Benjamin P. Saylor is associate editor of Urology Times, an Advanstar Communications publication.

Benjamin P. Saylor

Combination treatment with enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) yielded a high overall response rate (ORR) and a manageable safety profile in patients with locally advanced or metastatic urothelial cancer.

The findings, derived from Cohort K of the EV-103 trial (NCT03288545), were presented at ESMO Congress 2022 by Jonathan E. Rosenberg, MD.

“Enfortumab and pembrolizumab as monotherapy have each shown anti-tumor activity with a survival benefit in pretreated patients with locally advanced or metastatic urothelial cancer. EV-pembro was previously evaluated in the EV-103 dose escalation/Cohort A, which showed encouraging safety and efficacy activity with a response rate of 73.3%,”

 said Rosenberg, chief of the Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology, and Enno W. Ercklentz Chair at Memorial Sloan Kettering Cancer Center in New York, New York.

For the current study, “previously untreated cisplatin-ineligible patients with [locally advanced or metastatic urothelial cancer] were randomly assigned 1:1 to enfortumab vedotin (1.25.mg/kg) as monotherapy on Days 1 and 8 or in combination with P (200 mg) on Day 1 of 3-week cycles,” the authors wrote in their abstract. The primary end point was confirmed ORR by blinded independent central review. Duration of response (DOR) and safety were among the secondary end points.

In his presentation, Rosenberg stressed that the study was non comparative.

“We are not planning and we will not be performing any statistical comparisons formally between the arms. This study was really to understand the contribution of components of the different agents,” Rosenberg explained.

The patient population was predominantly male, and approximately 60% had impaired performance status. Visceral disease was presented more than 80% of patients, and approximately 40% were PD-L1 high; a proportion of patients were not evaluable because they did not have tumor to be submitted.

A total of 149 patients were included in the study, 76 of whom were treated with enfortumab vedotin plus pembrolizumab and 73 who were treated with enfortumab vedotin alone. The confirmed ORR (95% CI) for enfortumab vedotin plus pembrolizumab was 64.5%, and median DOR was not reached. Confirmed ORR for enfortumab vedotin alone was 45.2%, with a median DOR (95% CI) of 13.2 months.

Regarding adverse events (AEs), 15.6% of patients receiving enfortumab vedotin plus pembrolizumab stopped treatment due to an AE, and 24.3% of patients receiving enfortumab vedotin alone stopped treatment due to an AE. The most common AEs seen in patients receiving enfortumab vedotin plus pembrolizumab included fatigue, peripheral sensory neuropathy, alopecia, and maculo-papular rash. Eighteen (23.7%) serious treatment-related adverse events (TRAEs) were seen in the combination therapy group and 11 (15.1%) were seen in the monotherapy group. Three TRAEs leading to death (3.9%) were seen in the combination group and 2 (2.7%) were seen in the monotherapy group. Rosenberg reported that skin reactions were more frequent with patients receiving enfortumab vedotin plus pembrolizumab, although none were serious.

“Results from EV-103/KEYNOTE-869 Cohort K support the ongoing investigation of enfortumab vedotin and pembrolizumab in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who are in need of treatment options, and this combination may be an important therapeutic option for these patients,” Rosenberg said in a news release about the study.

1. Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC).

2022;33(suppl 7):LBA73. doi:10.1016/annonc/annonc1089

2. Hoimes CJ, Flaig TW, Milowsky MI, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. 

Published online August 30, 2022. doi:10.1200/JCO.22.01643

3. Seagen, Astellas and Merck Announce Results of Clinical Trial Investigating PADCEV (enfortumab vedotin-ejfv) with KEYTRUDA (pembrolizumab) and PADCEV as Monotherapy in First-Line Advanced Urothelial Cancer. News release. Seagen Inc/Astellas Pharma Inc/Merck. September 12, 2022. Accessed September 12, 2022. https://bwnews.pr/3xguTqr

Articles

The findings are from the EV-103 trial and were presented at the 2022 ESMO Congress by lead investigator Jonathan E. Rosenberg, MD.

Pembrolizumab/enfortumab vedotin combo hits high response rate in urothelial cancer

Results from a phase 3 trial evaluating perioperative nivolumab (Opdivo) in patients with renal cell carcinoma (RCC) at high risk for recurrence did not yield improved recurrence-free survival (RFS), although various analyses within the trial may help to inform future research.

The study was presented at the 2022 European Society for Medical Oncology Congress in Paris, France.

“Given the success of nivolumab in improving outcomes in metastatic renal cell carcinoma, there is tremendous enthusiasm for expanding the use of immunotherapy in those with early-stage disease at risk for recurrence,” explained lead investigator Mohamad Allaf, MD, urologist-in-chief and The Johns Hopkins Hospital Professor of Urology, Johns Hopkins University, Baltimore, Maryland.

The study population included patients with RCC with tumors greater than 7 cm or patients with smaller renal tumors with venous fat or nodal involvement. Patients with low-volume M1 disease were also included “provided it was completely resected within 12 weeks of enrollment,” Allaf said.

