bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I/II study to evaluate the safety, pharmacodynamics, and efficacy of entinostat in combination with atezolizumab and bevacizumab in patients with renal cell carcinoma.
Authors: Pili Roberto , Haas Naomi B. , Monk Paul , Logan Theodore F. , Narayan Vivek , Burney Heather , Adra Nabil
Published: June 2023

4526

Background: Immunosuppressive factors such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that histone deacetylase (HDAC) inhibitors have antitumor effects in combination with PD-1 inhibition by inhibiting the function of Tregs and MDSCs in preclinical models. We hypothesized that HDAC inhibition may enhance or resensitize patients (pts) with renal cell carcinoma (RCC) to immunotherapy. Thus, we conducted a Phase I/II clinical study with the HDAC inhibitor entinostat in combination with the immune check point inhibitor atezolizumab and the VEGF inhibitor bevacizumab in RCC pts, either treatment naïve or previously treated with immune checkpoint inhibitors. Methods: The primary objective was to evaluate the safety, tolerability, and efficacy of this combination strategy in a Phase I/II clinical trial. This clinical study was composed of a Dose Finding Phase (Phase I) and a two-stage Phase (Phase II) portion. Due to unforeseen circumstances, enrollment was halted during Stage I of the Phase II portion. In the Phase I dose finding cohorts, according to the 3+3 standard design, pts received oral entinostat at 1 mg (dose level or dl1), 3 mg (dl 2), or 5 mg (dl 3) every 7 days, continuously, with atezolizumab at a dose of 1,200 mg/kg mg IV every three weeks in combination with bevacizumab at a dose of 15 mg/kg IV every 3 weeks. Phase II patients were split into two distinct cohorts: Cohort A (no prior treatments with PD-1 or PD-L1 inhibitors) and Cohort B (at least one prior treatment with a PD-1 or PD-L1 inhibitor for metastatic disease). Pts treated at dl3 were included in the Phase II efficacy analyses. Results: 31 pts (18 and 13 pts during Phase I and II, respectively) were enrolled. Phase I was completed with the following DLTs: hypertension (3) in dl1, encephalopathy and hyponatremia (dl2), pneumonitis and pruritis (dl3). Dl3 was established as the recommended phase II dose. The most common treatment-related toxicities were thrombocytopenia, hypophosphatemia, proteinuria, diarrhea, fatigue, and neutropenia. A total of 21 grade≥3 events were observed. Nine pts achieved a partial response in Cohort A and one patient in Cohort B with an ORR 60% (CI 32.3-83.7) and 33.3% (28.2-56.4), respectively. According to Simon’s optimal two-stage design, the ORR met the Stage I primary objective. The median PFS was 13.7 months (CI 8.7-21.3) in Cohort A and 9.8 months (CI 1.3-NE) in Cohort B. We have collected blood samples to conduct several correlative studies on peripheral blood mononuclear cells. Conclusions: The preliminary results from this study suggest that the combination of entinostat and atezolizumab plus bevacizumab is relatively well tolerated and may be active in pts with ccRCC. Clinical trial information: NCT03024437 .
Head-to-head effectiveness and safety of pembrolizumab plus axitinib vs. nivolumab plus ipilimumab in metastatic renal cell carcinoma in the United States.
Authors: Aran Dvir , Granot-Hershkovitz Einat , Amar-Farkash Shlomit , Rosenberg-Katz Keren
Published: June 2023

4532

Background: Two main first-line combination therapies for metastatic renal cell carcinoma (mRCC) are pembrolizumab plus axitinib (P+A) and nivolumab plus ipilimumab (N+I). No head-to-head clinical trial comparing these treatments has been performed, and the available real-world data (RWD) on their effectiveness is limited. Here, we used RWD to compare the overall survival and posttreatment hospitalization rates of mRCC patients receiving P+A vs. N+I. Methods: We included mRCC patients treated with N+I or P+A between 6/2018 and 3/2022, utilizing data from Elevance Health administrative claims and clinical data from AIM Cancer Care Quality Program. Inverse probability of treatment weighting (IPTW) was used to adjust for age, sex, socioeconomic deprivation index (SDI), ECOG performance status (PS), Charlson Comorbidity Index (CCI), and metastatic sites. Real-world overall survival (rwOS) was defined from first treatment until death or last claim and was estimated using weighted Kaplan-Meier method. Favorable risk was defined based on PS (<2) and with a treatment initiated less than 1 year from diagnosis. Results: We identified 764 mRCC patients, of them 483 were treated with N+I (63%). The P+A group was slightly older (p=0.08), while other features were similar in both groups. Survival analysis using IPTW showed a borderline significant advantage of P+A vs. N+I (p-value=0.07). Inspection of the Kaplan-Meier curves suggested that P+A provides short-term survival benefit: 12-month rwOS was 86% for P+A vs. 77.8% for N+I (p<0.001), while at 24-months, where power was lower, the curves almost converged (rwOS: 68% in P+A vs. 65% in N+I; p=0.52). In a subset of patients with favorable risk (N=69 P+A, N=68 N+I), the P+A survival improvement extended to at least 24-months (p=0.06). Finally, the N+I group had significantly higher rates of posttreatment hospitalizations (3-months after treatment initiation) compared to the P+A group (31.9% vs. 19.6%; p-value<0.001). Conclusions: Our retrospective cohort study suggests that P+A may provide short-term survival benefits over N+I, and this benefit is extended in patients with favorable risk. P+A is also associated with fewer post-treatment hospitalizations. We argue that the higher toxicity of N+I may explain its lower short-term effectiveness and may also explain its lower effectiveness in patients with favorable risk. [Table: see text]
Health-related quality of life (HR-QOL) measures in renal cell carcinoma (RCC): Patient-reported relevance of items of the FKSI-19, EORTC QLQ-C30, and EQ-5D.
Authors: Bergerot Cristiane Decat , Mercier Benjamin D , Castro Daniela V. , Bergerot Paulo Gustavo , Toms Charlotte , Ali Adil A , Philip Errol James , Lages Dr. Paulo Sergio , Mota Augusto C. A. , Hutson Thomas E. , Grünwald Viktor , Bex Axel , Psutka Sarah P. , Rini Brian I. , Plimack Elizabeth R. , Master Viraj A. , Albiges Laurence , Choueiri Toni K. , Pal Sumanta Kumar , Powles Thomas
Published: June 2023

