Jason Harris

In some men with intermediate-risk prostate cancer, magnetic resonance (MR)–guided focused ultrasound (MRgFUS) focal therapy may be an effective alternative to radical therapy that improves quality-of-life measures such as sexual function and urinary incontinence, according to findings shared during the 2021 AUA Annual Meeting.

“ExAblate MR-guided focal therapy using real-time MR thermometry preserves urinary incontinence and sexual function and it’s effective for grade group 2 and 3 prostate cancer cancers based on 2-year biopsy outcomes,” said lead author Behfar Ehdaie, MD, MS, a urologic surgeon at Memorial Sloan Kettering Cancer Center. “ExAblate MR-guided focused ultrasound may enable men to consider a tissue preserving approach and defer or avoid radical therapy.”

Final results from a phase 2b study (NCT01657942) of MRgFUS showed that at 24 months, 88% of men had no evidence of grade group 2 or 3 prostate cancer in the treatment area according to targeted prostate biopsy. Additionally, 60% of men had no evidence of grade group 2 or 3 disease anywhere in the prostate gland, including outside of the treatment area. Serum PSA levels decreased by almost 50% after treatment and stabilized after 6 months.

Ehdaie said that men who undergo prostatectomy or radiation therapy often experience significant declines in erectile function and urinary incontinence. Data from a study of 3262 men published in 2020 showed that, at 12 months, about 60% experienced erectile dysfunction following nerve-sparing radical prostatectomy and approximately 50% experienced the same following external beam radiation therapy.

 Men who have intermediate-risk prostate cancer, grade group 2 or 3, are often ineligible for active surveillance or experience early disease progression, up to 40% in findings from the ProtecT trial (NCT02044172), leading to surgery or radiation therapy.

Ehdaie and colleagues explored MRgFUS as an alternative therapy that reduces side effects while maintaining cancer control by targeting areas of no cancer within the prostate gland. He said the ExAblate MR-guided focus ultrasound device delivers targeted high intensity focused ultrasound therapy through the rectum. Ehdaie added that multicenter retrospective studies have shown focal therapy for prostate cancer is safe, and approximately 80% of men require no further prostate cancer-directed treatment.

Investigators evaluated MRgFUS in a single arm, multicenter trial. Men (N = 101) were treated at 7 academic centers and 1 private practice. MRgFUS was delivered focally to the lesion with a margin of normal tissue of greater than or equal to 5 mm based on planning. Treatment was monitored with real-time MR thermometry. Concurrent grade group 1 prostate cancer foci were not treated.

Men with untreated unilateral and more visible, grade group 2 or 3 prostate cancer were eligible. Patients were excluded if they were unable to undergo MRI or had large calcification between the rectum and the planned targeted treatment zone that could interfere with treatment.

Patients underwent targeted and systematic biopsies at 6 and 24 months after treatment, and examinations with quality of life measurements every 3 months.

The primary end points were efficacy and safety. Secondary end points included change in baseline patient-reported quality of life at 24 months.

The average patient age was 63 years and 86% of the cohort was White. The median PSA was 5.7 ng/mL. Eighty-four patients had at least clinical stage T1c disease. Seventy-eight percent of patients were in grade group 2 and 22% were in grade group 3.

Ehdaie said investigators recorded no serious adverse events (AEs). Most minor or moderate AEs self-resolved by 90 days. Two patients had ejaculation disorder and 1 had hematospermia beyond 90 days.

Erectile function scores were slightly worse at 24 months compared with baseline (HR, -3.5; 95% CI, -5.4 to -1.6). Ten (13%) reported no sexual activity and 81% of patients achieved erections adequate for intercourse.

Lower urinary tract symptoms were similar at baseline and 24 months (mean score difference, 1.1; 95% CI, 0.33-1.8).

“Overall, approximately 75% of men were able to achieve functional reactions after treatment at 24 months without starting a new erectile function medication,” Ehadie said. “No patients reported urinary incontinence and the estimated probability of urinary continence over time was excellent.”

1. Ehadie B, Tempany C, Holland F, et al. MRI-guided focused ultrasound (MRgFUS) focal therapy for intermediate-risk prostate cancer: final results of a phase IIb multicenter study. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-12.

