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Clinical Trials: From the Editor

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Masked Antibody Therapeutics in Genitourinary Malignancies: Expanding the Therapeutic Window Through Tumor-Selective Activation

The development of immunotherapies for genitourinary (GU) malignancies has historically been hindered by the lack of truly tumor-exclusive targets. While antigens such as PSMA, HER2, EGFR, and EpCAM are highly expressed on malignant cells, they are also present in vital healthy tissues, leading to "on-target, off-tumor" toxicities.1 This challenge has driven the development of masked antibody technologies designed to restrict biologic activity to the tumor microenvironment. These agents utilize biochemical "locks" that prevent systemic activation, ensuring that target binding, T-cell recruitment, or payload delivery occurs preferentially within tumors. Masked antibodies, therefore, represent a rational evolution of targeted therapy, shifting from systemic target engagement toward spatially controlled activation. By separating systemic exposure from biologic activation, these platforms aim to preserve efficacy while minimizing toxicity, a balance that has historically limited the development of highly potent immune-engaging therapies in genitourinary malignancies.

From Payload to Preservation – Monomethyl Auristatin E (MMAE) in Enfortumab Vedotin as the next Radiosensitizer for Bladder Preservation?

The evolution of bladder preservation strategies has historically paralleled advances in systemic therapy for muscle-invasive bladder cancer (MIBC). Radiosensitizing agents incorporated into trimodality therapy have generally been drawn from systemic regimens that demonstrated efficacy in the perioperative setting. Cisplatin became the dominant radiosensitizer, not only because of its activity in metastatic disease, but because randomized trials established a survival benefit with neoadjuvant cisplatin-based chemotherapy. A similar transition may now be occurring with enfortumab vedotin. The rapid emergence of enfortumab vedotin–based therapy in earlier disease states, particularly after the presentation of data from the randomized phase 3 EV-303 and EV-304 trials, has redefined expectations for systemic therapy in MIBC and has created a compelling rationale to evaluate enfortumab vedotin in combination with radiation as part of contemporary bladder preservation approaches.

Tumor Suppressor Genes in Prostate Cancer – Currently Prognostic, but Soon to Be Predictive?

Tumor suppressor genes play a critical role in prostate cancer progression, with alterations in PTEN, TP53, and RB1 representing some of the most clinically significant genomic events. These alterations define aggressive biological phenotypes and serve as powerful prognostic biomarkers across disease states. However, despite increasing mechanistic and clinical insight, these alterations do not yet consistently dictate therapeutic decision-making outside of selected clinical trials.

Earning Platinum Status – Revisiting the Role of Carboplatin in the Genomic Era of Prostate Cancer

Carboplatin is a second-generation platinum-based chemotherapeutic agent developed to retain the antitumor efficacy of cisplatin while substantially reducing renal, neurologic, and gastrointestinal toxicity.1 Its antineoplastic activity derives from the formation of DNA inter- and intra-strand cross-links that disrupt DNA replication and transcription, leading to cell cycle arrest and apoptosis, particularly in tumors with impaired DNA repair capacity.2 Although platinum agents have demonstrated broad activity across solid tumors, their role in prostate cancer historically remained limited, in part because early clinical studies were conducted in unselected, heavily pretreated populations.

Seek and Treat: Targeting B7-H3 in Prostate Cancer

While immune checkpoint inhibition has reshaped the treatment of multiple solid tumors, prostate cancer has remained largely refractory to therapies directed against PD-1, PD-L1, or CTLA-4. In contrast, B7-H3 is highly and consistently expressed in prostate cancer, including advanced and castration-resistant stages, and is implicated in both immune evasion and intrinsic tumor aggressiveness, making it an especially compelling therapeutic target.

TROP2 in View for Prostate Cancer - Hope for a New Imaging and Therapeutic Target

The cell-surface glycoprotein TROP2 (also called TACSTD2) is increasingly recognized as a potential therapeutic target in advanced prostate cancer, owing to its membrane localization, maintained expression in castration-resistant disease, and the development of antibody-drug conjugates (ADCs) designed to exploit this antigen. In a recent transcriptomic analysis of 634 metastatic castration-resistant prostate cancers (mCRPC), TACSTD2 mRNA was found to be broadly expressed across luminal and basal adenocarcinoma subtypes, though relatively lower in neuroendocrine prostate cancer (NEPC).1 Importantly, evidence suggested that prior exposure to androgen-receptor signaling inhibitors and presence of Androgen Receptor Splice Variant 7 (ARv7) did not reduce TACSTD2 expression; in fact, ARv7 positivity was associated with increased expression in some cases.1 These findings support the feasibility of TROP2 as a drug target throughout the prostate cancer spectrum, including treatment‐resistant prostate cancer.

