Dr. Mary Samplaski discusses online resources regarding male infertility.

Speaking of Urology Podcast 

Most of us are familiar with the trope of a fictional legal drama in which a key witness or piece of evidence is revealed for the first time at the critical moment of a trial. However, a “Perry Mason moment” rarely occurs in real legal disputes. The reason is simple. In most lawsuits, including cases involving alleged medical malpractice, the parties must exchange all information they will use as evidence well before the trial begins, a process known as discovery. This column provides an overview of the discovery process, the different types of discovery, and why the process is important.

During discovery, each party can request information and documents from the other parties. This process prevents “trial by ambush,” where one side does not learn what information will be presented against them until it is too late to gather evidence to rebut the accusation. Discovery is necessary for achieving fair outcomes in legal disputes.

Although there are some limits on what information can be requested, the standard for whether a discovery request is permissible is broad. Generally, a discovery request is proper when it is “reasonably calculated to lead to the discovery of admissible evidence.” In other words, parties can ask for information that cannot be used as evidence if the party can show the request might lead to uncovering admissible facts.

What are the different types of discovery?

The exchange of information in a lawsuit consists of different forms of discovery requests, including:

 Some jurisdictions have enacted rules requiring parties to voluntarily produce basic information to opposing parties even before that information is requested. Typically, a party must reveal the identity of witnesses with relevant information, documents supporting a party’s claims, and any insurance policy that may cover the cost if the plaintiff is awarded damages.

 These are open-ended questions sent to the other parties. In a case involving allegations of medical malpractice, a plaintiff may ask the defendant to provide the names of all staff members who provided care, information about the defendant’s education and work experience, and other information concerning the defendant physician’s practice. On the other side of the case, a defendant will typically request information about any medical conditions that predate the care at issue, prior lawsuits filed by the plaintiff, and details of the injuries the plaintiff claims the defendant caused.

These requests are used to obtain relevant documents or physical evidence. In a medical malpractice lawsuit, the plaintiff will request all medical records related to the care at issue. Although producing a medical record may seem simple, things are rarely as easy as providing a printed copy of a patient’s chart. Plaintiffs often request the original files from the electronic record platform. These electronic files will show when information was added to the patient’s record and whether entries have been altered. A defendant can request records from care providers who treated the plaintiff before and after the care at issue. Through these records, a defendant can gain a complete picture of a plaintiff’s medical history and the course of a plaintiff’s recovery after an injury allegedly caused by the defendant’s negligence.

 These requests consist of carefully worded factual contentions that parties must either “admit” or “deny.” This type of request can narrow the scope of a dispute. For instance, a plaintiff may ask a defendant to admit that an injury occurred. If the defendant admits the truth of the request, the parties focus on whether the injury was caused by the defendant’s actions.

 In a deposition, a witness provides sworn responses to questioning by counsel for one of the parties. Depositions are used to obtain all relevant information a witness may have. Depositions allow a party to learn everything a witness will say if they testify at trial. Moreover, if a witness’s testimony at trial is different than their deposition, the witness’s credibility can be attacked. The question will become, “Is the witness lying now or were they lying in their deposition?”

Unlike other forms of discovery where the attorney representing a party can help craft a response, depositions involve directly questioning an opposing party. Before a defendant physician is deposed, they will typically meet with the lawyer defending the case to prepare for all questions opposing counsel is likely to ask.

Very few of the malpractice cases filed each year are ever presented to a jury. However, every lawsuit will involve discovery. The information obtained and admissions made during discovery are often the deciding factors in resolving a case. As such, an understanding of the purpose and mechanisms in the discovery process is critical for any urologist involved in a legal dispute.

Articles

Any aha! moments usually come before trial begins.

Urology malpractice consult: Discovery phase could hold key to case

 he discusses how the COVID-19 pandemic has affected burnout among health care providers. You can watch part 1 of the interview here: 

https://www.urologytimes.com/view/what-factors-drive-burnout-among-health-care-providers-

Videos

In terms of physician burnout, “The pandemic has only made a bad situation worse,” says Raj S. Pruthi, MD, MHA, FACS.

How has the COVID-19 pandemic affected burnout among clinicians?

