Clinical Trials: From the Editor
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Is TROP2 Just Not What We Thought It Was for Bladder Cancer? Where to Go after TROPiCS-04?
DLL3 as a Neuroendocrine Carcinoma Target
Can We Use ctDNA to Refine Selection of Urothelial Carcinoma Patients for Adjuvant Therapy?
Adjuvant therapy for urothelial carcinoma is a reasonable standard of care consideration for patients after radical cystectomy or nephroureterectomy, for those with lower and upper tract disease, respectively. Although neoadjuvant cisplatin-combination chemotherapy is still a current standard,1 many patients never receive neoadjuvant therapy. The Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer (POUT) trial results support the use of adjuvant chemotherapy with gemcitabine/cisplatin or gemcitabine/carboplatin, as the primary endpoint of disease free survival (DFS) was positive in favor of adjuvant chemotherapy over surveillance with a HR of 0.45 (95% CI 0.30-0.68, p=0.0001).2 Although overall survival was not the primary endpoint of the trial, the 5-year overall survival was 66% vs. 57%, with a univariable HR 0.68 (95% CI 0.46-1.00, p-0.049).3
Androgen Receptor Ligand Binding Domain Mutations in Prostate Cancer Help Lend Credence to Adrenal Annihilation Using CYP11A1 Inhibition
It has been many years since I addressed ligand binding domain (LBD) mutations of the androgen receptor (AR).1 At one time it was felt that these mutations were infrequent drivers of disease pathogenesis. Yet, the Prostate Cancer Foundation's (PCF) funding of the International Dream Team metastatic biopsy study found AR LBD mutations in 22/150 (14.7%) in those previously treated with docetaxel.2 In the modern era, with greater use of potent androgen and AR inhibiting therapies, such as abiraterone acetate, enzalutamide, apalutamide, and darolutamide, estimates for these AR LBD mutations approximate 20% of previously treated patients with metastatic castration-resistant prostate cancer after receipt of an AR pathway inhibitor.
VISTA as a New Immunotherapy Target
Metastatic Castration-Sensitive Prostate Cancer, If Treatment Intensification Is the Standard, Who and How Can We Treatment Deintensify?
Immunotherapy for Metastatic Castration-Sensitive Prostate Cancer…Patients Want It!”
Metastatic Castration-Sensitive Prostate Cancer, What is Left to Do? A Lot!
Selective HIF2A Inhibitors, What Started as a Von Hippel-Lindau Niche Is Now Gearing up for the Big Stage
Fibroblast Growth Factor Receptor 3 (FGFR3) Specificity, Promise of Efficacy with Less Toxicity for Patients with Urothelial Carcinomas?
HER3, Part of a Family of Targets, for Patients with Prostate Cancer and Other Genitourinary Malignancies
Imaging and Therapy for Prostate-Specific Membrane Antigen (PSMA) Low-Expressing Prostate Cancers; Could Gastrin-Releasing Peptide Receptor (GRPR) Be the Next Target?
The Next Revelation in Prostate Cancer Therapy? Antibody Drug Conjugates
Bladder Preservation – A New Age of Sparing Bladders That Includes Immunotherapy?
Is B7-H3 (PD-L2) the Target We Need for Prostate Cancer to Come into the Antibody Drug Conjugate Era?
Although anti-PD-1 or -PD-L1 (B7-H1) therapy is efficacious as an immunotherapy target for multiple malignancies, including bladder and renal cancers, we have not seen significant efficacy in prostate cancer, either as a single agent or in combination therapy regimens.1, 2 There are, of course, exceptions, as a patient with mismatch repair deficiency, microsatellite instability, and/or hypermutation, may have an outstanding response to immune checkpoint blockade.3, 4 However, estimates of the presence of these predisposing tumor alterations as a predictive marker for response to immune checkpoint blockade for patients with metastatic castration-resistant prostate cancer is low, approximately 3-5% of cases.5
Ataxia Telangiectasia Mutated and Rad3-Related Kinase (ATR) Inhibitors: Some Promise for Patients with Ataxia-Telangiectasia Mutated (ATM) Genitourinary Cancers?
Androgen Receptor Addiction in Prostate Cancer, Breaking the Habit
Androgen receptor (AR) signaling is the most important driver of prostate cancer initiation, development, and progression, even into the castration-resistant state. Androgen deprivation therapy (ADT) is the original “targeted therapy” in oncology. The next generation androgen- and AR-targeted agents, such as abiraterone acetate, enzalutamide, apalutamide and darolutamide further prove the concept that AR signaling remains critical in even later disease states. There are various mechanisms of resistance that continue to be inclusive of AR; this ranges from AR amplification, AR mutation, and potentially AR spliced variants.
Targeted Alpha Therapy for Prostate Cancer, the Next Generation of Alpha-Emitting Radiopharmaceuticals
It’s hard to believe that it’s been nearly a decade since the ALSYMPCA trial with radium-223 was published, showing an overall survival benefit for men with bone metastatic castration-resistant prostate cancer and symptoms.1 Radium-223 is an alpha-particle emitting radiopharmaceutical that incorporates into areas of osteoblastic activity, with subsequent induction of double-strand DNA breaks in neighboring tumor cells. Although radium-223 has clear efficacy, one of the practical challenges of use is that prostate-specific antigen (PSA) level does not always decline in response to treatment and the association with clinical outcomes is poor. As a result, it is sometimes difficult for patients and health care providers to determine if radium-223 is working well or not.
Third or Fourth Place in the Race? No Problem – The Case for More Trials Using Darolutamide for Patients with Prostate Cancer
Darolutamide first received regulatory approval for patients with non-metastatic (M0) castration-resistant prostate cancer based on the results of the ARAMIS trial.1 Although apalutamide and enzalutamide were regulatory approved prior to darolutamide, all three agents were successful in demonstrating both metastasis-free and overall survival benefit in their respective randomized phase 3 trials over placebo.1-3
Is There Synergism When Combining Antibody Drug Conjugates and Immune-Oncology Agents for Urothelial Carcinoma?
Patients with urothelial bladder cancer now have many efficacious treatment options, spanning many unique mechanisms of action. The immune-oncology agents in urothelial carcinoma have had significant success with current regulatory approvals in various disease states for pembrolizumab, nivolumab, atezolizumab, and avelumab. Likewise, antibody drug conjugates are monoclonal antibodies specific for a tumor antigen, connected by a linker molecule to a cytotoxic drug payload, offering selective intensification of therapy. Direction of increased drug concentration to the target cancer cell with minimal collateral damage to healthy tissue is a purported advantage of these antibody drug conjugates. Yet, there is now some discussion surrounding whether increased specificity of targeting is ideal or whether it may be advantageous to have a more cleavable linker that could allow for greater bystander effect against cancer cells that may lack target antigen expression.1
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