previously treated mCRPC in the phase 3 KEYLYNK-010 study (NCT03834519). Here, we present the results of prespecified biomarker analyses with respect to rPFS or OS. Methods: Pts were randomly assigned 2:1 to pembro + ola or NHA. PD-L1 combined positive score (CPS) was measured by IHC (22C3 pharmDx); HRRm, BRCAm, TP53, PTEN, SPOP, ATM, CDK12, TMB, and MSI were analyzed in tissue samples using FoundationOne CDx or ctDNA using FoundationOne Liquid CDx; AR-V7 was analyzed using Epic Sciences’ CTC assay. Associations (continuous scale) with outcomes were evaluated using adjusted Cox proportional hazards regression, and 1- (pembro + ola) and 2-sided (NHA) P values were calculated; significance was prespecified at α &lt; .05. For biomarkers with sufficient sample size for subgroup analysis, rPFS and OS HRs were evaluated for pembro + ola vs NHA. Results: Of 782 treated pts, PD-L1 was evaluable in 730 (pembro + ola, 490; NHA, 240); HRRm, BRCAm, TP53, PTEN, SPOP, ATM, and CDK12 in 718 (pembro + ola, 489; NHA, 229); TMB in 414 (pembro + ola, 275; NHA, 139); MSI in 316 (pembro + ola, 210; NHA, 106); and AR-V7 status in 544 (pembro + ola, 367; NHA, 177). In the biomarker-evaluable population, 28% had HRRm, 10% had BRCAm, 45% had TP53m, 34% had PTENm, 8% had SPOPm, 7% had ATMm, 7% had CDK12m, 4% were TMB-H (≥10 mut/Mb), 2% were MSI-H, and 13% were AR-V7 positive. For pembro + ola, positive associations were only observed between PD-L1 CPS and rPFS ( P = 0.034) and between HRRm and BRCAm and rPFS (adjusted P = 0.003 and &lt; 0.001, respectively). No associations were observed for NHA (all P &gt; 0.05). rPFS and OS HRs for pembro + ola vs NHA by biomarker status are shown (Table), with notable results observed for AR-V7 status. Conclusions: For pembro + ola, PD-L1 CPS had a weak positive association with rPFS, while HRRm and BRCAm had strong positive associations with rPFS; these biomarkers did not correlate with NHA outcomes. We observed a potential benefit with pembro + ola over NHA (for rPFS and OS) in AR-V7–positive mCRPC pts, which requires validation. Clinical trial information: NCT03834519 . [Table: see text]