Here’s our first case; pay attention to the dates here. In 2010, we have a 58-year-old white male who presents to urology with a PSA [prostate-specific antigen] of 15 ng/mL, normal DRE [digital rectal examination]. He undergoes a TRUS [transrectal ultrasound] guided biopsy, and shows 5/12 cores positive, all Gleason group 2, which as many of you know, now has been broken out as 3+4 [Gleason grade group 2 (3+4)]. Additionally, the staging work-up, bone scan CT was negative. The patient underwent robotically assisted radical prostatectomy, and surgical pathology shows a pathologic T3a, so he had capsular involvement. Again, all Gleason grade 2; surgical margins and seminal vesicles were negative. Six months post-operation, his PSA was 0.8 [ng/mL]. Then, the patient relocates for his job and has no follow-up. Let’s go to the next slide.

He returns to the area in 3 years, and he has a PSA of 8.3 [ng/mL] now. Remember, his nadir, his 6-month PSA after surgery was 0.8 [ng/mL]. He’s completely asymptomatic. He undergoes a work-up, restaging, and he has a bone scan and CT scan, which are negative for metastatic disease. To the audience, would you start this patient on ADT [androgen deprivation therapy]? Again, he had a radical prostatectomy, pathologic T3, Gleason [group] 3+4, asymptomatic, PSA was 0.8 at 6 months, and now the PSA is 8.3 [ng/mL], completely asymptomatic. Let’s see here, two-thirds of the audience say they would start ADT; 17% said no; 16% to 17% said there’s not enough information.

Raoul Concepcion, MD, presents the case of a 58-year-old man who had a radical prostatectomy 6 months prior and discusses how aspects of the case influence treatment selection. 

Case 1: 58-Year-Old Man 6 Months Post-Radical Prostatectomy 

Wayne Kuznar is a contributor to Urology Times.

Long-term follow-up for minimally invasive water vapor thermal therapy (Rezūm System) showed durable efficacy with no sexual dysfunction in patients with lower urinary tract symptoms due to benign prostatic hyperplasia (BPH), according to a manuscript published online in the 

In a randomized clinical trial with sham control, the mean reduction in the International Prostate Symptom Score (IPSS) from baseline to 5 years in the active treatment group was 11.3 points, translating to an approximately 48% reduction from the baseline IPSS of 22, which is considered severely symptomatic.

Water vapor thermal treatment also favorably affected other outcomes measures. The mean IPSS QoL score was 4.4 at baseline compared with 2.2 at 5 years (approximately 45% reduction).

Flow rate values were 9.9 mL/sec at baseline and 14.0 mL/sec at 5 years (approximately 49% reduction). Benign Prostatic Hyperplasia Impact Index (BPHII) showed a mean decline of 45% at 5 years (mean, 2.2). The surgical retreatment rate at 5 years in the intervention group was 4.4%.

The study investigators also noted that there were no reports of sexual dysfunction related to device or procedure and no reported cases of sustained de novo erectile dysfunction at 5 years.

"This new publication provides further clinical evidence confirming the Rezūm System’s capability to provide long-lasting relief for patients suffering from BPH-related symptoms, while preserving sexual function," principal investigator Kevin McVary, MD, stated in a press release.

“Further, the Rezūm System allows physicians to effectively treat middle lobe obstructions (MLO) without advanced training or complex techniques. This is good news given the high percentage of men in the study revealed to have had an MLO (31%). With Rezūm, these patients have a long-lasting treatment option with a minimally invasive therapy,” added McVary, who is a professor of Urology at Loyola University Medical Center.

A total of 197 men aged ≥50 years old with an IPSS greater ≥13, a maximum flow rate ≤15 mL/sec, and a prostate volume of 30 to 80 cc were enrolled into the trial. They were randomized 2:1 to thermal therapy (n = 136) or sham control rigid cystoscopy (n = 61). Thermal therapy involved injection of water vapor into obstructive tissue and could include the middle lobe, if present, and/or enlarged central zone.

Overall 82 patients from the Rezūm arm had a ≥30% reduction from baseline IPSS and were free from retreatment at 5 years.

