Ophthalmologic toxicities of antineoplastic agents in genitourinary cancers: Mechanisms, management, and clinical implications.

Genitourinary cancers affect over 480,000 patients in the United States annually. While promising therapeutic modalities continue to emerge, notably immune checkpoint inhibitors, molecular targeted therapies, antibody-drug conjugates, and radioligand therapies, these treatments are associated with a spectrum of adverse side-effects, including ophthalmologic toxicities. In this review, we cover the most commonly used antineoplastic agents for the kidneys, bladder, urinary tracts, prostate, testis, and penis, detailing mechanism, indication, and recent trials supporting their use.

Pairing the Right Individual with the Right Regimen: Patient Selection Criteria in the Treatment of Advanced Urothelial Carcinoma.

Enfortumab vedotin plus pembrolizumab is a very effective regimen in the treatment of advanced urothelial carcinoma but is difficult to tolerate. We discuss the rationale for establishing patient selection criteria for this combination, taking into consideration the potential for life-altering side effects, limited real-world experience with the regimen among oncologists, patient preferences in balancing treatment effectiveness against toxicity, and the precedent in establishing eligibility criteria for platinum-based chemotherapy.

TROPHY-U-01 Cohort 2: A Phase II Study of Sacituzumab Govitecan in Cisplatin-Ineligible Patients With Metastatic Urothelial Cancer Progressing After Previous Checkpoint Inhibitor Therapy.

Purpose: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate with an SN-38 payload, approved for patients with locally advanced (LA) or metastatic urothelial cancer (mUC) who progressed after platinum (PT)-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report results from Cohort 2 of TROPHY-U-01 trial, evaluating the efficacy and safety of SG in patients with mUC.

Methods: TROPHY-U-01 (ClinicalTrials.

Sacituzumab Govitecan Demonstrates Efficacy across Tumor Trop-2 Expression Levels in Patients with Advanced Urothelial Cancer.

Purpose: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression.

A Phase II Trial of the WEE1 Inhibitor Adavosertib in SETD2-Altered Advanced Solid Tumor Malignancies (NCI 10170).

Unlabelled: We sought to evaluate the efficacy of WEE1 inhibitor adavosertib in patients with solid tumor malignancies (cohort A) and clear cell renal cell carcinoma (ccRCC; cohort B). NCT03284385 was a parallel cohort, Simon two-stage, phase II study of adavosertib (300 mg QDAY by mouth on days 1-5 and 8-12 of each 21-day cycle) in patients with solid tumor malignancies harboring a pathogenic SETD2 mutation. The primary endpoint was the objective response rate.

A plain language summary of the TROPHY-U-01 study: sacituzumab govitecan use in people with locally advanced or metastatic urothelial cancer.

What Is This Summary About?: Sacituzumab govitecan (brand name: TRODELVY) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors.

A comparative study of spinal cord compression management in metastatic prostate cancer: Teaching versus non-teaching hospitals in the United States.

Background: Spinal cord compression (SCC) in metastatic prostate cancer (MPC) is a critical complication and multiple factors influence the optimal therapeutic strategy. We investigated the differences in practice patterns between teaching hospitals (TH) and non-teaching hospitals (NTH) across the United States.

Method: Using the National Inpatient Sample Database (NIS), we performed a retrospective study on hospitalizations with MPC and SCC between 2016 and 2020 in US.

A Phase 2 Study of Sitravatinib in Combination with Nivolumab in Patients with Advanced or Metastatic Urothelial Carcinoma.

Background And Objective: Checkpoint inhibitor therapy (CPI) has demonstrated survival benefits in urothelial carcinoma (UC); however, not all patients benefit from CPI due to resistance. Combining sitravatinib, a multitargeted receptor tyrosine kinase inhibitor of TYRO3, AXL, and MERTK (TAM) receptors and VEGFR2, with CPI may improve antitumor responses. Our objective was to assess the efficacy and safety of sitravatinib plus nivolumab in patients with advanced/metastatic UC.

Therapy With Metronomic Cyclophosphamide (mCyc) for Previously-Treated Metastatic Castrate-Resistant Prostate Cancer (mCRPC).

Introduction: Despite the introduction of various novel therapies for management of metastatic castrate resistant prostate cancer (mCRPC) in recent decades, available treatment options are finite and remain limited. Multiple historical studies have demonstrated activity and a favorable toxicity profile of oral metronomic cyclophosphamide (mCyc) in prostate cancer (PCa). Unlike the cytotoxic immunosuppressive effects of high-dose intravenously-administered cyclophosphamide, continuous low doses of oral mCyc have a unique immune-stimulatory mechanism of action.

Treatment approaches for urachal cancer: Use of immunotherapy and targeted therapies.

Urachal cancer is a rare genitourinary malignancy that arises from the embryologic remnant of the urachus. The malignancy is considered to be aggressive, with no clear consensus on appropriate management for advanced disease. Although traditionally considered to be related to bladder cancer given its embryologic origin, several next generation sequencing studies have revealed the genomic profile of this genitourinary malignancy most closely resembles colorectal cancer.

