Clinical Trials: From the Editor

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.

01 June 2023

Checkpoint inhibitor immunotherapy is regularly used for patients with urothelial carcinoma for many disease states now. Although the research started in the advanced disease scenarios, these immune-oncology agents have been imported earlier and earlier in the treatment paradigm. Monoclonal antibodies targeted PD-(L)1 now hold regulatory approvals in the United States for patients with metastatic disease who are 2nd-line and beyond,¹ for maintenance therapy using avelumab for patients with stable disease or response after platinum chemotherapy,² for first-line platinum-ineligible patients,³ most recently for first-line cisplatin-ineligible patients with metastatic disease using pembrolizumab in combination with enfortumab vedotin,⁴ for adjuvant therapy with nivolumab,⁵ and for BCG unresponsive non-muscle invasive bladder cancer with pembrolizumab.⁶

02 May 2023

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

03 April 2023

We now have FDA approval for the PARP inhibitor, olaparib, in prostate cancer, for men who harbor any one of many potential homologous recombination repair (HRR) gene mutations.¹ However, we have not seen extreme efficacy beyond the BRCA2 population of patients. In the PROFOUND randomized phase 3 trial that showed the survival benefit of olaparib over standard novel hormonal therapy for men with HRR-deficient metastatic castration-resistant prostate cancer, patients with ATM alterations had notably less profound outcomes with olaparib.²

01 March 2023

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.