Crossover from sham to active intervention was permitted at 3 months. The crossover group, which included 53 of 61 patients from the control arm, had symptoms and flow rate reassessed at crossover. The investigators observed similar outcomes in the crossover group as in the main treatment cohort at 5 years. 

"We are dedicated to providing innovative solutions that save physicians time and improve the lives of patients. The Rezūm System is a leading, minimally invasive treatment option that provides sustained relief for men with BPH, a condition that affects millions of men each year," Meghan Scanlon, senior vice president and president, Urology and Pelvic Health, Boston Scientific, the developer of Rezūm, stated in a press release. “This new publication strongly demonstrates the long-term durability of the Rezūm System, and underscores our ongoing commitment to delivering technologies that can transform the field of urology.”

1. McVary KT, Gittelman MC, Goldberg KA, et al. Final 5-year outcomes of the multicenter randomized sham-controlled trial of Rezūm water vapor thermal therapy for treatment of moderate-to-severe lower urinary tract symptoms secondary to benign prostatic hyperplasia [published online April 19, 2021]. 

There were also no reports of sexual dysfunction related to device or procedure and no reported cases of sustained de novo erectile dysfunction at 5 years.

Water vapor thermal therapy for BPH sustains efficacy at 5 years

Jeffrey Graham, MD, discusses study results shared during the 2021 Genitourinary Cancers Symposium which suggest that for patients with the rare histology of non–clear cell renal cell carcinoma (RCC), frontline immune checkpoint inhibitor therapy could improve overall survival (OS).

The study showed that in a population of 1181 patients with non–clear cell metastatic RCC, the median OS was 28.6 months in patients receiving an immune checkpoint inhibitor–based regimen compared with 19.2 months and 12.6 month, respectively, in patients being treated with a VEGF inhibitor and an mTOR inhibitor.

The median time-to-treatment failure in those who received an immunotherapy-based regimen was also longer at 6.9 months versus 5.1 months with a VEGF inhibitor and 3.9 months with an mTOR inhibitor.

In the entire population of patients included in the analysis, the objective response rate (ORR) achieved in those who received an immunotherapy-based regimen was 25%; it was 17.8% in those who received VEGF targeted therapy and 5.8% in those who received mTOR-targeted treatment.

When looking at ORR per histologic subgroup, those with papillary disease who received VEGF treatment experienced an ORR of 13.0% versus 3.7% with mTOR therapy and 31.6% with immunotherapy-based treatment. In patients with the chromophobe subtype, the ORRs were 20.6% versus 13.6% versus 9.1% in those who received VEGF therapy, mTOR therapy, and an immunotherapy-based regimen, respectively. Those with an unclassified disease subtype experienced ORRs of 15.2%, 0%, and 33.3%, respectively.

Graham is a medical oncologist and an assistant professor at the University of Manitoba in Canada.

Frontline immune checkpoint inhibitor therapy may improve overall survival in this setting. 

Dr. Jeffrey Graham on frontline immunotherapy in non–clear cell RCC

“The patients who use statins had longer overall survival, longer prostate cancer-specific survival, and a trend towards longer time before they became castration resistant,” 

says in this podcast. Hamilton is an associate professor of urology at the University of Toronto.

Podcasts

Hamilton discusses findings from a recent study published in European Urology.

Dr. Robert J. Hamilton on statin use in men starting ADT for prostate cancer

The first patient has been diagnosed in the pivotal phase 3 ENLIGHTED trial exploring padeliporfin Immune Photo Activated Cancer Therapy (ImPACT) for the treatment of patients with low-grade upper tract urothelial cancer (UTUC), according to Steba Biotech, the developer of the investigational treatment.

The padeliporfin ImPACT platform involves the intravenous delivery and activation of the photosensitive drug padeliporfin. Once the drug is in the patient, it is “activated by a non-thermal light delivery system that uses a lower energy laser light channeled through optical fibers.”

 The minimally invasive approach enables targeted ablation of the tumor. The treatment was initially explored in prostate cancer and is now being investigated in UTUC and other solid tumors.