Drug extravasation with Enfortumab vedotin.

Introduction: Enfortumab vedotin is an antibody drug conjugate approved for management of pretreated locally advanced or metastatic urothelial carcinoma, which is associated with a rare risk of drug extravasation and soft tissue reactions.

Case Report: We report two cases of EV extravasation with subsequent development of bullae and cellulitis.

Management And Outcome: They were both treated for cellulitis and had conservative management without surgical intervention and were able to resume treatment with Enfortumab vedotin without subsequent adverse events.

Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial.

Purpose: For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk.

Methods: Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel.

Telaglenastat plus Everolimus in Advanced Renal Cell Carcinoma: A Randomized, Double-Blinded, Placebo-Controlled, Phase II ENTRATA Trial.

Purpose: Glutaminase is a key enzyme, which supports elevated dependency of tumors on glutamine-dependent biosynthesis of metabolic intermediates. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus plus the oral glutaminase inhibitor telaglenastat showed preclinical synergistic anticancer effects, which translated to encouraging safety and efficacy findings in a phase I trial of 2L+ renal cell carcinoma (RCC). This study evaluated telaglenastat plus everolimus (TelaE) versus placebo plus everolimus (PboE) in patients with advanced/metastatic RCC (mRCC) in the 3L+ setting (NCT03163667).

Use of immunotherapy in clinical management of genitourinary cancers - a review.

Checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 have revolutionized oncologic care delivery, including clinical management of genitourinary malignancies. Despite significant associated improvement in patient outcomes, molecular heterogeneity of tumors, variable tumor engagement with the immune response, and unique patient factors likely account for different clinical responses to immunotherapy agents. A search for predictive biomarkers of treatment response to checkpoint inhibitors is underway and several candidates, although imperfect, have been identified.

Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial.

Background: Availability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)-targeted therapies.

Adjuvant pembrolizumab in genomically selected high-risk patients with muscle-invasive bladder cancer.

Introduction: Patients with muscle-invasive urothelial bladder cancer post neoadjuvant cisplatin-based chemotherapy with pathologic advanced disease (ypT3, ypT4, ypN+) at radical cystectomy have a significantly worse five-year overall survival. There is currently no preferred adjuvant therapy to reduce risk of cancer recurrence in this high-risk patient cohort and surveillance remains the standard-of-care.

Case Report: We present a case series of two patients who received cisplatin-based neoadjuvant chemotherapy and had pathologic node-positive urothelial carcinoma at the time of radical cystectomy.

TROPHY-U-01: A Phase II Open-Label Study of Sacituzumab Govitecan in Patients With Metastatic Urothelial Carcinoma Progressing After Platinum-Based Chemotherapy and Checkpoint Inhibitors.

Purpose: Patients with metastatic urothelial carcinoma (mUC) who progress on platinum-based combination chemotherapy (PLT) and checkpoint inhibitors (CPIs) have limited options that offer objective response rates (ORRs) of approximately 10% with a median overall survival (OS) of 7-8 months. Sacituzumab govitecan (SG) is a TROP-2-directed antibody-drug conjugate with an SN-38 payload that has shown preliminary activity in mUC.

Methods: TROPHY-U-01 (ClinicalTrials.

Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: Applying clinical trial findings to clinical practice.

Although urothelial carcinoma (UC) is considered a chemotherapy-sensitive tumor, progression-free survival and overall survival (OS) are typically short following standard first-line (1L) platinum-containing chemotherapy in patients with locally advanced or metastatic disease. Immune checkpoint inhibitors (ICIs) have antitumor activity in UC and favorable safety profiles compared with chemotherapy; however, trials of 1L ICI monotherapy or chemotherapy + ICI combinations have not yet shown improved OS vs chemotherapy alone. In addition to direct cytotoxicity, chemotherapy has potential immunogenic effects, providing a rationale for assessing ICIs as switch-maintenance therapy.

Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial.

Background: Despite standard curative-intent treatment with neoadjuvant cisplatin-based chemotherapy, followed by radical surgery in eligible patients, muscle-invasive urothelial carcinoma has a high recurrence rate and no level 1 evidence for adjuvant therapy. We aimed to evaluate atezolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma.

Method: In the IMvigor010 study, a multicentre, open-label, randomised, phase 3 trial done in 192 hospitals, academic centres, and community oncology practices across 24 countries or regions, patients aged 18 years and older with histologically confirmed muscle-invasive urothelial carcinoma and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2 were enrolled within 14 weeks after radical cystectomy or nephroureterectomy with lymph node dissection.

Management of Advanced Prostate Cancer in Clinical Practice: Real-World Answers to Challenging Dilemmas.

Advanced prostate cancer is a continuum of states distinguished by the presence or absence of metastasis and sensitivity or resistance to androgen deprivation therapy (ADT). Therapeutic options for this disease continue to rapidly evolve, making it a challenge to apply results of clinical trial data to daily patient management. One question relevant to providers is whether molecular biomarkers predictive of response or resistance to therapies are available to guide clinical treatment decisions.