4540

Background: Given the need to balance both quantity and quality of life among patients with advanced cancer, developing a robust, relevant, and consensus-driven patient-focused measurement strategy is a necessity. Our study expands upon previous findings (Bergerot et al., The Oncologist 2023) in evaluating the perceived relevance of questions on the FKSI-19, EORTC QLQ-C30, and EQ-5D among patients with RCC. Methods: Eligible patients were diagnosed with RCC and asked to evaluate the relevance of each question of the FKSI-19, EORTC QLQ-C30, and EQ-5D (items rated as relevant vs non-relevant). Patients also responded to 2 open-ended questions regarding topics not covered by these measures and their perception of wearable technologies. Questions identified as meaningful required ≥66% “relevant” ratings. Descriptive statistics were collated, and open-ended questions were analyzed by 2 independent reviewers (CB, PB). Results: 116 patients were recruited from Brazil and the US. Most (69%) were male with a median age of 64 (32-88) years. 83% were diagnosed with advanced disease, and 75% received immunotherapy and/or targeted therapy as primary treatment. Few items across surveys were identified as meaningful including 8/19 FKSI-19 questions (lack of energy, fatigue, appetite, sleeping, worry, able to work, enjoyment and quality of life), 3/30 EORTC QLQ-C30 questions (tired, overall health and quality of life), and 0/5 EQ-5D questions. Patients suggested items pertaining to treatment side effects, emotional symptoms, physical function, social/family support, and financial distress should be included. Notably, 58% of patients were open to using wearable devices to assess HRQOL. Conclusions: Our multi-institutional international study confirms findings from our single-institution pilot data suggesting that HRQOL measures for RCC require substantial refinement. These data will inform development of a novel-RCC specific HRQOL tool in a joint effort between experts and patients.
Biomarkers of response to first-line nivolumab therapy in patients with advanced renal cell carcinoma (RCC) enrolled in the HCRN GU16-260 trial.
Authors: El Ahmar Nourhan , Matar Sayed , Jegede Opeyemi , Savla Varunika , Bagheri Sheshdeh Aseman , Ghandour Fatme , Denize Thomas , West Destiny , Choueiri Toni K. , Catalano Paul J. , Braun David A. , Haas Naomi B. , Hammers Hans J. , Bilen Mehmet Asim , Stein Mark N. , Sosman Jeffrey A. , Wu Catherine J. , McDermott David F. , Atkins Michael B. , Signoretti Sabina
Published: June 2023

4549

Background: The HCRN GU16-260 study showed that nivolumab (nivo) monotherapy is active in treatment-naïve patients (pts) with RCC. Although efficacy correlated with tumor cell (TC) PD-L1 expression, more clinically relevant biomarkers are needed. We previously showed that levels of CD8+ tumor-infiltrating lymphocytes (TIL) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+ TIM3- LAG3-) were associated with response to nivo in previously treated clear cell RCC (ccRCC) pts (Pignon, 2019; Ficial, 2021). Here, we sought to validate these findings in the first-line setting. Methods: Primary tumor tissues from pts with ccRCC (n= 67) and non-ccRCC (n= 13) were analyzed by multiparametric immunofluorescence (IF), and the density of CD8+PD-1+TIM-3-LAG-3- TIL was quantified by image analysis. The correlation of the log-transformed biomarkers with objective response rate (ORR) and progression-free survival (PFS) was assessed in the ccRCC cohort and the combined (ccRCC + non-ccRCC) cohort (n=80) using Cox or logistic regression analysis, or Chi-square/Fisher’s exact test (as appropriate) for statistical inference – alpha level was set at 5% (1-sided). Results: In both the ccRCC and the combined cohort, density of CD8+PD-1+TIM-3-LAG-3- TIL (IF biomarker) measured as continuous variable was associated with ORR (ccRCC: OR = 1.54, p = 0.017; combined: OR = 1.35, p = 0.040) and PFS (ccRCC: HR = 0.79, p = 0.015; combined: HR = 0.85, p = 0.016). At a cutoff optimized for maximum sensitivity for ORR, ccRCC patients with a high (61/67) vs low (6/67) IF biomarker had higher ORR (44.3% vs. 0% p = 0.039) and longer median PFS (10.9 months vs. 4.2 months, p = 0.016). Of note, when combined with the IF biomarker, TC PD-L1 expression (≥1%) further separated the clinical outcomes of ccRCC pts. Conclusions: High levels of CD8+ PD1+ TIM-3-LAG-3- TILs were associated with response to first-line nivo in pts with advanced RCC and the combination with TC PD-L1 status further separated the outcomes of pts with ccRCC, validating our previous findings. Further investigations into the role of myeloid inflammation as determinant of clinical outcome to nivo therapy are ongoing. Clinical trial information: NCT03117309 . [Table: see text]
Impact of smoking status (SS) on the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first line (1L) immuno-oncology (IO)-combination regimens: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Gebrael Georges , Saad Eddy , Labaki Chris , Saliby Renee Maria , Sayegh Nicolas , Wells J Connor , Semaan Karl , Eid Marc , Takemura Kosuke , Ernst Matthew Scott , Lemelin Audreylie , Basappa Naveen S. , Wood Lori , Powles Thomas , Ernst D. Scott , Kapoor Anil , Xie Wanling , Agarwal Neeraj , Heng Daniel Yick Chin , Choueiri Toni K.
Published: June 2023

