Clinical Trials: From the Editor

01 February 2025

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

02 January 2025

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.

02 December 2024

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.

01 November 2024

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

01 October 2024

The world of genitourinary oncology is and should be quite enamored with radioligand therapy for men with prostate cancer.  The recent regulatory approvals that followed ¹⁷⁷Lu-PSMA-617 after the positive survival results from the VISION trial,¹ and the recent radiographic progression-free survival results from the PSMAfore trial in the earlier chemotherapy-naive metastatic castration-resistant prostate cancer disease state are compelling.²  This data is recently followed with data from the SPLASH trial, where ¹⁷⁷Lu-PNT2002 has shown a significant radiographic progression free survival benefit in the chemotherapy-naïve metastatic castration-resistant prostate cancer disease state.³  We will await to see what regulatory agencies do with the data from both the PSMAfore and SPLASH trials and whether radioligand therapy use moves earlier in the treatment paradigm.

30 August 2024

Six Transmembrane Epithelial Antigen of the Prostate (STEAP1) is a member of a family of metalloreductases that have ability to form heterodimers or heterotrimers with other STEAP family proteins.¹  The function of STEAP1 is quite broad.  It has known functional roles in cell proliferation, invasion, and epithelial to mesenchymal transition (EMT).^2-4  STEAP1 is an antigen highly expressed in most prostate cancers, with limited normal tissue expression.²  STEAP1 is especially highly expressed in metastatic castration-resistant prostate cancer in both metastatic lesions to the bone and also in lymph nodes.⁵  For this reason, it has been considered a highly promising therapeutic target for novel drug delivery systems for men who harbor metastatic castration-resistant prostate cancer.

01 August 2024

Tivozanib is a highly selective, oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor that is indicated for the treatment of adults with relapsed or refractory advanced renal cell carcinoma following two or more prior systemic therapies.¹ The regulatory approvals through the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) were based on data from the TIVO-3 randomized phase 3 trial of tivozanib 1.34 mg orally daily versus sorafenib, which showed improved progression-free survival at a median of 5.6 versus 3.9 months, respectively.² This was a third or fourth line patient population as the patients were mandated to have all received at least 2 prior systemic therapies, including at least one previous VEGFR inhibitor.

01 July 2024

Sacituzumab govitecan is an antibody drug conjugate that targets TROP-2, a cell-surface glycoprotein highly expressed by bladder cancers. The payload on Sacituzumab govitecan is SN-38, the active metabolite of irinotecan. Sacituzumab govitecan offers a progression-free (PFS) and overall survival (OS) benefit in patients with metastatic triple-negative breast cancer who have previously received at least two prior therapies for metastatic disease.¹ Subsequently, the TROPiCS-02 trial showed both PFS and OS benefit in patients with confirmed hormone receptor positive and HER2 negative locally-recurrent, inoperable, or metastatic breast cancer.² These patients had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor as well as 2 to 4 previous chemotherapy regimens for metastatic disease.

03 June 2024

Neuroendocrine cancers of the genitourinary tract are poorly differentiated with an awful prognosis. Most commonly, small cell carcinoma of the lung draws the most attention, and treatment of high-grade neuroendocrine carcinomas tends to follow the treatment paradigms for lung neuroendocrine tumors. Although de novo neuroendocrine carcinomas of the genitourinary tract are rare, we are seeing greater incidence due to treatment resistance, as a result of potent androgen receptor (AR) directed therapies for patients with prostate cancer.¹ Loss of AR expression and downstream signaling is now occurring in approximately 20% of castration-resistant prostate cancers.² As a result, treatment-emergent neuroendocrine tumors are essentially reprogramming through lineage plasticity.³

01 May 2024

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

01 April 2024

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.

01 March 2024

PD-1 and PD-L1 have had a significant clinical impact as an immunotherapy target for patients with multiple genitourinary malignancies, including bladder and renal cancers. We continue to find new settings and novel combinations for the use of the antibodies that target these checkpoints for our patients with genitourinary cancers. For example, just a few weeks ago, at ASCO GU 2024, we saw the data release from the AMBASSADOR randomized phase 3 clinical trial, offering supportive data for the use of pembrolizumab for adjuvant therapy for those with high-risk features after radical cystectomy for muscle invasive urothelial bladder cancer.¹ However, there is still an urgent need to identify new immunotherapy targets and develop new therapies to manipulate those targets.

01 February 2024

Metastatic castration-sensitive prostate cancer (mCSPC) is a disease state where the benefits of treatment intensification are clear. Androgen receptor pathway inhibitors (ARPIs) offer overall survival benefit when added to conventional androgen deprivation therapy (ADT). The specific ARPIs include abiraterone acetate,^1,2 enzalutamide,^3,4 and apalutamide.⁵ Docetaxel chemotherapy offers survival benefit for patients with high volume disease,⁶ and either abiraterone⁷ or darolutamide⁸ offer survival benefit when added to ADT and docetaxel for patients, especially for those with de novo and high-volume mCSPC.

