Clinical Trials: From the Editor
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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
Refractory Testicular Germ Cell Tumors – Where Should We Go Next?
Fortunately, most people are cured, however, 15-20% of patients with metastatic testicular germ cell tumors will relapse following initial chemotherapy. Approximately half will still be cured with salvage treatments, including either conventional cisplatin-based combination chemotherapy or high-dose chemotherapy followed by autologous stem cell rescue.1-3 Over the years, I’ve written a couple of different Urotoday Clinical Trials Portal articles summarizing the very few clinical trials, at the time, for those who have refractory/resistant germ cell tumors.4, 5 Unfortunately, to date, none of those previously highlighted clinical trials have changed the standard of care for this unmet need population. In these situations, palliative chemotherapy, with regimens containing oxaliplatin, is commonly used, yet it has limited efficacy.6
Cisplatinum-Ineligible Patients with Muscle-Invasive Localized Urothelial Carcinoma Still Do Not Have Good Systemic Therapy Options for Neoadjuvant Treatment
Five years ago, I wrote an article focused on neoadjuvant treatment options in clinical trials for patients with cisplatinum-ineligible, muscle-invasive urothelial carcinoma.1 The trials highlighted at that time were all focused on exploring immune-oncology agents. Since that time, we have learned that neoadjuvant pembrolizumab or atezolizumab may contribute significant complete response rates when administered prior to radical cystectomy.2, 3 Yet, the standard of care for patients who are ineligible to receive cisplatinum chemotherapy is the same today as it was 5 years ago and that is to proceed to radical cystectomy without any systemic therapy.
Relugolix Is Available, but Additional Clinical Trial Investigation Is Ongoing
The idea of oral androgen deprivation therapy (ADT) sounds great! Why take a big needle when you can take a pill? That certainly makes a lot of sense, but there are some major disadvantages to oral medications in the United States. Most importantly is that oral prescription coverage for high-cost oncologic medications is less than ideal, and our patients can be left with large copays. Even with copay assistance from sponsors and foundations, the overall cost to the health care system may be significant. Also, the risk of non-compliance is real, and patients may forget to take their medications. Yet, these are pragmatic considerations. In the field of oncology, the most important drivers tend to still be efficacy and tolerability.
Even with New Treatment Advances for Metastatic Castration-Sensitive Prostate Cancer, There Is Still Opportunity to Bring in Radiopharmaceutical Therapy
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