4555

Background: Active smoking is associated with decreased overall survival (OS) in patients (pts) with mRCC treated with VEGF targeted therapy (VEGF-TT) (Kroeger N. et al. 2019, IMDC investigators). Conversely, smoking history has been linked to improved OS in pts with advanced non-small cell lung carcinoma (NSCLC) receiving 1L pembrolizumab monotherapy (Popat S. et al., 2022). Herein, we assess the association between SS and outcomes in pts with mRCC treated with 1L standard of care (SOC) IO-based regimens. Methods: Real-world data from the IMDC were collected retrospectively. We included mRCC pts who received either dual IO therapy or IO + VEGF-TT in the 1L setting and known SS at disease diagnosis. Pts were categorized as current, former and non-smokers. The primary outcomes were OS, time to treatment failure (TTF) and objective response rate (ORR) on 1L IO-based regimens. OS and TTF were evaluated using Cox regression, adjusting for age at 1L treatment, IMDC risk groups, BMI, histological type and time from diagnosis to 1L treatment initiation. ORR was compared between the SS groups using a logistic regression, adjusting for the same confounders. Results: 989 pts were eligible and included. 438 (44.3%), 415 (42%), and 136 (13.7%) pts were non-smokers, former, and current smokers at diagnosis, respectively. Median time from diagnosis to initiation of 1L IO-based treatment was 0.47 years (IQR 0.13-2.15). At baseline, there were no significant differences in age at 1L, IMDC risk groups, KPS status, BMI, and presence of sarcomatoid features across the 3 groups (p>0.05). Median follow up was 21.2 months from 1L IO-based treatment initiation. On multivariable analysis, no significant differences in OS, TTF or ORR were seen between the SS groups (p>0.05). Conclusions: To our knowledge, this represents the first and largest effort to evaluate the impact of smoking on clinical outcomes in pts with mRCC treated with IO-based regimens. There was no association between SS at diagnosis and the clinical outcomes of patients with mRCC receiving current 1L SOC IO-based regimens. As opposed to other cancer types (i.e., NSCLC), current or past smoking history did not appear to be predictive of benefit from IO-based therapy. [Table: see text]
Kidney cancer mortality in the United States between 1999 and 2020: An observational analysis of outcomes by gender, race, and ethnicity.
Authors: Abdallah Nour , Jani Chinmay , Mouchati Christian , Chrysafi Pavlina , Singh Harpreet , McKay Rana R.
Published: June 2023

4563

Background: Kidney cancer (KC) is one of the leading causes of cancer mortality, with recent data showing an increase in incidence and mortality worldwide. Gender, racial, and ethnic disparities can impact KC outcomes. Studies investigating the outcomes of diverse patient populations spanning the cytokine, targeted therapy and immunotherapy eras have been limited. This study aims to investigate trends in age-adjusted mortality rates (ASMR) by gender, race, and ethnicity in the US at national and state levels. Methods: We utilized the Center for Disease Control Wonder database to extract national and state-wide KC mortality data (ICD-10 C64) from 1999-2020. ASMR and 95% confidence intervals (CI) were extracted based on gender, race and ethnicity reported per 100,000 population. To evaluate the difference between metro and non-metro regions, we divided the national trends based on 2013 Urban NCHS Urban-Rural scheme. Joinpoint regression analysis was performed to evaluate trends. Results: In total, 284,224 KC deaths were reported over twenty years, with an overall decrease in ASMR in recent years. Males had significantly higher ASMR throughout the study period, with a lower decrease than females. Amongst racial groups, American Indians (AI) had the highest mortality in 1999 (5.7). However, due to the smaller decrease of ASMR in Whites compared to Non-Whites, Whites showed the highest ASMR (3.9) in 2020. According to ethnicity, Non-Hispanics Whites (NHW) had significantly higher ASMR than Hispanics in 1999 (4.0 vs. 3.5) and 2020 (3.5 vs. 3.0) with a similar rate of decline (-11.4% vs. -12.5%). State-wise, ASMR decreased in all states except Utah (+45.8%), Arkansas (+18.4%), Hawaii (+15.4%), Montana (+5.3), Kansas (+2.7) and Nevada (+2.6). Interestingly, non-metro regions showed higher ASMR throughout the study period. Also, while there was a steep decline in ASMR (15%) in metro regions, only a minimal decline (-4.7%) was observed in non-metro regions. Conclusions: Over the last two decades, there has been a decrease in the ASMRs across all genders, races and ethnicities and in most states in the USA. The decrease in ASMR is likely multifactorial, related to earlier detection and improved treatments. However, differences in outcomes by gender, race, and ethnicity persist, highlighting the need for strategies to better understand the etiology of differences and mitigate disparities across social determinants of health across gender, racial, and ethnic groups. [Table: see text]
Mismatch repair deficiency and microsatellite instability-high in urothelial carcinoma: A systematic review and meta-analysis.
Authors: Chandran Elias , Iannantuono Giovanni Maria , Akbulut Dilara , Atiq Saad Omar , Gurram Sandeep , Teo Min Yuen , Coleman Jonathan , Sinaii Ninet , Apolo Andrea B.
Published: June 2023