The study’s primary end point was RFS, which the investigators defined as time from randomization to disease recurrence or death, whichever came first. Secondary end points included overall survival, RFS for clear cell RCC, safety and tolerability, patient-reported outcomes, and correlative science.

A total of 819 patients were enrolled in the study, 404 of whom were randomly assigned to receive surgery/nivolumab of 415 to surgery/observation. In the surgery/nivolumab arm, 353 patients started neoadjuvant nivolumab, 359 received surgery, and 314 started adjuvant nivolumab. In the surgery/observation arm, 387 patients underwent surgery. Patients were closely matched by age and gender. Thirty-one patients in the surgery/nivolumab arm were Black or African American vs 30 in the surgery/observation arm, and 332 patients in the surgery/nivolumab arm were White compared with 340 in the surgery/observation arm. Approximately 50% of patients enrolled had cT1/cT2 disease, approximately 15% had cN1 disease, and approximately 3% had cM1. Approximately 75% of patients had an ECOG performance status of 0.

Post surgery, more than 60% of patients had pT3/pT4 tumors, and more than 60% had high-grade tumors. Approximately 80% of patients had clear cell RCC and approximately 5% of patients in each group underwent partial nephrectomy.

Allaf explained that a preplanned futility analysis was based on recurrence and death events.

“At approximately 71% full information time, inefficacy analysis results were presented to the Data Safety Monitoring Committee, and it was recommended that the results be released for futility,” Allaf said.

At a median follow-up of 16 months, there was no difference in RFS between the 2 groups (HR: 0.97 [95% CI: 0.74-1.28], one-sided 

“OS was not mature at the time of analysis but was not statistically different between study arms (HR: 1.48; 95% CI: [0.89 – 2.48], one-sided 

value=0.93),” the authors wrote in their abstract.

“In terms of adverse events [AEs], the observed adverse event rates and types were fairly comparable to what is seen in other nivolumab monotherapy trials,” Allaf said. Ninety-three percent of patients in the surgery/nivolumab arm experienced an AE of any grade compared with 59% in the surgery/observation arm. Thirty-three percent of patients in the surgery/nivolumab arm experienced an AE of grade 3-4 as the highest grade vs 13% of patients in the surgery/observation arm. Treatment-related AEs with incidence greater than 10% included fatigue, abdominal pain, nausea, increased creatinine, pruritus, masculo-papular rash, diarrhea, arthralgia, increased alanine aminotransferase, increased aspartate aminotransferase, and hypothyroidism.

In his concluding remarks, Allaf said, “Perioperative nivolumab did not improve RFS in patients with renal cell carcinoma at high risk for recurrence in this trial…Ongoing radiomic, pathomic, and other biomarkers analyses within this trial may inform the design of future neoadjuvant renal cell carcinoma trials. Lastly, further analysis of patient subsets with this unique trial should help inform future research.”

1. Allaf M, Kim SE, Harshman LC, et al. Phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (Pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. 

2022;33(suppl 7):LBA67. doi:10.1016/annonc/annonc1089

“Further analysis of patient subsets with this unique trial should help inform future research,” said lead investigator Mohamad Allaf, MD.

Improved RFS is not seen with perioperative nivolumab in renal cell carcinoma

A recent qualitative study with transgender and gender-diverse participants yielded several insights related to genitourinary health issues.

“Many transgender and nonbinary people are on gender-affirming hormonal therapy, yet we don't have a really clear picture of how gender-affirming hormonal therapy affects the genitourinary system. So our goal is to understand the lived experiences of people on gender-affirming hormonal therapy, as it relates to their urinary and sexual health,” said first author Paige De Rosa, MD, urology resident at the University of Iowa, Iowa City. The study was presented at the North Central Section of the American Urological Association Annual Meeting in Chicago, Illinois.

De Rosa and medical anthropologist Ana-Monica Racila, PhD, conducted semi-structured virtual interviews with 23 participants; questions covered demographics, sexual health, bathroom habits, urinary health, and reproductive health. Participant age ranged from 18 to 61 years. “Participants identified their gender using terms including nonbinary, male, transgender woman, transfemme, and transgender male. [Seven] participants were assigned male at birth and 16 were assigned female at birth,” wrote the authors.

De Rosa said one of the key findings from the interviews was the changing bathroom habits of the interviewees, “specifically holding urine until a single stall or gender neutral stall becomes available.”

“Many transfeminine people describe sitting to urinate. Some folks found that to be a gender-affirming practice, and some people felt compelled to do so by social pressures, to conform to gender norms, both for safety and just to blend in. And then notably, some transfeminine folks reported a sensation of incomplete bladder emptying when they were sitting to urinate,” De Rosa added.

De Rosa said many transfeminine participants reported increased urinary frequency when taking spironolactone. In addition, transmasculine interviewees reported pungent urine, increased sweat production, and increased perineal hair growth after starting testosterone treatment.

Participants also discussed changes in libido and their experience of orgasm, with some transfeminine interviewees reporting “an overall increase in their sensitivity to non-genital touch, as well as slower building orgasms,” De Rosa said. In addition, transmasculine participants starting testosterone noted an erotic sensation that was more localized to the genitals and an increase in their libido.