2. Hoffman KE, Penson DF, Zhao Z, et al. Patient-reported outcomes through 5 years for active surveillance, surgery, brachytherapy, or external beam radiation with or without androgen deprivation therapy for localized prostate cancer. 

. 2020;323(2):149-163. doi:10.1001/jama.2019.20675

3. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. 

. 2016;375(15):1415-1424. doi: 10.1056/NEJMoa1606220

4. Guillaumier S, Peters M, Arya M, et al. A multicentre study of 5-year outcomes following focal therapy in treating clinically significant nonmetastatic prostate cancer. 

. 2018;74(4):422-429. doi:10.1016/j.eururo.2018.06.006

Articles

Magnetic resonance–guided focused ultrasound (MRgFUS) may be an effective alternative to radical therapy that improves outcomes for sexual function and urinary incontinence in men with intermediate-risk prostate cancer. 

MR-guided focal therapy emerges as alternative to radical therapy for intermediate-risk prostate cancer

A randomized phase 3 trial will evaluate TAR-200 plus cetrelimab for patients with muscle-invasive bladder cancer (MIBC).

“Patients with MIBC often have poor prognosis and are at high risk for death. Standard treatment is neoadjuvant platinum-based chemotherapy for cisplatin-eligible patients followed by radical cystectomy, which is associated with high treatment burden,” said study coauthor Stephen B. Williams, MD, MS, professor and chief of the Division of Urology at the University of Texas Medical Branch. “Trimodal therapy is another bladder-sparing treatment; however, we have shown over 50% of MIBC patients receive no definitive therapy. The combination of TAR-200 and cetrelimab is being studied to determine whether it can improve patient outcomes.”

Williams, discussing the trial during the 2021 American Urological Association Annual Meeting, went on to say that TAR-200 is a novel, intravesical drug delivery system enabling sustained release of gemcitabine into the bladder, which increases dwell time and local drug dose.

“Treatment with TAR-200 has demonstrated early clinical benefit with favorable toxicity in patients with MIBC. Cetrelimab is an investigational immunoglobulin g4 antibody that targets the PD-1 receptor, blocking signaling from both PD-L1 and PD-L2,” Williams said.

SunRISe-2 (NCT04658862) is a prospective, multicenter, open-label, randomized phase 3 study evaluating the efficacy and safety of intravesical TAR-200 plus systemic cetrelimab versus chemoradiotherapy in participants with MIBC. To be eligible, adults must have an ECOG performance status of 0 to 2, and histologically proven, newly diagnosed cT2 to T4a, N0, M0 MIBC, and they must be ineligible for or refuse radical cystectomy.

Investigators opened enrollment at 272 locations worldwide in December 2020 and hope to recruit 550 patients. Participants will be stratified based on transurethral resection of bladder tumor screening results (visibly complete vs incomplete) and screening tumor stage (T0 vs Ta/T1/Tis vs T2-T4a).

Participants in arm 1 will receive intravesical TAR-200 every 3 weeks for the first 18 weeks. Beginning at week 24, dosing will shift to every 12 weeks until 144 weeks. Cetrelimab will be dosed every 3 weeks until month 18. Patients in arm 2 will receive standard-of-care chemoradiotherapy with cisplatin or gemcitabine for up to 6 weeks, plus investigator’s choice of conventional hypofractionated chemotherapy.

The primary end point is bladder intact event-free survival (BI-EFS) defined as time from randomization to first BI-EFS event, including histologically proven MIBC, clinical evidence of nodal or metastatic disease per RECIST 1.1, radical cystectomy, or death.

Investigators will conduct primary disease assessment in both arms at week 18. They will conduct axial imaging and cystoscopy at week 24 and every 12 weeks thereafter through year 2 of the study, and then every 24 weeks through study year 5.

Key secondary end points include metastasis-free survival, overall survival, overall response rate at 18 weeks, and safety and tolerability. Exploratory end points include assessments of cancer-specific survival, time to symptomatic progression, pharmacokinetics, immunogenicity, health-related quality of life, healthcare resource utilization, and biomarkers.

