Wayne Kuznar

The benefits of minimally invasive water vapor thermal therapy (RezÅ«m System) on lower urinary tract symptoms due to benign prostatic hyperplasia (BPH) are durable, with a reduction in symptom score and an improvement in flow rate sustained to 5 years, according to researchers. In addition, treated patients maintain their sexual function.

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 10.4 points, compared with a mean reduction of 11.2 points at 3 months, reported Kevin McVary, MD, during the 

American Urological Association 2020 Virtual Experience.

 Baseline score on the IPSS was 22, which is considered severely symptomatic.

The change from baseline in maximum urinary flow rate was 6.4 mL/sec at 3 months and 4.3 mL/sec at 5 years. Flow rate values were 9.9 mL/sec at baseline, 16.4 mL/sec at 3 months, and 14.0 mL/sec at 5 years, with no statistical difference in values between 3 months and 5 years.

“Symptoms improve and they stay improved,” McVary said. “Men respond forcefully with a strong urinary flow, starting at the 3-month mark, and again, it is maintained over the 5-year period.”

Water vapor thermal treatment also favorably affected other outcomes measures. The surgical retreatment rate at 5 years in the intervention group was 4.4%, which was identical to years 3 and 4, compared with 3.7% at 2 years. Some 11.1% of the men in the intervention arm initiated medication for BPH at 5 years.

These rates compare favorably to the rates observed with other therapies, said McVary, professor of urology at Loyoloa University Medical Center in Maywood, Illinois. “The surgical retreatment rate is exceedingly positive compared to what we see over the field,” he said. “It is a pronounced strength of this technology that these retreatment rates are very impressive.”

A total of 197 men greater than or equal to 50 years old with an IPSS greater than or equal to 13, a maximum flow rate of 5 to 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 or sham control rigid cystoscopy. Thermal therapy involved injection of water vapor into obstructive tissue and could include the middle lobe, if present, and/or enlarged central zone.

Crossover from sham to active intervention was permitted at 3 months. The crossover group, which included 53 patients, had symptoms and flow rate reassessed at crossover.

The trial was notable in that 35% of patients at study entry had an obstructed middle lobe. “One of the strengths of the technology is the ability to treat the middle lobe,” said McVary. “Men with middle lobes are often excluded from clinical trials of minimally invasive surgical treatments. When we compared men with a middle lobe to those without a middle lobe in our study, we see nearly identical responses in every category.”

Five-year data for sexual function were not presented but should be available soon. “At least up to 4 years, this technology has had a minimum impact on sexual function,” McVary said.

Disclosure: The study was funded by Boston Scientific Corp.

Articles

The benefits of minimally invasive water vapor thermal therapy (Rezūm System) on lower urinary tract symptoms due to benign prostatic hyperplasia are durable, with a reduction in symptom score and an improvement in flow rate sustained to 5 years, according to researchers.

Water vapor thermal therapy results found durable at 5 years

Disease progression within 6 months was the strongest surrogate marker for overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer treated with combination therapy in a retrospective analysis of the CHAARTED trial.

Although metastatic-free survival is a standard surrogate for OS in men with nonmetastatic prostate cancer, the best predictor of OS in the metastatic hormone-sensitive setting has not been established.

The data were presented in poster format at the 

“We feel that this information has several important clinical implications,” coauthors John Pfail, MD candidate (class of 2021) at the Icahn School of Medicine at Mount Sinai Hospital in New York, New York, and Alberto Martini, MD, from UniversitÃ  Vita-Salute San Raffaele, in Milan, Italy, said via email. “First, it can be used for patient counseling for individuals who have progressed within the first 6 months of treatment. Second, it can be used for early identification of those individuals who might benefit from second-line treatments or might be enrolled in trials aimed at evaluating the role of novel therapies.”

In the CHAARTED trial, patients with metastatic hormone-sensitive prostate cancer were randomized to androgen-deprivation therapy (ADT) or ADT plus docetaxel. Response by prostate-specific antigen level, progression, and development of castration-resistant prostate cancer (CRPC) within 6 and 12 months were examined as a potential surrogate for OS in 790 patients from the study-393 who received ADT alone and 397 who received ADT plus docetaxel.

The investigators used the proportion-of-treatment effect (PTE) to measure how much of the OS outcome could be explained by the surrogate. The PTE is calculated from 2 proportional hazards models and is computed as 1 minus the ratio of the estimated regression coefficient for treatment effect in the adjusted model (model containing the surrogate) over the estimated regression coefficient for treatment in the unadjusted model.