4570

Background: Mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) occur in a small subset of urothelial carcinoma (UC) and confer a sensitivity to immunotherapy in multiple solid tumors. Due to the rarity of this patient subset in UC, there is a lack of prospective data on their prevalence or of clinical outcomes with immunotherapy and other treatment modalities. Methods: We performed a systematic review with the objectives of estimating the prevalence of dMMR and MSI-H in urothelial bladder cancer (BC) and upper tract urothelial carcinoma (UTUC) apart from estimating survival and clinical outcomes of treatment. We searched for published prospective and retrospective studies, review articles, case reports, case series, conference proceedings, letters, commentaries, and editorials on dMMR and MSI-H in BC and UTUC published up to 10/26/2022 in PubMed, Cochrane CENTRAL, Embase and Web of Science: Core Collection databases. The study protocol is registered on the PROSPERO database (CRD42022365690). Prevalence data were analyzed using meta-analysis with random-effects models and are reported here. Results: A total of 1,750 studies were screened, of which 125 were included. Thirty-six studies (including 5,113 patients) reported frequencies of dMMR, and 42 studies (including 21,291 patients) reported on MSI-H. Of the total included patients, sex was reported in 11,225, with 72.6% being male and 27.4% female. Age ranged from 17-97 years. Reported primary site was BC in 64.4%, UTUC in 16.3% and not stated in 19.3%. Disease stage reported in 5,341 patients was M0 in 75.0% and M1 in 25.0%. Of the M0 patients, tumor stage data were available in 3,149 patients: Ta-T1 in 33.6% and T2-T4 in 66.4%. The pooled weighted prevalence of dMMR in UC patients was 6% (95% CI 5-8%). The breakdown for BC and UTUC were 2% (95% CI 1-3%) and 9% (95% CI 7-12%), respectively. The three most frequent MMR protein loss patterns in UC, BC and UTUC are shown in the table. Out of 42 studies reporting MSI status, 21 used polymerase chain reaction (PCR) and 21 used next-generation sequencing (NGS). Pooled weighted prevalence of MSI-H in UC was 3% (95% CI 2-3%). In BC, the prevalence was 1% (95% CI 1-1%) and in UTUC, it was 11% (95% CI 8-13%). Conclusions: dMMR and MSI-H were observed more frequently in UTUC than BC. Further analysis on survival and clinical outcomes of dMMR/MSI-H UC with different treatment modalities is ongoing. Additionally, clinical trials in dMMR and/or MSI-H UC are in development to study immunotherapeutic strategies to improve outcomes in both early and advanced stages for this small but important subset of patients. [Table: see text]
Outcomes with immune checkpoint inhibitors (ICI) in patients (pts) with MTAP alterations (alt) in advanced urothelial carcinoma (aUC).
Authors: Talukder Rafee , Bakaloudi Dimitra Rafailia , Lin Genevieve Ihsiu , Enright Tom , Leary Jacob Beck , Makrakis Dimitrios , Tripathi Nishita , Agarwal Neeraj , Jindal Tanya , Koshkin Vadim S , Brown Jason R , Johnson Jeffrey , Zakharia Yousef , Park Joseph J. , Alva Ajjai Shivaram , Morales Barrera Rafael , Drakaki Alexandra , Barata Pedro C. , Khaki Ali Raza , Grivas Petros
Published: June 2023

4574

Background: MTAP loss of function alt in aUC has been associated with poor prognosis. MTAP is an enzyme involved in the adenine salvage pathway and deficiency of the protein leads to susceptibility to antifolate agents, e.g., pemetrexed. MTAP loss has also been correlated with immunosuppressive tumor microenvironment, inducing a “cold tumor” that may be less responsive to ICI. Response and outcomes to ICI in pts with MTAP altered aUC need further assessment. We hypothesized that pts with MTAP altered aUC would have lower response and shorter survival on ICI. Methods: We used our database from 26 centers (US/Europe) of pts with aUC treated with ICI. We included pts with available NGS data who received ICI for aUC. We excluded pts with pure non-UC, treated with adjuvant ICI, ICI combinations, or on clinical trials. Outcomes (observed response rate [ORR], progression free survival [PFS] and overall survival [OS]) were compared in pts who received either 1st line [1L] or 2nd line and beyond [2+L] ICI with and without MTAP alt. We compared ORR using logistic regression; PFS and OS were compared using Kaplan-Meier and Cox proportional hazards. We separately describe outcomes in pts with MTAP alt who received avelumab switch maintenance. Results: 211 pts from 8 centers met inclusion criteria with available MTAP alt status; 174 received ICI as distinct aUC treatment line (16% had MTAP alt; n=28) either in 1L or 2+L setting; 37 pts received avelumab switch maintenance (19% had MTAP alt; n=7). Pts with known MTAP status were 72% men, 91% White, 72% pure UC, 25% upper tract UC, 64% ECOG PS 0-1, 56% visceral mets, 18% bone mets, 15% liver mets. Median follow up from starting ICI was 44 months [mo] (IQR 29-51). ORR to ICI (1L + 2+L) in pts with MTAP alt was 25% (95%CI 10-47) vs 47% (95%CI 39-55%) in pts without MTAP alt [OR 3.11 (95%CI 1.15-7.82)]. PFS for pts with MTAP alt was not significantly different vs pts without MTAP alt (median 3 vs 6 mo, respectively: HR 1.46 [95%CI 0.91-2.35]). OS was similar between groups (median 14 vs 15 mo, respectively: HR 0.93 [95%CI 0.53-1.63]). Table describes outcomes by ICI treatment line (1L, 2+L, maintenance) in pts with and without MTAP alt. Conclusions: In pts with aUC receiving ICI, the presence of MTAP alt was significantly associated with lower ORR and a trend towards shorter PFS compared to absence of MTAP alt. Limitations include retrospective nature, small sample size, selection/confounding biases, lack of randomization and central scan review. Findings need external validation and might inform discussion on the optimal therapy sequence in aUC. [Table: see text]
Long term follow-up analysis of plasma miR371 expression to detect early relapse in patients with clinical stage I testicular germ cell tumors on surveillance.
Authors: Nappi Lucia , Saxena Neetu , Pautasso Sara , Mazurek Sylwia , Ozgun Guliz , Kollmannsberger Catarina , Trottier Chi Max , Morin Coulombe Antoine , Soleimani Maryam , Chi Kim N. , Eigl Bernhard J. , Black Peter C. , So Alan I. , Gleave Martin , Kern Sean , Daneshmand Siamak , Adra Nabil , Einhorn Lawrence H. , Nichols Craig R. , Kollmannsberger Christian K.
Published: June 2023

