Optimizing outcomes in men with prostate cancer: the cardiovascular event lowering (CaELo) pathways.

INTRODUCTION: Risk of cardiovascular disease is higher among men with prostate cancer than men without, and prostate cancer treatments (especially those that are hormonally based) are associated with increased cardiovascular risk. MATERIALS AND METHODS: An 11-member panel of urologic, medical, and radiation oncologists (along with a men's health specialist and an endocrinologist/preventive cardiologist) met to discuss current practices and challenges in the management of cardiovascular risk in prostate cancer patients who are taking androgen deprivation therapies (ADT) including LHRH analogues, alone and in combination with androgen-targeted therapies (ATTs). RESULTS: The panel developed an assessment algorithm to categorize patients by risk and deploy a risk-adapted management strategy, in collaboration with other healthcare providers (the patient's healthcare "village"), with the goal of preventing as well as reducing cardiovascular events. The panel also developed a patient questionnaire for cardiovascular risk as well as a checklist to ensure that all aspects of cardiovascular disease risk reduction are completed and monitored. CONCLUSIONS: Prostate cancer patients receiving ADT with or without ATT need to be more zealously assessed for prevention and aggressively managed to reduce cardiovascular events. This can and should include participation from the entire multidisciplinary healthcare team.

A Modular Trial of Androgen Signaling Inhibitor Combinations Testing a Risk-Adapted Strategy in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers (mCRPC). EXPERIMENTAL DESIGN: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone and apalutamide (AAPA; Module 1), then allocated to Modules 2 or 3 based on Satisfactory (≥50% PSA decline from baseline and <5 CTC/7.5 mL) versus Unsatisfactory status. Men in the former were randomized to continue AAPA alone (Module 2A) or with ipilimumab (Module 2B). Men in the latter had carboplatin+cabazitaxel added to AAPA (Module 3). Optional baseline biopsies were subject to correlative studies. RESULTS: Median overall survival (from allocation) was 46.4 (95% CI 39.2, 68.2), 41.4 (95% CI 33.3, 49.9) and 18.7 (95% CI 14.3, 26.3) months in Modules 2A (n=64), 2B (n=64) and 3 (n=59) respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pre-treatment metastatic biopsies. The aggressive variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with Unsatisfactory status. Exploratory analyses suggested SPP1+ and IGFBP2+ macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the Unsatisfactory group. CONCLUSIONS: Adding ipilimumab to AAPA did not improve outcomes in men with androgen responsive mCRPC. Despite the addition of carboplatin+cabazitaxel, men in the Unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups, to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer.

Efficacy, Safety, and Tolerability of Tivozanib in Heavily Pretreated Patients With Advanced Clear Cell Renal Cell Carcinoma.

BACKGROUND: Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC). METHODS: We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) for ≥ 6 months], progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Of 30 analyzed patients, 23% had performance status ≥ 2; 47% had International Metastatic RCC Database Consortium (IMDC) poor-risk disease. Median number of prior therapies was 4 (range 1-8). All patients received prior ICT, 87% cabozantinib and 60% lenvatinib ± everolimus. Of 26 evaluable patients, 2 patients had confirmed partial response (ORR 7.7%); 5 patients had SD for ≥ 6 months (CBR 23.3%). Median PFS was 3.8 months (range 0.7-13.9); median OS was 14.1 months (range 0.3-28.5). Fifteen patients (50%) had ≥ 1 treatment-related adverse event (TRAE). There were 6 grade ≥ 3 TRAEs [hypertension, congestive heart failure (3), mucositis, and GI perforation (grade 5)]. CONCLUSIONS: In this cohort of heavily pretreated patients with advanced ccRCC, tivozanib yielded a modest clinical benefit in a minority of patients who received prior ICT, cabozantinib, and lenvatinib ± everolimus. TRAEs were consistent with previously published reports.

Differential Treatment Effects of Subgroup Analyses in Phase 3 Oncology Trials From 2004 to 2020.