“To the best of our knowledge, this method [PTE] is widely accepted in the scientific community and has been used in numerous analyses to validate potential surrogates,” according to the co-investigators, working under William K. Oh, MD, chief of the Division of Hematology and Medical Oncology at Mount Sinai Hospital.

Four intermediate clinical end points emerged as surrogates:

• Progression within 6 months (HR, 5.70; 95% CI, 4.26-7.64; 

• Progression within 12 months (HR, 7.09; 95% CI, 5.16-9.76; 

• Development of CRPC within 6 months (HR, 5.11; 95% CI, 3.81-6.85; 

• Development of CRPC within 12 months (HR, 6.24; 95% CI, 4.58-8.51; 

Of these, progression within 6 months had the highest PTE at 88%, followed by development of CRPC within 6 months (80%), progression within 12 months (52%), and development of CRPC within 12 months (46%).

“According to our analyses, progression within 6 months can identify almost 9 out of 10 men that will ultimately die from any cause,” according to the coinvestigators.

The 2-year OS rate for patients who progressed within 6 months of randomization was 42%, compared with 89% for the men who did not progress that quickly.

“According to our study, among the patients that were alive and not censored 6 months after randomization and did progress on treatment, the survival rate was almost one-fourth after 2 years. The prompt administration of second-line therapies or the exploration of novel medications for this patient category might potentially translate to a survival benefit for this patient population,” the coauthors indicated.

The study is the first to evaluate potential surrogates for metastatic hormone-sensitive prostate cancer and should be validated in other datasets, they added. “Nonetheless, if a novel medication determines an unprecedented response in terms of progression within 6 months from patient randomization, then regulatory agencies might consider expediting approval of such a medication,” they wrote.

Whether patients who progressed within 6 months from randomization did so because of an intrinsic resistance to docetaxel or the presence of a lethal phenotype due to specific genomic alterations, or a combination of both factors, is not known.

“It would be interesting to see if patients could be clustered from a genomic standpoint, according to the potential response within 6 months of therapy and use this eventual genomic classifier as a stratification factor in future trials,” the coinvestigators wrote.

Disease progression within 6 months was the strongest surrogate marker for overall survival in patients with metastatic hormone-sensitive prostate cancer treated with combination therapy in a retrospective analysis of the CHAARTED trial.

6-month progression is strong survival surrogate in mHSPC

Compared with local radiation therapy (RT), radical prostatectomy (RP) as primary treatment for prostate cancer may result in a lower risk of castration-resistant disease and superior overall survival (OS) from the time of metastasis.

In a retrospective analysis of a nationwide database of men who had undergone prior RT or surgery for localized prostate cancer, those who received radiation were found to have a 32% adjusted higher risk of developing a castration-resistant state compared with those undergoing RP, reported Mohammed Shahait, MBBS, in a poster presented at the 

On multivariable analysis, after developing metastatic disease, mortality was significantly higher among the men who received RT alone versus those who underwent RP (

The findings come from an examination of the Flatiron Health electronic health record–derived database, which includes about 2.5 million patients with cancer.

“Metastatic prostate cancer is a heterogeneous disease and includes men with de novo metastases upon presentation and a subgroup who present with local disease who underwent a local treatment and then progress to metastasis,” said Shahait, who was a clinical instructor in urology at the University of Pennsylvania in Philadelphia, at the time of the study. “Most of the data in the literature mix these patient groups when assessing outcomes, and we believe that it’s wrong from a biologic point of view. Therefore, we aimed to study only patients who received local treatment and progressed to metastases to have a more homogeneous cohort.”

The cohort consisted of 664 patients who had received prior RP with or without adjuvant radiation (n = 310) or RT alone (n = 354) for local disease and had progressed to metastatic disease between 2010 and 2018.

At the time of metastasis, patients in the RP group were younger (63.8 ± 7.25 vs 69.3 ± 7.67 years; 

<.0001), had a lower prostate-specific antigen (PSA) level at prostate cancer diagnosis (7.8 vs 10.9 ng/mL; 

<.0001), and were more likely to have a Gleason score greater than or equal to 8 (64.5% vs 54.5%; 

= .0089). The men in the PR group also had lower PSA levels at the time of metastasis compared with those in the radiation group (6.4 vs 17.2 ng/mL; 

<.0001). The group treated with radiation was more likely to receive androgen-deprivation therapy (ADT) before metastasis compared with the RP group (76% vs 60.7%; 

The association between prior local treatment and progression to castration-resistant state and OS was tested, adjusting for age, race, PSA level, Gleason score, castration-resistant state, administration of ADT before metastasis, and treatment year.