MIBC is a potentially lethal disease, but many patients do not receive the recommended aggressive, curative therapy. The standard of care is radical cystectomy with pelvic lymphadenectomy or chemoradiotherapy, and the addition of platinum-based neoadjuvant chemotherapy improves survival outcomes.

 However, previous data show that neoadjuvant chemotherapy is underused, especially in the elderly and in groups with poor socioeconomic status.

In April 2018, the FDA granted Fast Track designation to TAR-200 for the treatment of patients with organ-confined or locally-advanced MIBC who are ineligible for curative therapy.

In 2019, investigators initiated a phase 1b clinical trial (NCT03518320) evaluating TAR-200 in combination with nivolumab (Opdivo) for safety, tolerability, and preliminary efficacy in patients with MIBC. The open-label, multi-center, single-arm study will enroll up to 25 patients who are scheduled for radical cystectomy. Prior to radical cystectomy, patients will receive both TAR-200 and nivolumab on day 1 of 4 consecutive 21-day dosing cycles.

1. Williams SB, Curtie C, Keegan KA, et al. SunRISe-2: A phase 3, multicenter, randomized study evaluating the efficacy of TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy in participants with muscle-invasive urothelial carcinoma of the bladder. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP13-17

2. Huo J, Ray-Zack MD, Shan Y, et al. Discerning patterns and quality of neoadjuvant chemotherapy use among patients with muscle-invasive bladder cancer

. 2019;2(5):497-504. doi:10.1016/j.euo.2018.07.009

3. Gray PJ, Fedewa SA, Shipley WU, et al. 

. 2013;63(5):823-829. doi:10.1016/j.eururo.2012.11.015

4. U.S. FDA grants Fast Track designation to TARIS for TAR-200 (GemRIS) in muscle invasive bladder cancer. News release. TARIS Bio. April 3, 2018. Accessed September 11, 2021. https://bwnews.pr/2XaB3ci

5. TARIS initiates clinical trial of TAR-200 in combination with Opdivo (nivolumab) for patients with muscle-invasive bladder cancer. News release. TARIS Bio. July 10, 2019. Accessed September 11, 2021. https://prn.to/3k4afn2

“The combination of TAR-200 and cetrelimab is being studied to determine whether it can improve patient outcomes,” says study coauthor Stephen B. Williams, MD, MS.

Phase 3 trial to evaluate TAR-200/cetrelimab for muscle-invasive bladder cancer

Among men with metastatic castration-resistant prostate cancer (mCRPC) and a body mass index (BMI) categorized as obese, both overall and disease-specific survival were higher than in men with BMIs in the overweight and normal weight categories, according to a recent analysis of three phase 3 trials.

“The BMI effect on cancer-specific mortality was also confirmed as a continuous and as a categorical variable,” study coauthor Giuseppe Ottone Cirulli, MD, a urology resident of Vita-Salute San Raffaele University in Milan, Italy, said during the 2021 American Urological Association Annual Meeting. “Additionally, the protective effect of BMI is not related to the higher dose of chemotherapy.”

Cirulli said that prior data have demonstrated the correlation between BMI and survival outcomes in prostate cancer. In this study, investigators sought to determine whether BMI among patients with mCRPC is associated with overall survival (OS) and disease-specific mortality.

Investigators identified 1577 patients in the ASCENT2 (NCT00273338), MAINSAL (NCT00988208), and VENICE (NCT00519285) trials, 655 of whom had died by the end of the studies. The median follow-up for survivors was 12 months. The Cox semi-proportional hazard model was utilized to predict for OS, while the competing risks regression was utilized to predict for cancer-specific mortality.

There were adjusted analyses for age, prostate-specific antigen, ECOG, number of metastasis, and prior therapy.