Systemic Therapy Advances in Muscle-Invasive Bladder Cancer: A Critical Juncture for Cisplatin-Based Trials

In patients with muscle-invasive bladder cancer (MIBC) managed with radical cystectomy, the perioperative systemic therapy landscape is transforming rapidly. Historically, cisplatin-eligible patients have been offered neoadjuvant cisplatin-based chemotherapy followed by surgery, yet relapse rates remain high, and many patients are ineligible for cisplatin due to comorbidities. The NIAGARA trial, a randomized phase 3 trial, compared neoadjuvant gemcitabine/cisplatin plus the PD-L1 inhibitor durvalumab, followed by surgery and adjuvant durvalumab, versus neoadjuvant gemcitabine/cisplatin alone. The trial enrolled 1,063 patients with operable MIBC and demonstrated at 24 months an event-free survival (EFS) rate of 67.8% in the durvalumab arm versus 59.8% in chemotherapy alone, corresponding to a hazard ratio (HR) of 0.68 (95% CI 0.56–0.82; P < 0.001).

AKT Inhibitors for Prostate Cancer – Let’s Try Again

The PI3K/AKT/mTOR signaling pathway plays a critical role in regulating cellular growth, survival, metabolism, and proliferation. In prostate cancer, especially in advanced stages, this pathway becomes dysregulated in a significant proportion of patients, most notably through the loss of the tumor suppressor PTEN. PTEN loss, observed in approximately 40–60% of metastatic castration-resistant prostate cancer (mCRPC) cases, results in unchecked AKT activation and tumor progression.1 This biological rationale has prompted the investigation of AKT inhibitors as a therapeutic strategy, particularly in patients with PTEN-deficient prostate cancer.

Mismatch Repair Deficiency, Microsatellite Instability and Hypermutation in Prostate Cancer…a Good Match for Immunotherapy

Mismatch repair deficiency (dMMR), microsatellite instability (MSI-H), and high tumor mutational burden (TMB-H) have emerged as clinically important biomarkers in prostate cancer with direct therapeutic implications. Although they occur in only a small fraction of cases, these alterations define a subset of tumors with increased immunogenicity and enhanced sensitivity to immune checkpoint blockade. In metastatic castration-resistant prostate cancer (mCRPC), where immunotherapy typically has limited benefit, identification of MSI-H/dMMR or TMB-H provides access to pembrolizumab under FDA tissue-agnostic approvals.1,2

Improving upon Enfortumab Vedotin plus Pembrolizumab for First-Line Metastatic and Locally-Advanced Urothelial Carcinoma

For decades, platinum-based chemotherapy was the mainstay of first-line treatment, offering modest efficacy. Anticipated median survival was limited at around 15 months.1 Additionally, many patients are ineligible for cisplatin due to age, comorbidities, or poor performance status. Recent advances have transformed the treatment paradigm, particularly with the emergence of enfortumab vedotin (EV), in combination with pembrolizumab (pembro), as a highly efficacious first-line treatment option.

KLK2 Is an Extremely Promising Prostate Cancer Drug Target

Prostate cancer has entered a new era of cell surface targeted biomarkers and therapies with the introduction of prostate-specific membrane antigen (PSMA) PET imaging and treatment with 177Lutetium-PSMA-617.1 Now that radioligand therapy against PSMA has become standard, other therapeutic approaches, including antibody drug conjugate, bispecific antibody, and cellular immunotherapy, are all being tested in clinical trials. However, PSMA is expressed in many normal tissues, including the salivary and lacrimal glands and renal tubules, which can lead to on-target, off-tumor toxicities.

Neuroendocrine Prostate Cancer…A Potential Role for Pembrolizumab and Other Newer Therapeutics?

Neuroendocrine prostate cancer (NEPC), as defined in the literature, is a heterogeneous group of cancers. The classic de novo small cell carcinoma of the prostate is quite rare, and what we typically see more often is treatment emergent NEPC. The common use of androgen receptor (AR) pathway inhibitors has led to adaptive escape mechanisms through lineage plasticity.1 Loss of AR expression and downstream signaling is occurring in approximately 20% of castration-resistant prostate cancers.2 As a result, we are seeing more metastatic castration-resistant prostate cancers reclassified as treatment-emergent NEPC.3

Finding Substitutes for Intravesical Bacillus Calmette-Guerin (BCG) for High-Risk, Non-Muscle Invasive Bladder Cancer (NMIBC) – What’s Around the Corner?

Non-muscle invasive bladder cancer (NMIBC) is a pesky topic due to high recurrence rates after transurethral resection. Prognostic factors for recurrence include number of tumors, tumor size, prior recurrence, stage, grade, and concurrent carcinoma in situ (CIS).1 Patients with high-risk features have a 60-70% likelihood of recurrence and a 10-45% rate of progression to muscle-invasive bladder cancer over a 5 year period. Intravesical Bacillus Calmette-Guerin (BCG) is the cornerstone of treatment for intermediate and high-risk disease due to its ability to stimulate an immune response that helps prevent tumor recurrence. However, BCG is not adequate to prevent relapses or frank resistance in approximately 50% of treated patients.2 To make matters more challenging, there has been a persistent worldwide shortage of BCG, coupled with increased global demand over recent years. This shortage has spurred efforts on multiple fronts: regulatory and manufacturing solutions to restore BCG supply and clinical research to identify and validate substitute treatments that can safely and effectively replace BCG therapy.