“The treatment of UTUC remains a clinical challenge with limited options available to effectively help our patients while avoiding the risk of significant morbidity. This study will work closely with investigators in the United States, Europe, and Israel with the goal of confirming the safety and efficacy of padeliporfin ImPACT as a promising new therapy for treating patients with urothelial cancers involving the upper urinary tract,” Jonathan Coleman, MD, principal investigator of ENLIGHTED and urologic surgeon at Memorial Sloan Kettering Cancer Center, stated in a press release.

The open-label, single-arm ENLIGHTED trial is enrolling patients with low-grade UTUC in either the ureter or the kidney. Treatment will comprise 2 phases, induction and maintenance. The target enrollment is 100 patients. Follow-up will last 1 to 5 years after treatment. The primary end point is the number of patients with absence of UTUC tumors in the entire ipsilateral calyces’ renal pelvis and ureter. This outcome measure will be assessed endoscopically. The investigators anticipate that data for the primary end point will be available in 2022.

Padeliporfin ImPACT previously received FDA Fast Track and Orphan Drug designations for the treatment of patients with UTUC. The designations are designed to expedite the review and development of novel treatments that will fill an unmet medical need.

Overall, about 6000 to 8000 new cases of low-grade UTUC occur annually in the United States. Despite some breakthroughs, there remains a high unmet need for novel UTUC treatments.

“The successful initiation of the pivotal trial for padeliporfin ImPACT is an important milestone in our ambitious new development program. Our aim is to unlock the potential of our novel oncology platform, padeliporfin ImPACT, on solid tumors with high unmet medical need. Targeting diseases such as UTUC, where surgery is either impossible or clinically undesirable could be very beneficial for patients living with these conditions. The ENLIGHTED trial is 1 of 2 clinical and 5 preclinical programs that we are advancing this year,” Dr. David Perry, head of Research and Development, Steba, stated in the press release.

1. Steba Biotech Treats First Patient in Pivotal ENLIGHTED Study of Padeliporfin ImPACT in Low Grade Upper Tract Urothelial Cancer. Published online April 20, 2020. Accessed April 20, 2020. https://bit.ly/3x9tHDF

2. Steba biotech. A Novel Treatment Path. Accessed March 8, 2021. https://www.stebabiotech.com/technology-innovation.

Padeliporfin ImPACT previously received FDA Fast Track and Orphan Drug designations for the treatment of patients with upper tract urothelial cancer. 

Phase 3 study launches of padeliporfin ImPACT for UTUC

The addition of the Oncotype DX Genomic Prostate Score (GPS) assay to standard risk counseling did not increase the selection of active surveillance (AS) among a predominantly African-American population of men with favorable-risk prostate cancer, according to findings from the ENACT trial published in the 

The ENACT trial randomized patients to standard NCCN-based risk counseling alone (control) or in combination with GPS. Across the entire population, AS selection was high; however, the choice of AS was slightly lower among patients receiving GPS, at 77% compared with 88% in the control arm. Further, in the GPS arm, patients with lower health literacy were 7 times less likely to select AS versus the control arm. In contrast, no difference in choice was observed in those patients with higher health literacy.

Adoption of AS was also independently associated with having health insurance and having a family history of prostate cancer; however, there was no independent association between race and selecting AS.

“In this trial, acceptance of AS for management of relatively favorable-risk prostate cancer was remarkably high, regardless of race, both among men who received the GPS prognostic assay and those who received only conventional risk counseling. Thus, we found that the GPS assay did not increase AS acceptance, and there was no apparent difference in its effect associated with race,” the authors wrote.

“The GPS effect was highly dependent on health literacy, with essentially no effect among men with higher literacy, but much lower adoption of AS among men with low health literacy,” the authors added.

The ENACT trial included 200 patients with very low to low-intermediate prostate cancer as defined by the NCCN guidelines. The study was conducted at 3 hospitals in Chicago: the University of Illinois at Chicago, John H. Stroger Jr. Hospital of Cook County, and the Jesse Brown VA Medical Center.

In general, patient characteristics were well balanced between the study arms. Across all patients, the median age was 63.6 years, 70% of patients were African American, 16.5% were European American, 12.5% were Hispanic/Latino, and 1% were Asian. About 56% of patients had at least some college, 16% were college graduates, 16% were self-pay/uninsured, and 29% had a family history of prostate cancer.