5006

Background: Clinical Stage I (CSI) is the most common presentation of germ cell testicular tumors (GCT) and patients are usually managed with active surveillance, in absence of reliable biomarkers of relapse. Circulating plasma miR371a-3p (miR371) has demonstrated high sensitivity and specificity in advanced non teratoma GCT. However, its operating characteristics and power to detect early relapse are still undefined. Methods: CSI GCT patients enrolled in the British Columbia provincial biobank with available plasma samples after radical orchiectomy were included in this study. Plasma miR371 was qualitatively assessed by RT-PCR. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC in predicting tumor recurrence were evaluated in the post-orchiectomy blood samples and/or during the follow-up prior to or at the time of the clinically evident relapse. Relapse free survival (RFS) was correlated to post-orchiectomy miR371 status. Results: One-hundred-one patients were analyzed, 35 (34.6%) experienced a disease relapse with a median follow-up of 41 months. miR371 was positive in 22/35 of the relapsed patients. The specificity and PPV were 100% (95% CI: 94.5 - 100 for both), sensitivity 62.8% (95% CI: 44.9 - 78.5), NPV 83.5% (95%CI: 76.7 - 88.6) and AUC 0.81 (95% CI: 0.71 - 0.91). No false positive results were observed. The RFS of the patients with positive post-orchiectomy miR37 was significantly shorter (median: 3.5 months vs. not reached; p<0.0001) compared to the patients with a negative post-orchiectomy miR371 (HR: 16.9; 95% CI: 2.1 - 135.7; p<0.0001). miR371 sensitivity correlated with tumor burden, time between tumor relapse and miRNA testing and histology (nonseminoma > seminoma). Conclusions: miR371 has high specificity and PPV in detecting GCT at an early stage and could be used to predict GCT relapse during surveillance and to guide treatment selection after orchiectomy. Further studies have been planned for validation of miR371 clinical utility.
Patient reported quality of life (QOL) and survival outcomes: Analysis of ECOG-ACRIN E3805 chemohormonal androgen ablation randomized trial (CHAARTED) in prostate cancer (PCa).
Authors: Sentana Lledo Daniel , Chu Xiangying , Jarrard David Frazier , Carducci Michael Anthony , DiPaola Robert S. , Wagner Lynne I. , Cella David , Sweeney Christopher , Morgans Alicia K.
Published: June 2023

5014

Background: Chemohormonal therapy with androgen deprivation therapy and docetaxel (ADT+D) improves overall survival (OS) and quality of life (QOL) at 12 months compared to ADT alone in metastatic hormone sensitive prostate cancer (mHSPC). However, the prognostic relationship between QOL, disease characteristics, and OS has not been described in this population. Methods: In this post-hoc exploratory analysis of the CHAARTED trial, the QOL instrument Functional Assessment of Cancer Therapy-Prostate (FACT-P) was completed by patients treated with ADT and ADT+D. Log-rank test and Cox proportional hazards models were used to test the association between QOL and OS by clinical and disease characteristics. Results: 790 men were included in the study (ADT+D, n = 397; ADT, n = 393). Baseline higher QOL by FACT-P (n = 790) was associated with better OS in univariate regression (HR 0.70 [0.55,0.90], p = 0.005), however the association was not significant in multivariate analysis (HR 0.80 [0.62-1.04], p = 0.09). There was a trend towards improved survival for patients with the lowest baseline QOL (lowest quartile) treated with ADT+D compared to ADT (HR 0.75 [0.53, 1.05], p = 0.09). In contrast, patients with the highest baseline QOL (highest quartile, 63% high volume disease) had similar survival regardless of treatment arm (HR 0.92 [0.63-1.36], p=0.69). Higher 3-month QOL by FACT-P (n = 654) was associated with survival in the multivariate analysis independently of treatment arm (HR 0.76 [0.58, 1.0], p = 0.05). Patients with the highest 3-month QOL had comparable survival regardless of treatment arm (HR 1.11 [0.73, 1.67], p = 0.63), while patients with the lowest 3-month QOL experienced a survival benefit with ADT+D compared to ADT (HR 0.69 [0.48, 0.99], p = 0.047). Conclusions: In this analysis, 3-month QOL by FACT-P was significantly associated with survival for patients with mHSPC. Patients with the poorest QOL ("most symptomatic”) appeared to experience survival benefit from ADT+D regardless of disease volume. Conversely, patients reporting the highest QOL (“least symptomatic”) did not seem to benefit from ADT+D despite a predominance of patients with high volume disease in that cohort. These findings suggest that consideration of QOL may enhance decision making and patient selection when considering chemohormonal treatment for mHSPC. [Table: see text]
A prospective trial of apalutamide and abiraterone acetate plus prednisone in Black and White men with metastatic castrate-resistant prostate cancer.
Authors: George Daniel J. , Halabi Susan , Fleming Mark T. , Heath Elisabeth I. , Tutrone Ronald F. , Sutton Linda , Whang Young E. , Lewis Brian E. , Humeniuk Michael Sandon , Berry William R. , Harrison Michael Roger , Hurrelbrink Julia , Shobe Kellie , Rasmussen Julia , Anand Monika , Reyes-Martinez Marco , Howard Lauren , Patierno Steven R. , Freedman Jennifer A , Armstrong Andrew J.
Published: June 2023