Importance: Subgroup analyses are often performed in oncology to investigate differential treatment effects and may even constitute the basis for regulatory approvals. Current understanding of the features, results, and quality of subgroup analyses is limited. Objective: To evaluate forest plot interpretability and credibility of differential treatment effect claims among oncology trials. Design, Setting, and Participants: This cross-sectional study included randomized phase 3 clinical oncology trials published prior to 2021. Trials were screened from ClinicalTrials.gov. Main Outcomes and Measures: Missing visual elements in forest plots were defined as a missing point estimate or use of a linear x-axis scale for hazard and odds ratios. Multiplicity of testing control was recorded. Differential treatment effect claims were rated using the Instrument for Assessing the Credibility of Effect Modification Analyses. Linear and logistic regressions evaluated associations with outcomes. Results: Among 785 trials, 379 studies (48%) enrolling 331 653 patients reported a subgroup analysis. The forest plots of 43% of trials (156 of 363) were missing visual elements impeding interpretability. While 4148 subgroup effects were evaluated, only 1 trial (0.3%) controlled for multiple testing. On average, trials that did not meet the primary end point conducted 2 more subgroup effect tests compared with trials meeting the primary end point (95% CI, 0.59-3.43 tests; P = .006). A total of 101 differential treatment effects were claimed across 15% of trials (55 of 379). Interaction testing was missing in 53% of trials (29 of 55) claiming differential treatment effects. Trials not meeting the primary end point were associated with greater odds of no interaction testing (odds ratio, 4.47; 95% CI, 1.42-15.55, P = .01). The credibility of differential treatment effect claims was rated as low or very low in 93% of cases (94 of 101). Conclusions and Relevance: In this cross-sectional study of phase 3 oncology trials, nearly half of trials presented a subgroup analysis in their primary publication. However, forest plots of these subgroup analyses largely lacked essential features for interpretation, and most differential treatment effect claims were not supported. Oncology subgroup analyses should be interpreted with caution, and improvements to the quality of subgroup analyses are needed.

The association of body mass index with tumor aggression among men undergoing radical prostatectomy.

OBJECTIVES: To evaluate the association of preoperative body mass index (BMI) on adverse pathology in peripheral (PZ) and transition zone (TZ) tumors at time of prostatectomy for localized prostate cancer. METHODS: Clinical and pathologic characteristics were obtained from up to 100 consecutive prostatectomy patients from 10 prostate surgeons. BMI groups included normal (18.5-24.9), overweight (25-29.9) and obese (> 29.9). "Aggressive" pathology was defined as the presence of Grade Group (GG) 3 or higher and/or pT3a or higher. Pathologic characteristics were evaluated for association with BMI using univariate analyses. Our primary outcome was the association of BMI with adverse pathology, which was assessed using logistic regression accounting for patient age. We hypothesized that obese BMI would be associated with aggressive TZ tumor. RESULTS: Among 923 patients, 140 (15%) were classified as "normal" BMI, 413 (45%) were "overweight", and 370 (40%) were "obese." 474 patients (51%) had aggressive PZ tumors while 102 (11%) had aggressive TZ tumors. "Obese" BMI was not associated with aggressive TZ tumor compared to normal weight. Increasing BMI group was associated with overall increased risk of aggressive PZ tumor (HR 1.56 [95CI 1.04-2.34]; P = 0.03). Among patients with GG1 or GG2, increasing BMI was associated with presence of pT3a or higher TZ tumor (P = 0.03). CONCLUSIONS: Increased BMI is associated with adverse pathology in PZ tumors. TZ adverse pathology risk may be increased among obese men with GG1 or GG2 disease, which has implications for future studies assessing behavioral change among men whose tumors are actively monitored.

Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide.

PURPOSE: Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist. PATIENTS AND METHODS: Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D). RESULTS: A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65-38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation. CONCLUSIONS: Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.

Challenging the Prevailing Therapeutic Dogma for Prostate Cancer: The Case for an Overlap Syndrome.

There is a need to understand what accounts for the modest impact of therapy on overall survival among men with potentially lethal prostate cancer. Given converging lines of evidence, we hypothesize that in a subset of men, prostate cancer is part of an "overlap syndrome" of age-related illnesses with shared biologic vulnerability.

Venous Thromboembolism Among People With HIV: Design, Implementation, and Findings of a Centralized Adjudication System in Clinical Care Sites Across the United States.