02 January 2024

Immunotherapy for prostate cancer is a loaded topic. This is one of the first solid tumors to instill immunotherapy as a standard of care, with sipuleucel-T offering a survival benefit for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer.¹ To rewind even further back, our field of genitourinary oncology has been using immunotherapy, with Bacillus Calmette-Guerin (BCG), for non-invasive muscle invasive bladder cancer. Yet, the rest of the field of oncology has seen dramatic gains with immunotherapy, especially in the form of checkpoint inhibitors; its use has become common practice for most cancers. Unfortunately, prostate cancer has not seen major immunotherapy advances, with accumulation of many negative randomized phase 3 trial attempts, spanning vaccines, like Prostvac,² and checkpoint inhibitors, like anti-PD-(L)1^3,4 or anti-CTLA-4^5,6 antibodies.

01 December 2023

Metastatic castration-sensitive prostate cancer (mCSPC) is a disease state that has grown in complexity, with arguably some of the greatest gains in our field of genitourinary oncology. That’s because the benefits of treatment intensification are indisputable with outstanding clinical trial hazard ratios and large median overall survival benefits. To briefly summarize, androgen receptor pathway inhibitors (ARPI) offer overall survival benefits when added to conventional androgen deprivation therapy (ADT). These benefits extend to abiraterone acetate,^1,2 enzalutamide,^3,4 and apalutamide.⁵ Docetaxel chemotherapy offers survival benefit for patients with high volume disease,⁶ and either abiraterone⁷ or darolutamide⁸ offer survival benefits when added to ADT and docetaxel for patients with de novo and high-volume mCSPC. There is also supportive data for low volume prostate cancer to apply prostate directed radiation for survival benefit from a subgroup analysis of the STAMPEDE trial.⁹

01 November 2023

Von Hippel-Lindau (VHL) loss is a near critical event for clear cell renal cell carcinoma, the most predominant histologic subtype of kidney cancers. The actual VHL genetic syndrome is an autosomal dominant inherited disorder resulting from a deletion or mutation in the VHL gene, which is located on the short arm of chromosome 3. The clinical phenotype manifests with the development of clear cell renal cell carcinomas, pheochromocytomas, pancreatic neuroendocrine tumors, and hemangioblastomas.¹ However, the inherited syndrome is not mandatory for clear cell renal cell carcinoma development, as the 3p chromosomal region is lost in 91% of these tumors.² Subsequent loss of heterozygosity generally occurs through mutation or hypermethylation, resulting in biallelic inactivation of the VHL tumor suppressor gene.³

03 October 2023

It has been almost 6 years, since I’ve talked about the fibroblast growth factor receptor (FGFR) family in the Urotoday Clinical Trials Portal.¹ Since then, the United States Food and Drug Administration granted accelerated approval to erdafitinib for patients with locally advanced or metastatic urothelial carcinoma, with susceptible FGFR3 or FGFR2 genetic alteration, that has progressed during or following platinum-containing chemotherapy, including within 12 months of perioperative platinum-containing chemotherapy.² This accelerated approval was based on tumor response rate from the phase 2 trial,³ and required confirmation of clinical benefit from additional clinical trials.

01 September 2023

Like HER2, HER3 is a receptor tyrosine kinase that plays a key role in cell growth and survival signaling pathways. Together, along with epidermal growth factor receptor, EGFR (HER1), and HER4, they make up the EGFR family. These are all well-known targets for diseases like lung and colon cancer with EGFR, and breast and gastric cancer with HER2. In earlier articles, I’ve mentioned how important HER2 might be for urothelial bladder cancer.^1,2 Similarly, HER3 has a significant role in disease progression and treatment resistance of multiple genitourinary cancers, particularly prostate cancer.³ As a result, targeting HER3 may be a fruitful therapeutic strategy.

24 July 2023

PSMA is all the craze in the field of prostate cancer. We now sensitively image PSMA on prostate cancer with using various PET imaging radiotracers. We also are therapeutically targeting PSMA using radioligand therapy, with the regulatory approval of 177Lutetium-PSMA-617 as the first example of this class of agents.¹ This is likely the first of many other PSMA-targeted radioligand therapies. Yet, many other viable mechanisms of therapeutic targeting of PSMA are currently being explored with antibody-drug conjugates, bispecific antibodies, and even CAR-T cell therapeutics.

30 June 2023

Antibody drug conjugates (ADCs) have now worked their way into the standard treatment of many malignancies, including urothelial carcinoma. We already have FDA approvals for both Enfortumab vedotin¹ and Sacituzumab govitecan² for patients with advanced urothelial carcinoma. Some of the advantages of this class of agents include high objective response rates, reasonable durability, and acceptable adverse event profiles, as the chemotherapeutic payload is delivered directly to the target to decrease systemic toxicity.