Intravesical Therapy with a TAR-200 Gem-stuffed Pretzel

Non-muscle invasive bladder cancer (NMIBC) has a long history of intravesical therapies. Intravesical treatments range from Bacillus Calmette-Guerin (BCG), valarubicin, gemcitabine/docetaxel, nadofaragene firadenovec, and most recently nogapendekin alfa inbakicept, most of which are used for BCG unresponsive NMIBC. Alternatively, intravenous pembrolizumab has FDA approval for BCG unresponsive NMIBC.

Given the convenience for urologists to manage NMIBC with intravesical therapy, with minimization of systemic adverse events, additional efforts are underway to develop more such therapies. Early localized therapy successes have driven the development of additional intravesical therapies, with consideration to extend beyond non-muscle invasive to muscle-invasive bladder cancer.

Overall Survival with Talazoparib and Enzalutamide…Is This a Game Changer or Do We Need More Data?

Germline testing, next generation sequencing, and the use of PARP inhibitor monotherapy for select patients have been part of our treatment paradigm for patients with metastatic castration-resistant prostate cancer (mCRPC) for many years now. FDA approvals exist for monotherapy with rucaparib for those with BRCA1 or BRCA2 mutated mCRPC, while olaparib has a broader label for patients with pathogenic mutations in any one of 14 homologous recombination repair (HRR) genes.

EZH2 Inhibition for Prostate Cancer; It’s Taken Awhile, but We Just May Be onto Something Here

The polycomb group protein enhancer of zeste homolog 2 (EZH2) has been a potentially promising target for prostate cancer dating back to an early Nature publication from the Chinnaiyan lab in 2002.1 In that manuscript, they showed that EZH2 is overexpressed in metastatic castration-resistant prostate cancer (mCRPC). Inhibition through genetic methods, in cell lines, decreased cell proliferation in vitro, and EZH2 expression correlated with worse prognosis, implicating a significant role of dysregulated EZH2 expression in prostate cancer progression.

Nectin-4, A Validated Target for Urothelial Cancer; Opening the Door for Novel Imaging and Therapeutic Development

We have had enfortumab vedotin for use in the clinic for patients with metastatic bladder cancer for many years now. The more recent FDA approval for enfortumab vedotin in combination with pembrolizumab on December 15, 20231 has yielded impressive results, essentially doubling the median overall survival for patients with previously untreated metastatic or locally advanced urothelial cancer.2

Testosterone Is Not the Enemy…Reconsidering Treatment Options for Metastatic Castration-Resistant Prostate Cancer

As a physician who has treated many patients with prostate cancer, I have heard the question about testosterone supplementation countless times over the years. It comes in many varieties. Most commonly the request is to help recover energy after previous androgen deprivation therapy. However, some recognize that there may be antitumor effects in some situations. I always enter such engagements with multiple disclosures that include the fact that using testosterone for antitumor therapy is not an FDA approved regimen, it is not ideal to work for many patients, especially those who do not have castration-resistant prostate cancer (CRPC), it is not for a patient symptomatic from prostate cancer, and that the testosterone level must be driven to truly supraphysiologic levels for potential efficacy.

CONTACT-02 – Signs of Activity with Cabozantinib for Prostate Cancer, Yet There Is Still More to Be Desired

Cabozantinib, an oral tyrosine kinase inhibitor against MET and vascular endothelial growth factor receptor 2 (VEGFR2), is an agent that has had success in multiple tumor types, such as renal cell, hepatocellular and medullary thyroid cancer.  There have been multiple randomized phase 3 trial attempts for patients with prostate cancer.  The COMET-1 trial randomized 1,028 men in the post docetaxel and androgen pathway inhibitor (ARPI) disease state 2:1 to cabozatinib 60 mg po qd or prednisone 5 mg po BID.  Although radiographic PFS was statistically significant in favor of cabozantinib, overall survival was negative.1  This led to the early termination of the randomized phase 3 COMET-2 trial, which was studying men with symptomatic bone metastatic castration-resistant prostate cancer, also in the post-docetaxel and post-ARPI disease state.

CD46 as an Imaging and Therapeutic Target for Prostate Cancer

CD46 is a type I membrane protein that binds to C3b and C4b, offering protection against complement-dependent cytotoxicity.1 In essence, it is an inhibitor complement receptor that serves as a negative regulator of the complement system.2 Therefore, it is logical that it would be upregulated during tumorigenesis to help early cancer cells evade immune detection and complement-dependent killing.3 In evaluating metastatic castration-resistant prostate cancer patients, CD46 mRNA levels are actually even higher than prostate-specific membrane antigen (PSMA); this could potentially be an encouraging imaging and therapeutic target, given the prior successes of PSMA-targeting in both of these areas.4

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