Disease risk level was very low for 40% of patients, low for 35% of patients, and low-intermediate for 25% of patients. The median PSA level was 5.98 ng/mL, 81% were Gleason grade group 1 (GG1; 3 + 3), and 19% were GG2 (3 + 4). IPSS (urinary function) was 9.7 and Sexual Health Inventory for Men (SHIM) score (sexual function) was 6.4.

In their manuscript, the authors noted, “Random assignment evenly balanced key variables at baseline, except for prostate cancer in a first- degree relative and Sexual Health Inventory for Men score indicating severe erectile dysfunction, which were less common in the intervention group and thus were given particular attention as potential confounders in the analysis.”

At their first visit to the hospital (V1), all patients received their diagnosis and identical counseling describing their treatment options. Also at V1, the investigators randomized the patients to standard counseling alone or standard counseling with GPS. The GPS test examines biopsy tissue and, using a model that examines expression levels of 12 genes plus clinical features, predicts outcomes. 

Visit 2 (V2) took place 2 to 3 weeks later. At V2, all patients received reinforced NCCN-based risk counseling, those assigned to GPS discussed their GPS report, and all patients made a treatment decision with their clinician. Four weeks after V2, visit 3 was held to collect patient surveys and find out whether a change in choice of treatment had occurred. The fourth visit was held at the initial clinical interaction following recovery from surgery, completion of radiation treatment, or the first clinical visit for AS monitoring.

Treatment selection at V2 was the primary end point of the study. Additionally, “The proportion of patients choosing AS was compared, and multivariable modeling was used to estimate the effects of various factors on AS acceptance,” the authors explained.

Overall, there were 191 evaluable patients, comprising 99 patients in the intervention arm and 92 patients in the control arm. There were 76 patients (77%) in the GPS arm who chose AS, compared with 81 patients (88%) in the control arm. Twenty-one patients (21%) in the GPS arm and 11 patients (12%) in the control arm selected surgery or radiation. There were 2 patients in the control arm categorized as “undecided.”

“As more biomarkers yielding probability estimates enter the clinic, it is important to understand their impact on cancer treatment choice and decision quality in diverse patient populations. Any reasonable strategy for attacking the racial disparity in prostate cancer outcomes should include AS, provided patients are judiciously selected for this option,” the authors wrote in their conclusion. “However, this strategy must also emphasize improved early detection, as highlighted by the fact that nearly three quarters of the newly diagnosed men screened for this trial were ineligible because of an excessive NCCN risk level.”

1. Murphy AB, Abern MR, Liu L, et al. Impact of a genomic test on treatment decision in a predominantly African American population with favorable-risk prostate cancer: a randomized trial [published online April 9, 2021]. 

The genomic assay did not increase use of active surveillance in a predominantly African-American population of men with favorable-risk prostate cancer.

Use of genomic test does not increase active surveillance adoption in African-American men

If that patient presented today, and came to you as a second opinion, is bone scan and CT your choice still? Describe to me what other imaging modalities you might consider.

 Thank you again for inviting me. It’s an honor and privilege to be on this panel. With regard to the current day and age, the answer to this also will depend on which geographic region you are in, because there are certain agents that are approved that are widely available, and there are others that have more limited availability, because of either half-life limitation of the agent, or the way the FDA approval has been structured. Let me expand on that. Going back first to your question, the bone scan and the CT scan would not be the standard of care now, because there are other options. These options include the PET [positron emission tomography scan]/CT agents or PET MRI, if there are certain geographic regions that have it available. The most widely available agent right now is the fluciclovine, which is a fluorine-18–based agent. It has a half-life of close to 2 hours. Therefore, for most commercial radiopharmacies around the country, there is a network sufficient that if there is any PET scanner in any geographic region in the country, they will have access to fluciclovine.