“What really was interesting to hear about was not just the physical changes that people were going through on gender-affirming hormones, but [also] how that affected them when they had lived experiences of dealing with pyelonephritis, nephrolithiasis, [urinary tract infections] […] itleads to consequences in your health… We know that people hold urine but not as much about the prevalence of urinary tract infections and young people developing pyelonephritis from holding urine all day at school, and what that feels like to them,” De Rosa said.

In their abstract’s conclusion, the investigators wrote about the goal to improve patient-provider communication.

“What we hope is that our work helps the practicing urologist become familiar with some of the common GU concerns of transgender and gender-expansive people. We want urologists to recognize the need to lower barriers to accessing gender-affirming health care. I think urologists are well poised to do that,” De Rosa told 

Specific steps urologists can take in their practice, said De Rosa, include having gender-neutral bathrooms in the office, using gender-neutral patient forms, displaying lesbian, gay, bisexual, transgender, queer, intersex, and asexual (LGBTQIA) pride flags, and training all office staff on LGBTQIA-inclusive health care practices.

1. De Rosa P, Racila A-M, Pearlman A. A qualitative study investigating transgender and gender diverse participant perspectives on gender affirming hormone therapy and the genitourinary system. Presented at: North Central Section of the AUA Annual Meeting, August 28-31, 2022, Chicago, Illinois. Abstract 14

"Our goal is to understand the lived experiences of people on gender-affirming hormonal therapy, as it relates to their urinary and sexual health,” said first author Paige De Rosa, MD, urology resident at the University of Iowa, Iowa City.

Researchers interview transgender and gender expansive individuals regarding genitourinary health issues

The use of active surveillance for men with favorable intermediate-risk prostate cancer has risen in recent years, investigators reported at the North Central Section of the American Urological Association Annual Meeting in Chicago, Illinois.

Discussing the rationale for the study, first author Raghav Madan, MD, said, “Active surveillance has been used for grade group 1, or Gleason 6 prostate cancer for quite some time with remarkable success. Those cancers are very slow growing; in relative terms, they don't advance quickly, so it's safe to actively survey them and then operate when necessary. There's been recent interest in expanding [active surveillance] to men with favorable intermediate-risk prostate cancer and examine whether that is a safe approach.” Madan is a PGY-2 urology resident at Wayne State University in Detroit, Michigan.

For the study, the investigators identified 4291 men in the Michigan Urological Surgery Improvement Collaborative (MUSIC) prostate cancer registry with favorable intermediate-risk disease. “We estimated the proportion of men with FIRPC that selected [active surveillance] by year of diagnosis. A multivariable logistic regression model was fit to assess for factors associated with the selection of [active surveillance] and used to estimate the adjusted probability of men with FIRPC selecting [active surveillance] at each contributing practice,” wrote the authors.

Of the cohort, 1326 men (31%) chose active surveillance. Use of active surveillance increased from 13% in 2012 to 45% in 2020. The investigators also observed that increasing age was associated with the selection of active surveillance, whereas grade group 2 disease on diagnostic biopsy was associated with a lower likelihood of choosing active surveillance (

The investigators also examined oncologic outcomes, and Madan noted that approximately 50% to 60% of patients were able to delay treatment by 5 years. For men undergoing radical prostatectomy, the rate of adverse pathology was slightly worse in patients opting for active surveillance, but importantly, the risk of biochemical recurrence was similar when comparing men who underwent immediate vs delayed treatment.

Senior author Kevin Ginsburg, MD, said he and his coauthors observed wide variation by practice in the use of active surveillance in this patient population.

“When we look at this from a practice standpoint, we see some practices have 50% to 60% of their men with favorable intermediate-risk prostate cancer selecting active surveillance, and we see other practices [where the number is] very low—closer to 5% to 10%. And then [there are] a lot of practices in the middle, around the 20% to 40% range. So there's still quite a remarkable amount of variability in there,” said Ginsburg, an assistant professor of urology at Wayne State University.

®, Ginsburg attributed the variability to uncertainty surrounding the use of active surveillance in men with favorable intermediate-risk prostate cancer.

“There's a question about how appropriate are these men for active surveillance? We don't quite know yet,” Ginsburg said.

Ginsburg concluded, “We just want to be thoughtful about who should be treated with favorable intermediate-risk disease. We think a lot of these men would be appropriate for active surveillance. And with diligent surveillance, I think their long-term oncological outcomes are not going to be compromised.”

1. Madan R, Paudel R, Qi J, et al. Factors associated with the use of active surveillance in men with NCCN favorable intermediate-risk prostate cancer: The initial MUSIC experience. Presented at: North Central Section of the AUA Annual Meeting, August 28-31, 2022, Chicago, Illinois. Abstract 30

Benjamin P. Saylor

Articles

Pembrolizumab/enfortumab vedotin combo hits high response rate in urothelial cancer

Improved RFS is not seen with perioperative nivolumab in renal cell carcinoma

Researchers interview transgender and gender expansive individuals regarding genitourinary health issues

Surveillance for favorable intermediate-risk prostate cancer is on the rise