5015

Background: Abi Race was the first prospective parallel cohort study of abiraterone acetate plus prednisone (AAP) in Black and White men with metastatic castrate-resistant prostate cancer (mCRPC) and demonstrated greater prostate-specific antigen (PSA) response, time to PSA progression (TTP) and toxicity rates among Black patients (pts). We designed the PANTHER trial to estimate clinical outcomes among Black and White pts with mCRPC treated with apalutamide, abiraterone, plus prednisone. Methods: This parallel cohort multicenter study treated androgen receptor pathway inhibitor naïve mCRPC pts with oral apalutamide (240 mg/d), abiraterone (1000 mg/d) and prednisone (10 mg/d) (AAAP) continuously until disease progression, unacceptable toxicity or 2 years. The primary endpoint was radiographic progression free survival (rPFS); secondary endpoints were to estimate TTP, overall survival (OS) and best PSA response, among Black and White pts, separately. Exploratory endpoints included safety and correlative biomarkers of outcome by race and ancestry. Results: Between July 2017 and January 2021, we enrolled 43 Black and 50 White pts from 8 sites. Baseline prognostic characteristics were largely similar with some differences. We report an interim analysis as the pts are still followed for OS. At the time of the abstract submission, there were 18 and 36 rPFS events and 15 and 30 deaths in Black and White pts, respectively. We present the time to event endpoint rates at 12 and 24 mos and PSA declines for Black and White pts. Conclusions: We hypothesize that treatment with the combination of AAAP may result in clinical efficacy in Black men with mCRPC. Black pts were underrepresented in the phase III ACIS trial which compared AAP to AAAP and demonstrated longer rPFS but not OS. Further studies of AAAP combination therapy among Black men with advanced prostate cancer are needed to determine potential clinical benefits in this understudied population. Clinical trial information: NCT03098836 . [Table: see text]
Clinical analysis of optimized neural network risk models to predict clinically significant prostate cancer and avoid unnecessary prostate biopsies.
Authors: Wallis Christopher J.D. , Paproski Robert J , Pink Desmond , Vasquez Catalina , Fairey Adrian S. , Hyndman M Eric , Aprikian Armen G. , Kinnaird Adam , Beatty Perrin , Pavlovich Christian P. , Marks Leonard S. , Lewis John D
Published: June 2023

5023

Background: Given the low specificity of the current standard of care diagnostic tests for prostate cancer (PCa), there is an unmet clinical need for higher specificity tests to counter overdiagnosis of grade group (GG) 1 PCa. The aim of the study was to create optimized neural network risk models using PSA, free PSA, and other useful clinical features, and to validate the accuracy of the risk models to predict GG ≥2 PCa using real-world samples and data. Methods: Men aged 40-75 years with PSA >=3ng/mL and a biopsy referral were recruited into cohorts from sites in Canada (Kipnes Urology Centre (KUC), Edmonton, AB, and Prostate Cancer Centre (PCC), Calgary, AB) and the United States (Johns Hopkins University (JHU), Baltimore, ML and UCLA, Los Angeles, CA). Risk models to predict all GGs or GG ≥2 PCa were fit using data from KUC and JHU (train cohort n = 1037) while fixed models were validated on PCC (n = 401) and UCLA (n = 945). Prediction models were created using neural networks to generate the patient’s risk score. To compare the risk model test with PSA, the high-grade cancer detection sensitivity was fixed, and the number of biopsies needed to achieve that sensitivity was evaluated. Threshold values for the training cohort were determined using at least 95% sensitivity and maximum specificity. Threshold values for other clinical features and risk calculator outputs were set to match the test sensitivity when possible. Results: The optimized neural network risk models test had the highest area under the curve (AUC 0.81) for predicting GG ≥2 PCa on the validation cohorts compared to four other risk calculators; Prostate Cancer Prevention Trial Risk Calculator 2.0 (PCPTRC) with free PSA (0.78, p-value<0.001), Prostate Biopsy Collaborative Group risk calculator (PBCG, 0.73, p-value<0.0001), European Randomized study of Screening for Prostate Cancer risk calculator 3 (ERSPC-3, 0.72, p-value<0.0001), and PCPTRC with no free PSA (0.71, p-value<0.0001) and PSA (0.66, p-value<0.0001). At a threshold of 18.6%, this test provided 94% sensitivity, 37% specificity, 49% positive predictive value, and 90% NPV for predicting GG ≥2 PCa. If a biopsy was performed only when the tests’ risk score prediction was ≥17.8% for GG ≥2 PCa, 36-44% of unnecessary prostate biopsies could be avoided while missing 4-12% of patients with GG ≥2 prostate cancer. Conclusions: This neural network risk model is a tool that can be used to inform the physician of a patient’s risk of having GG ≥2 PCa on prostate biopsy. Using this novel test in the clinic is expected to significantly reduce the number and burden of unnecessary prostate biopsies. [Table: see text]
The performance of prostate specific antigen (PSA) testing in the population based NPCC cohort.
Authors: Oldenburg Jan , Bjerner Johan Lars , Pasovic Lara , Müller Stig , Fossa Sophie D. , Carlsson Sigrid V. , Albertsen Peter C.
Published: June 2023