There are a few other agents, such as C-11 choline, which is available and approved. However, because of its half-life, the availability is going to be limited very close to a cyclotron, or most of the times, the sites that have a cyclotron can access that agent. As of November, or December of 2020, the very first PSMA [prostate-specific membrane antigen] agent was approved by the FDA, and that is the gallium PSMA agent. That has the approval primarily through UCLA [the University of California, Los Angeles] and UCSF [the University of California, San Francisco]. However, UCLA and UCSF have been kind enough not to hold onto the IND [investigational new drug] proprietarily, so there is access if there is a cross reference to the IND for the sites that are doing the studies and have approached the FDA to cross reference it. Finally, there are many other PSMA agents that are available through the clinical trials. So, if any one of the sites is participating in these trials, there is access to those PSMA agents that are still not approved by the FDA. However, we’ll discuss them later during our subsequent discussions on the imaging side, but that is also an available access through the clinical trials.

Perfect. We’re going to go to a second polling question. I think the audience has already seen this. If this patient presented today, and assuming you would re-stage the patient, what imaging modality would you choose? Dr Ghesani gave a nice and brief summary on this. Would the audience continue to do their first restaging technetium bone scan and CT of the abdomen and pelvis, with and without IV [intravenous] contrast, whole body MRI, fluciclovine, gallium PSMA PET, C-11 choline, or other? This will give us [an idea about], as Dr Ghesani said, what’s available out there in your various marketplaces, because it’s not equal around the country. I think your point is very well taken. I don’t think a lot of people realize that when the gallium PSMA scan was approved, that it was specifically for UCLA and UCSF.

Looking at the polling question, we’ve got about 23%, a quarter, would still do bone scan, CT. Nobody would do a whole-body MRI. Close to 50% is going to use fluciclovine. Finally, 30% are going to do gallium PSA [prostate-specific antigen]. Judd, what do you have over there at Duke [Cancer Center]?

 I really appreciated Munir’s comments. I think from an academic standpoint, he’s right on target. The problem is, at least in the trenches where I’m at in North Carolina, a lot of times insurance carriers will not cover the Axumin [fluciclovine] scan until you’ve done the bone scan and CT. Often, I don’t know if Brian’s running into that in Chicago, but you order it, and then I’ll get a call to do a peer-to-peer [discussion], which is never really a peer-to-peer, it’s someone on the other end who doesn’t really know what they’re talking about, but that’s another story. They will say, “Have you done a bone scan and a CT? We need to see a negative bone scan and a CT before we’ll pay for the Axumin.” I don’t know, that needs to change, because it’s a waste of money. Nevertheless, that’s what we’re facing in early 2021.

 I think that most clinicians, and certainly insurance companies, don’t necessarily recognize that the sensitivity of a bone and CT scan is very limited. Historically, as you said, and back even in the early to mid-2000s, and even today, we order these tests. However, half of it’s out of necessity to meet insurance standards, but the sensitivity, at levels less than 10, and less than 20 [ng/mL] certainly, are poor. Moreover, it’s been studied and suggested that up to 90% of scans at that level will be negative, but nonetheless, that’s our gold standard for what we compare against. When those studies came out, it was because choline was being FDA approved at the time, and you needed a PSA level recurrence of about 2 [ng/mL], at minimum.

Therefore, a lot of these insurance companies adopted a level that said, “Hey, not only would you have to get a CT and a bone scan first, but I want to see your patients’ PSA level at about 2 [ng/mL] before we’re going to approve that.” There is some variability there, and certainly Medicare is better, but it’s frustrating. The point here is that if we can locate that disease and we can treat this at volumes when the tumor is still small, certainly, patients are going to have better outcomes.

Post-surgery, there have been many trials that say if you treat patients at an early time, when their PSA values are between 0.2 and 0.5 [ng/mL], they’re going to do better than if we wait until those values are higher. We typically want to get these types of what we call next-generation imaging scans, or these PET/CT scans, whether it’s fluciclovine or a PSMA scans, at earlier levels, which we believe help patients better. I agree with Judd that often, I must go through those hoops, although it’s a futile exercise and extra radiation exposure to the patient. From there, the patients become frustrated because I don’t hide my angst for these hoops. But I think it’s the way that we get the right scans these days.

An expert panel reacts to polling data on choice of imaging modalities for patients with prostate patients after definitive therapy and share their insights about best practices.  

