Jason M. Broderick

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]. 

Articles

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

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. 

Combo of Novel BET inhibitor and enzalutamide advances in mCRPC pipeline

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

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. 

Jason M. Broderick

Articles

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

Combo of Novel BET inhibitor and enzalutamide advances in mCRPC pipeline

Water vapor thermal therapy for BPH sustains efficacy at 5 years

Phase 3 study launches of padeliporfin ImPACT for UTUC