5029

Background: Prostate cancer (PCa) screening using prostate-specific antigen (PSA) is controversial. Benign prostate hyperplasia increases PSA in aging men independent of PCa such that PSA’s test performance differs between younger and older men. Age-specific cut-off values might therefore be advisable. The large Norwegian Prostate Cancer Consortium (NPCC) database might be able to contribute with clinically relevant information on age-specific PSA cut-off values. Methods: The Norwegian Prostate Cancer Consortium (NPCC) collected 8 857 761 PSA tests from 1.291.151 men. Results were linked with the date of diagnosis and grade of PCa. Analyses were restricted to men aged 45-75 years. PSA results were grouped into two groups: PCa negative vs PCa positive. The PCa negative group comprised PSA measurements from 2005 to 2015 men being alive and without PCa diagnosis five years after PSA measurement, in total 1 775 986 PSA measurements from 533 216 men. The PCa positive group comprised PSA measurements from 2005 to 2020 of men diagnosed with PCa during this period. PCa diagnoses at autopsy, as incidental finding at cystectomy, with metastases or with PSA > 50 ng/ml were excluded, in total 242 874 PSA measurements from 48 659 men with PCa. Sensitivity, specificity, area under the curve (AUC) as well as top decile and proportion of PCa in the top decile were calculated. Results: For men of 50 years of age, PSA at a threshold of 3 ng/ml yielded a sensitivity and specificity of ~ 95%. In 70–74-year-old men, a 3 ng/ml PSA threshold resulted in a 95% sensitivity but declining specificity of 70%. Maintaining specificity requires increasing PSA cut-off values to 4.5, 6, 7 and 8 ng/ml for men aged 55-59, 60-64, 65-69 and 70-74 years, respectively. The increasing cut-off values for the top PSA decile as well as the decreasing proportion of PCA within the top decile are in line with a declining AUC in older men. Conclusions: PSA test performance declines with increasing age. PCa screening in well-informed men should take into account age adjusted PSA cut-off values. [Table: see text]
Associations between androgen-directed treatments and AR mutational landscapes in the circulating tumor DNA of a real-world metastatic prostate cancer cohort.
Authors: Ledet Elisa M. , Jayaraj Arockia , Jaeger Ellen B. , Stoppler Melissa Conrad , Huang Minqi , Chao Calvin Y. , Sartor A. Oliver
Published: June 2023

5061

Background: AR alterations evolve under the selective pressure of testosterone suppression and AR targeted agents. In metastatic, castration-resistant prostate cancer (mCRPC) AR’s mutational landscape and therapeutics targeting is still an unexplored area. Here we evaluate AR mutations in the circulating tumor DNA (ctDNA) of patients treated with AR targeted agents such as abiraterone (abi), enzalutamide (enza) and in combination (abi + enza) setting in a large Tempus real-world mCRPC cohort. Methods: De-identified records of patients with mPC who underwent Tempus xF next-generation sequencing (NGS) ≥ 6 months after treatment initiation of abi, enza, or abi + enza were selected for analysis. If patients had multiple NGS samples, the most recent sample was used. The assay is a targeted liquid biopsy panel that detects single-nucleotide variants and insertions and/or deletions in 105 genes, copy number variants in six genes, and chromosomal rearrangements in seven genes. Results: The cohort included 1,122 patients treated with abi only (n=483), enza only (n=374), or prior exposure to abi + enza (n=265). Pathogenic/likely pathogenic mutations were detected in 15% (n=71) of patients treated with abi,15% (n=56) treated with enza, and 27% (n=71; P<0.001) treated with both.The most frequent AR alterations were L702H (18%, 32%, and 25%) and T878A (34%, 3.6%, and 21%) and H875Y (7%, 12%, and 8.5%) in abi, enza, and abi + enza, respectively (Table). L702H and T878A alterations were found in an additional 8.5%, 3.6% and 9.9% of patients treated with abi, enza, or abi + enza, respectively. Alterations in L702A and H875T were found in 2.8%, 8.9% and 9.9% of patients treated with abi, enza, and abi + enza respectively. Approximately 4.2%, 1.8% and 1.4% (abi, enza, abi +enza) of treated patients had alterations in T878A and H875Y. Other single-hit alterations included 6 patients with W742C and 4 patients with F877L. Conclusions: AR mutations have implications for clinical decision making and drug development in patients treated with abiraterone and/or enzalutamide. [Table: see text]
Treatment and survival of de novo metastatic hormone sensitive prostate cancer among African American US Veterans.
Authors: De Jesus Pizarro Rigoberto , Montgomery Robert Bruce , Etzioni Ruth Douglas , Sanfilippo Kristen Marie , Khan Saira , Knoche Eric Marshall , Lynch Julie Ann , Schoen Martin W.
Published: June 2023

5079

Background: Combinations of androgen deprivation therapy (ADT) plus docetaxel (DOC) or androgen signaling inhibitors (ASIs: abiraterone, enzalutamide, etc.) have revolutionized treatment of metastatic hormone sensitive prostate cancer (mHSPC), particularly for high volume disease. However, little is known about the use of and outcomes of combination therapy in African Americans (AA) with de novo mHSPC, due to their lack of representation in clinical studies. This study evaluates the patient characteristics, treatment, and survival in a cohort of US veterans with mHSPC with equal access to treatment under the Veterans Affairs Health System (VA). Methods: Veterans with mHSPC were identified from 2014-2022 in the VA using the initial pathological diagnosis of prostate cancer with SEER stage ‘distant’ and first ADT initiated within 1 month prior and 3 months after diagnosis. Therapies including DOC or ASIs were collected if initiated from 1 month prior to 4 months after ADT. Additional information at the time of diagnosis was collected including Prostate Specific Antigen (PSA), race from VA enrollment, and Charlson Comorbidity Index (CCI). Median survival was obtained for each group and stratified by PSA level >100 ng/mL. Chi-square and ANOVA testing were used differences in survival (OS) were assessed by log-rank testing. Results: 4,248 veterans with de novo mHSPC were identified, 1138 (26.8%) were AA and 3110 (73.2%) white. Black veterans were younger (70.8 vs. 74.8, p<0.001) and had higher median PSA (183 vs. 86.3, p<0.001) with similar mean CCI (4.4 vs. 4.4, p=0.78). AA veterans were likely to have a PSA >100 ng/mL at diagnosis (61.6% vs. 46.1%, p<0.001) and to receive combination therapy than white veterans (36.8% vs. 32.7%, p=0.01). The median OS among AA and white veterans was similar (32.5 months vs. 32.1, p=0.75). In 2,120 veterans with PSA>100 ng/mL (a surrogate for higher volume disease), AA veterans were more likely to receive combination therapy (39.5% vs. 32.9%, p=0.003) without differences in survival in AA veterans compared to white (31.0 vs. 26.9 months, p=0.18). Conclusions: In an equal access health care system, AA veterans had similar survival to white veterans despite having double the PSA levels, reflecting higher risk disease. AA presented 4 years younger and are likely treated with doublet therapy. The differences in the age of onset and burden of disease highlight persistent differences in populations with mHSPC. Further investigations to understand environmental, social, and tumor factors are warranted to explain these disparities. [Table: see text]
Androgen-deprivation therapy and risk of dementia in patients with prostate cancer: Clinical outcomes from real-world data.
Authors: Elantably Dina , Wang Jiasheng , Al Armashi Abdul Rahman , Al Zubaidi Anas , Alkrekshi Akram
Published: June 2023