The median age was 69 years, and the median BMI was 28 kg/m

. Investigators analyzed the role of BMI on survival outcomes both as a continuous and categorical variable (<20 vs 20-25 vs 25-30 vs >30 km/m

BMI emerged as a protective factor for OS both as a continuous variable (HR, 0.96; 

= .015) and as a categorical variable (HR, 0.71; 

= .027). Similarly, BMI’s effect on cancer-specific mortality was confirmed both as a continuous (HR, 0.94; 

= .002) and as a categorical variable (HR, 0.65; 

Cirulli and colleagues selected patients from ASCENT2, MAINSAL, and VENICE because all 3 included men with mCRPC treated with docetaxel. Chemotherapy dose is determined in part by weight, but investigators determined there was no interaction between the BMI categories and the docetaxel dose (all 

In ASCENT2, patients were randomly assigned to 45 μg DN-101, 36 mg/m

docetaxel, and 24 mg dexamethasone weekly for 3 weeks of a 4-week cycle (n = 476) or 5-mg twice-daily prednisone plus 75 mg/m2 of docetaxel and 24 mg dexamethasone every 3 weeks (n = 477).

The median follow-up for patients alive at last assessment was 11.7 months. The median OS was 17.8 months (95% CI, 16.0-19.5) in the experimental arm and 20.2 months (95% CI, 18.8-23.0) in the control arm (log-rank 

 = .002). Survival remained poorer in the experimental arm even after adjusting for baseline variables (HR, 1.33; 

In MAINSAL, chemotherapy-naïve patients with progressive mCRPC were randomized to 75 mg/m2 docetaxel on day 1 and 5 mg twice-daily prednisone on days 1 to 21 and either 25 mg once-daily lenalidomide (n = 533) or once-daily placebo (n = 526) on days 1 to 14 of each 21-day treatment cycle.

The median OS was 17.7 months (95% CI, 14.8-18.8) in the lenalidomide group and was not reached in the placebo group (HR, 1.53; 95% CI, 1.17-2.00; 

= .0017). The trial was subsequently closed early due to futility.

In VENICE, 1224 chemotherapy-naïve patients with adequate organ function were assigned to 75 mg/m

 docetaxel every 3 weeks plus 5 mg twice-daily oral prednisone (5 mg twice daily). They were then randomly allocated to 6 mg/kg of aflibercept (Eylea; n = 612) or placebo (n = 612) every 3 weeks. Results showed that the median OS was 22.1 months (95.6 CI, 20.3-24.1) in the aflibercept group vs 21.2 months (95.6% CI, 19.6-23.8) in the placebo group (HR, 0.94; 95.6% CI, 0.82-1.08; 

1. Martini A, Cirulli GO, Gandaglia G, et al. The obesity paradox in metastatic castration resistant prostate cancer. Presented at: the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD05-01.

2. Scher HI, Jia X, Chi K, et al. Randomized, open-label phase III trial of docetaxel plus high-dose calcitriol versus docetaxel plus prednisone for patients with castration-resistant prostate cancer. 

. 2011;29(16):2191-2198. doi:10.1200/JCO.2010.32.8815

3. Petrylak DP, Vogelzang NJ, Budnik N, et al. Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial. 

. 2015;16(4):417-425. doi:10.1016/S1470-2045(15)70025-2

4. Tannock IF, Fizazi K, Ivanov S, et al. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. 

. 2013;14(8):760-768. doi:10.1016/S1470-2045(13)70184-0

An analysis of three phase 3 trials highlighted the "obesity paradox" in prostate cancer. 

Obesity associated with improved survival in advanced prostate cancer

The investigational combination of belzutifan (MK-6482) and cabozantinib (Cabometyx) showed promising clinical activity in patients with previously treated advanced clear cell renal cell carcinoma (ccRCC), according to findings from a phase 2 study.

Results from a cohort of 52 patients presented during the 2021 Genitourinary Cancers Symposium showed that the combination shrank tumors in 88% of patients and led to a disease control rate of 90%. When presenting the data, lead study author Toni K. Choueiri, MD, expressed cautious optimism about the findings.

“These preliminary, interim results for the combination of belzutifan and cabozantinib showed promising activity in previously treated metastatic clear cell RCC,” said Choueiri, director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute (DFCI)/Brigham and Women’s Hospital and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School. “We believe that targeting the underlying pathology of clear cell RCC, targeting the transcription factor HIF-2α with belzutifan and targeting downstream with the VEGF receptor inhibitor, among other kinases, cabozantinib could be an effective treatment for patients with metastatic clear cell RCC.”

