Clinical Trials: From the Editor

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.

31 January 2023

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.

03 January 2023

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

30 November 2022

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

31 October 2022

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

28 September 2022

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.

06 September 2022

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.

15 August 2022

I’ve recently focused on metastatic castration-sensitive prostate cancer (mCSPC) as a disease state undergoing significant novel therapeutic investigation.  With the PEACE-1¹ and ARASENS² publications, the concept of triple combination therapy with androgen deprivation therapy (ADT), novel androgen pathway inhibitor, and docetaxel chemotherapy for front line treatment of patients with metastatic castration-sensitive prostate cancer is now ripe for digestion.  Beyond the triple combination therapy approach, there are yet many ongoing clinical trials for patients with this disease state.  I have recently concentrated on novel chemohormonal therapy, PD-1/PD-L1 antibody, and PARP inhibitor trials.^3-5

30 June 2022

I’ve now written many articles about PARP inhibitor use in prostate cancer.  We currently have United States Food and Drug Administration (FDA) approval, on an accelerated pathway, for rucaparib for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who harbor a deleterious BRCA1 or BRCA2 germline or somatic alteration and who have been treated with androgen receptor (AR)-directed therapy and taxane-based chemotherapy.¹  We also have full FDA approval for olaparib for the treatment of patients with pathogenic germline or somatic homologous recombination repair gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone.²  Recognizing that response rates still approximate the 40-50% range, even with DNA repair gene alteration biomarker selection, there have been many proposals for rationale combination therapies with PARP inhibitors.

03 June 2022

The most commonly recognized prostate cancer aggressive variant is a high-grade neuroendocrine carcinoma.  De novo neuroendocrine prostate cancer (NEPC) is very rare, and it is much more common to see treatment-emergent NEPC arise after treatment with androgen deprivation therapy.^{1, 2}  Some of these tumors may exhibit small cell morphology, although that is not a uniform characteristic.  By immunohistochemistry, NEPC typically has low expression of prostate lineage markers (e.g. androgen receptor [AR], NKX3.1, and HOXB13), yet high expression of neuroendocrine markers ( e.g. synaptophysin, chromogranin, and INSM1).  For this disease, it is well accepted that platinum chemotherapy is the standard of care.  Beyond that, our therapeutic options are limited, without any clear standard in patients who have previously been treated with platinum chemotherapy.

01 May 2022

Non-muscle invasive bladder cancer is a topic that I tackled in previous UroToday Clinical Trials Portal articles, including last month’s discussion.  Although transurethral resection is standard of care, recurrence rates are high.  Prognostic factors for recurrence include the number of tumors, tumor size, prior recurrence, stage, grade, and concurrent carcinoma in situ (CIS).¹  Patients with high risk features have approximately a 60-70% chance of recurrence and a 10-45% chance of progression to muscle invasive bladder cancer over a 5 year period.  Intravesical Bacillus Calmette-Guerin (BCG) is the standard for intermediate and high-risk disease, but BCG is not adequate to prevent relapses or frank resistance in approximately 50% of treated patients.²

01 April 2022

It has now been over a year since pembrolizumab received FDA approval on January 8, 2020, for treatment for Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or who have elected to not undergo radical cystectomy.  This approval was a nice step towards expanding treatment options for a patient population that harbors a clear unmet medical need. Intravesical BCG is the standard for intermediate and high-risk disease, but BCG is not adequate to prevent relapses or frank resistance in approximately 50% of patients.¹  BCG-unresponsive disease includes both BCG-refractory and BCG-relapse populations.  BCG-refractory refers to the presence of persistent high-grade cancer 6 months after the start of induction therapy or cancers that have progressed by either stage or grade 3 months after the initiation of induction therapy.²

03 March 2022

I recently wrote about “triple combination therapy” with androgen deprivation therapy (ADT), docetaxel, and a novel hormonal agent a few months ago.¹  In that article, I described a list of enrolling trials utilizing either novel hormonal, chemotherapy and/or chemohormonal strategies for patients with metastatic castration-sensitive prostate cancer.  Yet, we are fortunate, as a field, that the landscape is rapidly changing as new advances continue to be reported.