5086

Background: Androgen deprivation therapy (ADT) is the cornerstone for the treatment advanced prostate cancer. However, there has been growing concerns regarding increased risk of dementia with ADT. Previous studies of dementia risk following ADT were controversial and inconclusive. Methods: Data was collected from an electronic health record database (TriNetX LLC., Cambridge, MA) which includes over 89 million patients from 56 healthcare systems in the United States. We identified males over the age 50 years who were diagnosed with any stage of prostate cancer between 2005 and 2022. Patients receiving ADT were 1:1 propensity score-matched with non-exposed controls for demographics and risk factors for dementia; diabetes mellitus, hypertension, hyperlipidemia, obesity, depression, cerebrovascular disease, tobacco use, alcohol dependence and benzodiazepine use. Patients with prior dementia, stroke, or TIA were excluded. Results: In a cohort of 627,025 men with prostate cancer, 73,933 patients (mean age of 70.8 years) received ADT and 57,005 patients (mean age of 70.4 years) did not. ADT exposure was associated with a diagnosis of dementia (Alzheimer’s disease, vascular dementia, or unspecified dementia); HR 1.6; 95% CI (1.49, 1.73). Subgroup analysis by dementia subtype is highlighted in (table). Compared to non-ADT group, exposure to ADT was associated with a statistically higher risk of dementia among whites (78.6% vs. 77.7%, P <0.001), whereas there was no significant difference among African Americans. The risk of dementia with different ADT regimens is shown. Conclusions: This is the largest real-world study describing the association between ADT and the risk of dementia, including over 600 thousand prostate cancer patients. The risk of dementia was significantly higher in patients on ADT, with a 60% increased risk. The highest risk was witnessed with GnRH antagonists (degarelix), with a 92% increased risk. Interestingly, the increased risk of dementia in ADT groups was observed only among whites but not in African Americans. Possible causes of this discrepancy include socioeconomic disparities, bias that resulted in underdiagnosis, or biological differences. [Table: see text]
Comparative real-world (RW) evidence on darolutamide (Daro), enzalutamide (Enza), and apalutamide (Apa) for patients (Pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC) in the United States: DEAR.
Authors: Morgans Alicia K. , Shore Neal D. , Khan Nasreen , Constantinovici Niculae , Khan Javeed , Chen Guifang , Xu Julie , Ortiz Jorge A. , George Daniel J.
Published: June 2023

5097

Background: Novel androgen receptor inhibitors (ARIs) are recommended for pts with nmCRPC. Daro has a distinct structure with low blood-brain barrier penetration which may lead to a lower risk of central nervous system-related adverse events (AEs) and minimal risk of AEs commonly associated with ARIs. DEAR is the first study comparing RW utilization, outcomes, and AEs between daro and enza/apa in nmCRPC pts. Methods: This retrospective chart review cohort study uses electronic medical records from the PPS network of US urology practices. Eligible pts had nmCRPC, no prior novel hormonal therapy, and initiated first ARI treatment (index date) between 8/2019-3/2022. We describe the % of pts who discontinued initial ARI treatment (DISC), % who progressed to metastasis (PROG), and % with AEs. A comparative analysis was performed between daro and enza/apa using Cox proportional hazards models for time to DISC/time to PROG, adjusting for observed baseline (BL) factors. Results: 870 pts were included (daro/enza/apa, n=362/382/126). Median age (80/79/80 y), median BL prostate-specific antigen (PSA) doubling time (6.8/6.4/7.4 mo), other BL characteristics, and median follow-up (22.2/22.7/23.3 mo) were similar for daro/enza/apa. A lower % of pts had a DISC event on daro vs enza/apa (30.4 vs 40.8/46.0) or a PROG event (17.7 vs 28.3/27.8) during the study period. Multivariate analyses adjusting for BL factors showed that pts on daro had a lower risk of DISC and PROG over time vs enza/apa. A lower % of pts on daro had AEs vs enza/apa (24.9 vs 29.3/30.2). Conclusions: Overall, a lower % of pts discontinued initial ARI treatment, progressed to metastasis, or had AEs on daro vs enza/apa. In analyses adjusting for observed BL factors, pts on daro had considerably lower risk of DISC and PROG vs enza/apa. This study confirms daro’s strong efficacy and favorable tolerability profile in a RW setting. The longer treatment duration seen with daro may be associated with a lower risk of progression to mCRPC vs enza/apa. [Table: see text]