Investigators for the ongoing trial (NCT03634540) analyzed 41 patients for efficacy. The confirmed objective response rate (ORR) was 22% (9/41); all responses were partial responses. Investigators also observed another 5 (12%) unconfirmed partial responses. Twenty-eight (68%) patients had stable disease as best responses. The median duration of response was not reached, and all confirmed responses were still ongoing as of data cutoff of October 15, 2020. The median time from enrollment to data cutoff was 8.9 months.

The researchers are still enrolling a cohort of untreated patients into the study.

Eligible patients were assigned to 120 mg belzutifan plus 60 mg cabozantinib orally once daily for 21 days. This efficacy analysis includes patients who received at least 1 dose of treatment and had an opportunity for at least 6 months of follow-up.

The progression-free survival (PFS) rate was 78% at 6 months and 65% at 12 months. Choueiri noted that 95% of patients were alive at 6 months.

“The median should not be considered real given only 1 patient was at risk at month 17, [but] the median PFS here was 16.8 months,” he said.

David A. Braun, MD, PhD, a physician and investigator with Dana-Farber, urged caution. He delivered a discussant on Choueiri’s presentation. “The median follow up was only about 11 months and the minimum follow up only 5.6 months. This is interesting and potentially exciting, but we really need to have further follow up.

“When we look at the PFS curve, which looks impressive, it’s a median of 16.8 months. But, again, there are very few patients that are out that far. It’s definitely preliminary.”

Nearly all (98%) of patients experienced any-grade treatment-related adverse events (TRAEs). Grade 3 TRAEs were fairly common (60%), but there was no incidence of grade 4/5 TRAEs.

Six (12%) patients discontinued belzutifan due to treatment-emergent AEs and 8 (15%) discontinued cabozantinib. Seven (13%) patients experienced serious TRAEs.

In July 2020, the FDA granted breakthrough therapy designation to belzutifan for the treatment of patients with von Hippel-Lindau (VHL) disease-associated RCC with nonmetastatic RCC tumors smaller than 3 cm in size unless immediate surgery is required. The agency also granted orphan drug designation to belzutifan for VHL disease.

 Both designations were based on data from a phase 2 trial evaluating patients with VHL-associated clear cell RCC that was presented at the 2020 American Society of Clinical Oncology Annual Meeting.

Results showed that the agent induced a confirmed ORR of 27.9%; all responses were partial response. Notably, most (86.9%) of the patients on the trial experienced a reduction in the size of their target lesions.

Previous data from a phase 1/2 trial (NCT02974738) showed encouraging single-agent activity with belzutifan in patients with heavily pretreated clear cell RCC, a benefit that was observed across all International Metastatic RCC Database risk groups analyzed.

In 55 patients enrolled to the dose escalation/expansion cohort of the trial, the ORR was 24% with the agent, while the disease control rate was 80%. The ORR was comprised of 13 confirmed PRs. Moreover, the median PFS reported with belzutifan in the overall patient population studied was 11.0 months. At 1 year, 49% of patients remained progression free.

1. Choueiri TK, Bauer TM, McDermott DF, et al. Phase 2 study of the oral hypoxia-inducible factor 2α (HIF-2α) inhibitor MK-6482 in combination with cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). 

. 2021;39(suppl 6; abstr 272). doi: 10.1200/JCO.2021.39.6_suppl.272

2. FDA grants breakthrough therapy designation to Merck’s novel HIF-2α inhibitor MK-6482 for treatment of certain patients with Von Hippel-Lindau disease-associated renal cell carcinoma. News release. Merck. July 29, 2020. Accessed February 13, 2021. bit.ly/3qkNRGK

3. Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. 

. 2020;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003

4. Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II of the oral HIF-2α inhibitor MK-6482 in patients with advanced clear cell carcinoma (RCC). 

. 2020;38(suppl 6):611. doi:10.1200/JCO.2020.38.6_suppl.611

The combination regimen shrank tumors and led to disease control in the majority of patients.

Jason Harris

Articles

MR-guided focal therapy emerges as alternative to radical therapy for intermediate-risk prostate cancer

Phase 3 trial to evaluate TAR-200/cetrelimab for muscle-invasive bladder cancer

Obesity associated with improved survival in advanced prostate cancer

Combo of belzutifan plus cabozantinib active in advanced kidney cancer