BACKGROUND: People with HIV (PWH) are at increased risk for venous thromboembolism (VTE). We conducted this study to characterize VTE including provoking factors among PWH in the current treatment era. METHODS: We included PWH with VTE between 2010 and 2020 at 6 sites in the CFAR Network of Integrated Clinical Systems cohort. We ascertained for possible VTE using diagnosis, VTE-related imaging, and VTE-related procedure codes, followed by centralized adjudication of primary data by expert physician reviewers. We evaluated sensitivity and positive predictive value of VTE ascertainment approaches. VTEs were classified by type and anatomic location. Reviewers identified provoking factors such as hospitalizations, infections, and other potential predisposing factors such as smoking. RESULTS: We identified 557 PWH with adjudicated VTE: 239 (43%) had pulmonary embolism with or without deep venous thrombosis, and 318 (57%) had deep venous thrombosis alone. Ascertainment with clinical diagnoses alone missed 6% of VTEs identified with multiple ascertainment approaches. DVTs not associated with intravenous lines were most often in the proximal lower extremities. Among PWH with VTE, common provoking factors included recent hospitalization (n = 134, 42%), infection (n = 133, 42%), and immobilization/bed rest (n = 78, 25%). Only 57 (10%) PWH had no provoking factor identified. Smoking (46%), HIV viremia (27%), and injection drug use (22%) were also common. CONCLUSIONS: We conducted a robust adjudication process that demonstrated the benefits of multiple ascertainment approaches followed by adjudication. Provoked VTEs were more common than unprovoked events. Nontraditional and modifiable potential predisposing factors such as viremia and smoking were common.

The Influence of Obesity on Outcomes with Immune Checkpoint Blockade: Clinical Evidence and Potential Biological Mechanisms.

Immune checkpoint blockade (ICB) is a mainstay of treatment for advanced cancer, yet tumor response and host toxicity are heterogenous in those patients who receive ICB. There is growing interest in understanding how host factors interact with tumor intrinsic properties and the tumor microenvironment to influence the therapeutic index with ICB. Obesity, defined by body mass index, is a host factor associated with improved outcomes in select cancers when treated with ICB. While the biological mechanism for this obesity paradox is not fully understood, pre-clinical and translational studies suggest obesity may potentially impact tumor metabolism, inflammation, and angiogenesis. Herein, we summarize clinical studies that support an obesity paradox with ICB, explore potential biological mechanisms that may account for the obesity paradox, and address methodological challenges to consider when studying obesity and treatment outcomes.

Treatment Outcomes in Patients With Metastatic Renal Cell Carcinoma With Sarcomatoid and/or Rhabdoid Dedifferentiation After Progression on Immune Checkpoint Therapy.

BACKGROUND: Metastatic RCC with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is an aggressive disease associated with improved response to immune checkpoint therapy (ICT). The outcomes of patients treated with VEGFR-targeted therapies (TT) following ICT progression have not been investigated. PATIENTS AND METHODS: Retrospective review of 57 patients with sarcomatoid (S), rhabdoid (R), or sarcomatoid plus rhabdoid (S + R) dedifferentiation who received any TT after progression on ICT at an academic cancer center. Clinical endpoints of interest included time on TT, overall survival (OS) from initiation of TT, and objective response rate (ORR) by RECIST version 1.1. Multivariable models adjusted for epithelial histology, IMDC risk, prior VEGFR TT, and inclusion of cabozantinib in the post-ICT TT regimen. RESULTS: 29/57 patients had S dedifferentiation and 19 had R dedifferentiation. The most frequently used TT was cabozantinib (43.9%) followed by selective VEGFR TT (22.8%). The median time on TT was 6.4 months for all, 6.1 months for those with S dedifferentiation, 15.6 months for R dedifferentiation, and 6.1 months for S + R dedifferentiation. Median OS from initiation of TT was 24.9 months for the entire cohort, and the ORR was 20.0%. Patients with R dedifferentiation had significantly longer time on TT than those with S dedifferentiation (HR 0.44, 95% CI, 0.21-0.94). IMDC risk was associated with OS. CONCLUSIONS: A subset of patients with S/R dedifferentiation derive clinical benefit from TT after they have progressive disease on ICT. Patients with R dedifferentiation appeared to derive more benefit from TT than those with S dedifferentiation.