Imaging Modalities for Evaluating Biochemical Recurrence in Prostate Cancer 

A phase 2b randomized trial is launching exploring the combination of the investigational BET inhibitor ZEN-3694 and enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on a prior androgen receptor signaling inhibitor (ARSi).

Patients will be randomized to the combination or the ARSi enzalutamide alone. Previously, phase 1b/2a data published in 

 showed promising early activity with the combination.

 Zenith Epigenetics and Astellas Pharma, the developers of ZEN-3694 and enzalutamide, respectively, anticipate that the phase 2b study will officially launch in the second quarter of this year.

“We are delighted to collaborate with Astellas to continue the development of ZEN-3694 in combination with enzalutamide in mCRPC patients, who are resistant to an ARSi,” said Donald McCaffrey, President and Chief Executive Officer of Zenith.

“Data from our recently executed single arm phase 1b/2a study has shown that the aforementioned combination may prolong radiographic progression-free survival (rPFS) in mCRPC patients and particularly in a subset of patients who had a poor response to prior ARSi and whose tumors had low androgen receptor signaling activity. There is a significant unmet need in mCRPC patients who are ARSi resistant and their current treatment options only include chemotherapy with considerable side effects. We are looking forward to validating our initial clinical findings with this well-designed randomized study.”

ZEN-3694 works by inhibiting expression of the 

 gene, which blocks cellular growth in prostate cancer tumors. The phase 1b/2a study of ZEN-3694/enzalutamide enrolled patients with progressive mCRPC with prior resistance to the ARSi abiraterone acetate (Zytiga) and/or enzalutamide. Dose escalation was followed by dose expansion in parallel cohorts, which were administered ZEN‑3694 at 48 and 96 mg orally once daily, respectively. Overall, 75 patients were enrolled, including 26 and 14 in dose expansion at low- and high-dose ZEN-3694.

Thirty (40%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 mg to 144 mg daily without reaching a maximum-tolerated dose. Patients were treated for a median duration of 3.5 months (range, 0-34.7+).

The median rPFS was 9 months. Additionally, the composite median radiographic or clinical PFS was 5.5 months. The investigators also reported a link between lower androgen receptor transcriptional activity in baseline tumor biopsies and longer rPFS (10.4 vs 4.3 months).

Regarding safety, grade ≥3 toxicities occurred in 14 patients (18.7%). Of note, there were 3 patients with grade 3 thrombocytopenia.

 (NCT04471974) is examining a triplet regimen combining ZEN-3694 with the PD-1 inhibitor pembrolizumab (Keytruda) and enzalutamide in patients with mCRPC who have become resistant to first-line treatment with an ARSi.

The open-label, nonrandomized phase 2 trial is accruing patients with prostate adenocarcinoma that is histologically confirmed at diagnosis, with ensuing development of mCRPC. At the time of enrollment, there must be evidence of progressive disease as shown by PSA and/or radiographic progression (PCWG3 criteria).

1. Zenith Epigenetics Announces Clinical Collaboration with Astellas. Published online April 22, 2021. Accessed April 22, 2021. https://yhoo.it/3vdoCZe.

2. Aggarwal RR, Schweizer MT, Nanus DM, et al. A phase 1b/2a study of the pan-BET bromodomain inhibitor ZEN-3694 in Combination with enzalutamide in patients with metastatic castration resistant prostate cancer. 

. 2020;26(20):5338-5347. doi: 10.1158/1078-0432.CCR-20-1707

3. NIH US National Library of Medicine Clinical Trials.gov. ZEN-3694, Enzalutamide, and Pembrolizumab for the Treatment of Metastatic Castration-Resistant Prostate Cancer. Last updated December 22, 2020. Accessed March 17, 2021. https://clinicaltrials.gov/ct2/show/NCT04471974.

Exploration of the novel combination continues after early-phase published data showed promising clinical activity. 

Use of genomic test does not increase active surveillance adoption in African-American men

Imaging Modalities for Evaluating Biochemical Recurrence in Prostate Cancer

Combo of Novel BET inhibitor and enzalutamide advances in mCRPC pipeline

Imaging Modalities for Evaluating Biochemical Recurrence in Prostate Cancer 