Monitoring Glucocorticoid Receptor in Plasma-derived Extracellular Vesicles as a Marker of Resistance to Androgen Receptor Signaling Inhibition in Prostate Cancer.

Disease progression following androgen ablation was shown to be associated with upregulation of the glucocorticoid receptor (GR). Longitudinal monitoring of GR expression in circulating extracellular vesicles (EV) may reflect changes in the tumor cell and facilitates detection of acquired resistance. We utilized LNCaP, LREX cells and a patient-derived xenograft, MDA PDX 322-2-6a, for in vitro and in vivo experiments. Plasma-derived EVs were isolated from patients with localized high-risk prostate cancer undergoing androgen ablation. The mRNA levels of GR in EVs and their responsive genes were detected by transcriptome analysis, qRT-PCR and the protein levels by Western blot analysis. We detected changes in GR expression at mRNA and protein levels in EVs derived from LNCaP and LREX cells in in vitro studies. In in vivo experiments, LNCaP and the PDX MDA 322-2-6a-bearing mice were treated with enzalutamide. GR levels in plasma-derived EVs were increased only in those tumors that did not respond to enzalutamide. Treatment of mice bearing enzalutamide-resistant tumors with a GR inhibitor in combination with enzalutamide led to a transient pause in tumor growth in a subset of tumors and decreased GR levels intracellular and in plasma-derived EVs. In a subgroup of patients with high-risk localized prostate cancer treated with androgen signaling inhibition, GR was found upregulated in matching tissue and plasma EVs. These analyses showed that GR levels in plasma-derived EVs may be used for monitoring the transition of GR expression allowing for early detection of resistance to androgen ablation treatment. SIGNIFICANCE: Longitudinal monitoring of GR expression in plasma-derived EVs from patients with prostate cancer treated with androgen signaling inhibitors facilitates early detection of acquisition of resistance to androgen receptor signaling inhibition in individual patients.

Cardiometabolic healthcare for men with prostate cancer: an MD Anderson Cancer Center experience.

BACKGROUND: Men diagnosed with prostate cancer are at risk for competing morbidity and mortality due to cardiometabolic disease given their advanced age at diagnosis, high prevalence of pre-existing risk factors, and receipt of systemic therapy that targets the androgen receptor (AR). Expert panels have stressed the importance of cardiometabolic risk assessment in the clinic and proposed evaluating key risks using consensus paradigms. Yet, there is a gap in real-world evidence for implementation of comprehensive cardiometabolic care for men with prostate cancer. METHODS: This is a retrospective, descriptive study of patients with prostate cancer who were referred and evaluated in the Healthy Heart Program at MD Anderson Cancer Center, which was established to mitigate cardiometabolic risks in men with prostate cancer. Patients were seen by a cardiologist and exercise physiologist to evaluate and manage cardiometabolic risk factors, including blood pressure, cholesterol, blood glucose, tobacco use, and coronary artery disease, concurrent with management of their cancer by a medical oncologist. RESULTS: From December 2018 through October 2021, the Healthy Heart Program enrolled 55 men with prostate cancer, out of which 35 had biochemical, locoregional recurrence or distant metastases, while all received at least a single dose of a luteinizing hormone-releasing hormone (LHRH) analog. Ninety-three percent of men were overweight or obese, and 51% had an intermediate or high risk of atherosclerotic cardiovascular disease at 10 years based on the pooled cohort equation. Most men had an overlap of two or more cardiometabolic diseases (84%), and 25% had an overlap of at least 4 cardiometabolic diseases. Although uncontrolled hypertension and hyperlipidemia were common among the cohort (45% and 26%, respectively), only 29% of men followed up with the clinic. CONCLUSIONS: Men with prostate cancer have a high burden of concurrent cardiometabolic risk factors. At a tertiary cancer center, the Healthy Heart Program was implemented to address this need, yet the utility of the program was limited by poor follow-up possibly due to outside cardiometabolic care and inconvenient appointment logistics, a lack of cardiometabolic labs at the time of visits, and telemedicine visits.

Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors.

BACKGROUND: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. METHODS: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. RESULTS: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. CONCLUSIONS: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

Obesity and renal cell carcinoma: Biological mechanisms and perspectives.

Obesity, defined by body mass index (BMI), is an established risk factor for specific renal cell carcinoma (RCC) subtypes such as clear cell RCC, the most common RCC histology. Many studies have identified an association between obesity and improved survival after diagnosis of RCC, a potential "obesity paradox." Clinically, there is uncertainty whether improved outcomes observed after diagnosis are driven by stage, type of treatment received, or artifacts of longitudinal changes in weight and body composition. The biological mechanisms underlying obesity's influence on RCC are not fully established, but multiomic and mechanistic studies suggest an impact on tumor metabolism, particularly fatty acid metabolism, angiogenesis, and peritumoral inflammation, which are known to be key biological hallmarks of clear cell RCC. Conversely, high-intensity exercise associated with increased muscle mass may be a risk factor for renal medullary carcinoma, a rare RCC subtype that predominantly occurs in individuals with sickle hemoglobinopathies. Herein, we highlight methodologic challenges associated with studying the influence of obesity on RCC and review the clinical evidence and potential underlying mechanisms associating RCC with BMI and body composition.

Tobacco Smoking and Pack-Years Are Associated With Frailty Among People With HIV.

BACKGROUND: Tobacco smoking increases frailty risk among the general population and is common among people with HIV (PWH) who experience higher rates of frailty at younger ages than the general population. METHODS: We identified 8608 PWH across 6 Centers for AIDS Research Network of Integrated Clinical Systems sites who completed ≥2 patient-reported outcome assessments, including a frailty phenotype measuring unintentional weight loss, poor mobility, fatigue, and inactivity, and scored 0-4. Smoking was measured as baseline pack-years and time-updated never, former, or current use with cigarettes/day. We used Cox models to associate smoking with risk of incident frailty (score ≥3) and deterioration (frailty score increase by ≥2 points), adjusted for demographics, antiretroviral medication, and time-updated CD4 count. RESULTS: The mean follow-up of PWH was 5.3 years (median: 5.0), the mean age at baseline was 45 years, 15% were female, and 52% were non-White. At baseline, 60% reported current or former smoking. Current (HR: 1.79; 95% confidence interval: 1.54 to 2.08) and former (HR: 1.31; 95% confidence interval: 1.12 to 1.53) smoking were associated with higher incident frailty risk, as were higher pack-years. Current smoking (among younger PWH) and pack-years, but not former smoking, were associated with higher risk of deterioration. CONCLUSIONS: Among PWH, smoking status and duration are associated with incident and worsening frailty.

Cancer Cell-Extrinsic Roles for the Androgen Receptor in Prostate Cancer.

Given the central role of the androgen receptor (AR) in prostate cancer cell biology, AR-targeted therapies have been the backbone of prostate cancer treatment for over 50 years. New data indicate that AR is expressed in additional cell types within the tumor microenvironment. Moreover, targeting AR for the treatment of prostate cancer has established side effects such as bone complications and an increased risk of developing cardiometabolic disease, indicating broader roles for AR. With the advent of novel technologies, such as single-cell approaches and advances in preclinical modeling, AR has been identified to have clinically significant functions in other cell types. In this mini-review, we describe new cancer cell-extrinsic roles for AR within the tumor microenvironment as well as systemic effects that collectively impact prostate cancer progression and patient outcomes.

Phase I study of sapanisertib with carboplatin and paclitaxel in mTOR pathway altered solid malignancies.

Pre-clinically, the mTORC1/2 inhibitor sapanisertib restored sensitivity to platinums and enhanced paclitaxel-induced cancer cell killing. NCT03430882 enrolled patients with mTOR pathway aberrant tumors to receive sapanisertib, carboplatin and paclitaxel. Primary objective was safety and secondary objectives were clinical response and survival. One patient had a dose-limiting toxicity at dose level 4. There were no unanticipated toxicities. Grade 3-4 treatment-related adverse events included anemia (21%), neutropenia (21%), thrombocytopenia (10.5%), and transaminitis (5%). Of 17 patients evaluable for response, 2 and 11 patients achieved partial response and stable disease, respectively. Responders included a patient with unclassified renal cell carcinoma harboring EWSR1-POU5F1 fusion and a patient with castrate resistant prostate cancer harboring PTEN loss. Median progression free survival was 3.84 months. Sapanisertib in combination with carboplatin plus paclitaxel demonstrated a manageable safety profile, with preliminary antitumor activity observed in advanced malignancies harboring mTOR pathway alterations.

Cytoreductive Nephrectomy for Patients with Metastatic Sarcomatoid and/or Rhabdoid Renal Cell Carcinoma Treated with Immune Checkpoint Therapy.

BACKGROUND: Renal cell carcinoma (RCC) with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is a highly aggressive tumor with a poor prognosis. Immune checkpoint therapy (ICT) has shown significant treatment efficacy in this subtype. There remains uncertainly regarding the role of cytoreductive nephrectomy (CN) for patients with metastatic RCC (mRCC) with S/R who received ICT. OBJECTIVE: Here, we report the outcomes with ICT for patients with mRCC and S/R dedifferentiation by CN status. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was conducted of 157 patients with sarcomatoid, rhabdoid, or sarcomatoid plus rhabdoid dedifferentiation who received an ICT-based regimen at two cancer centers. INTERVENTION: CN performed at any time point; nephrectomy with curative intent was excluded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ICT treatment duration (TD) and overall survival (OS) from ICT initiation were recorded. To address the immortal time bias, a time-dependent Cox regression model was generated that accounted for confounders identified by a directed acyclic graph as well as a time-dependent nephrectomy variable. RESULTS AND LIMITATIONS: A total of 118 patients underwent CN, and of them, 89 underwent upfront CN. The results did not contradict the supposition that CN does not improve ICT TD (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.65-1.47, p = 0.94) or OS from ICT initiation (HR 0.79, 95% CI 0.47-1.33, p = 0.37). In patients who underwent upfront CN compared with those who did not undergo CN, there was no association with ICT duration or OS (HR 0.61, 95% CI 0.35-1.06, p = 0.08). A detailed clinical summary of 49 patients with mRCC and rhabdoid dedifferentiation is provided. CONCLUSIONS: In this multi-institutional cohort of mRCC with S/R dedifferentiation treated with ICT, CN was not significantly associated with improved TD or superior OS when accounting for the lead time bias. There appears to be a subset of patients who derive meaningful benefit from CN, so improved tools for stratification prior to CN are needed to optimize outcomes. PATIENT SUMMARY: Immunotherapy has improved outcomes for patients with metastatic renal cell carcinoma (mRCC) who have sarcomatoid and/or rhabdoid (S/R) dedifferentiation, which is an aggressive and uncommon feature; yet, the utility of a nephrectomy in this setting is unclear. We found that nephrectomy did not significantly improve survival or time on immunotherapy for these patients with mRCC and S/R dedifferentiation; yet, there may be a subset of patients who benefit from this surgical approach.

Immune Checkpoint Therapy Combinations in Adult Advanced MiT Family Translocation Renal Cell Carcinomas.

BACKGROUND: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC). METHODS: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods. RESULTS: There were 29 patients identified with median age of 38 (21-70) years, and F:M ratio 0.9:1. FISH revealed TFE3 and TFEB translocations in 22 and 7 patients, respectively. Dual ICT and ICT + VEGF TT were used in 18 and 11 patients, respectively. Seventeen (59%) patients received ICT combinations as first-line therapy. ORR was 1/18 (5.5%) for dual ICT and 4/11 (36%) for ICT + VEGF TT. At a median follow-up of 12.9 months, median PFS was 2.8 and 5.4 months in the dual ICT and ICT + VEGF TT groups, respectively. Median OS from metastatic disease was 17.8 and 30.7 months in the dual ICT and ICT + VEGF TT groups, respectively. CONCLUSION: In this retrospective study of advanced tRCC, limited response and survival were seen after frontline dual ICT combination therapy, while ICT + VEGF TT therapy offered some efficacy. Due to the heterogeneity of tRCC, insights into the biological underpinnings are necessary to develop more effective therapies.