“As urologists and radiation therapists, we don’t know what happens to all patients after metastasis because most of the management is led by medical oncologists. The focus here is to see what would happen after metastasis,” said Shahait, who is a urology consultant at King Hussein Cancer Center, Amman, Jordan.

Median follow-up from the date of metastasis was 30 months for the RP group and 29.4 months for the radiation group. The unadjusted hazard ratio for castration-resistant state in the group that received radiation was 1.45 (

<.001). The association remained significant upon adjusting for patient- and disease-specific parameters (HR, 1.326; 

On multivariable analysis, men who received radiation alone had 77% higher overall mortality after developing metastatic disease (

= .0013) compared with men who underwent RP.

Notwithstanding the inherent selection bias at the time of choosing the type of local treatment because of unmeasured confounding variables, the results add to a growing body of evidence that support the benefit of extirpation of the primary disease on OS after developing metastatic disease, the researchers concluded in their poster.

One theory for the finding is that early use of ADT as well as RT may potentiate epithelial-mesenchymal transition, which mediates tumor invasion, metastasis, and development of castration-resistant tumors, leading to a worse outcome, Shahait said.

Compared with local radiation therapy, radical prostatectomy as primary treatment for prostate cancer may result in a lower risk of castration-resistant disease and superior overall survival from the time of metastasis.

RP leads to better survival vs radiation from time of metastasis

Durvalumab (IMFINZI) appears to be feasible as neoadjuvant therapy with preliminary evidence of antitumor activity in patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy.

From cohort 1 of a single-center sequential multicohort trial, all 10 patients who entered completed all three doses of durvalumab per protocol and proceeded to radical cystectomy, with only one patient experiencing a grade 3 treatment-related adverse event ([TRAE] anemia), reported Guru P. Sonpavde, MD, and colleagues at the Genitourinary Cancers Symposium in San Francisco.

Eight of the 10 patients had at least 12 weeks of follow-up at the most recent analysis in October 2019. Of the eight, two (25%) had a pathologic response, defined as less than pT2N0 disease, and one (12.5%) had a pathologic complete response (pCR), defined as pT0 disease.

There is no established neoadjuvant therapy for patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy preceding radical cystectomy. Prospective data with PD-1/PD-L1 inhibitors, including pembrolizumab (Keytruda) and atezolizumab (Tecentriq), are encouraging, indicating safety and activity in this setting, said Dr. Sonpavde, director of the Bladder Cancer Program, Dana-Farber Cancer Institute, Boston.

Durvalumab is a PD-L1 inhibitor approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma following platinum-based chemotherapy, but its performance in the neoadjuvant setting had not been tested previously.

“The goal in this phase I trial was primarily to demonstrate feasibility and safety of using durvalumab before radical cystectomy for muscle-invasive bladder cancer. Achieving pCR was a secondary endpoint, which needs to be evaluated in a larger trial employing and powering the trial for pCR as the primary endpoint,” Dr. Sonpavde told 

The data presented here were from cohort 1 of the study, which assessed durvalumab at a dosage of 750 mg intravenously (IV) every 2 weeks for three cycles followed by radical cystectomy 2 to 4 weeks after the last durvalumab dose in patients who were ineligible for or declined chemotherapy.

“Population pharmacokinetic modeling of durvalumab supports the switch from the 10 mg/kg IV every 2 weeks schedule to a ï¬at-dosing regimen of 750 mg IV every 2 weeks, or a regimen of 1,500 mg every 4 weeks IV,” said Dr. Sonpavde.

Cohort 2 is examining durvalumab plus oleclumab, a CD73 antagonist monoclonal antibody that enhances the immune response, in 10 patients with cT2 to T4a N0M0 muscle-invasive bladder cancer.

Patients in cohort 1 were a median age of 67 years, 80% were men, and 100% were Caucasian. Eight had clinical stage T2 disease at baseline, one had stage T3, and one had stage T4. Five were not eligible for cisplatin due to grade >1 hearing loss, three due to creatinine clearance level <60 mL/min, and one due to both grade >1 hearing loss and low creatinine clearance. One patient declined chemotherapy.

No dose-limiting toxicities were observed and no TRAEs led to treatment discontinuation. The most frequent TRAEs of any grade were fatigue (n=3), an increase in lipase (n=2), and dry skin (n=2), all of which were grade 1 or 2. Six of the eight patients (75%) who proceeded to surgery underwent cystoprostatectomy; one underwent cystectomy plus hysterectomy, bilateral salpingo-oophorectomy, and anterior vaginectomy; and one underwent cystectomy plus anterior pelvic exenteration.

“While it is reasonable to hypothesize that pCR with PD1/L1 inhibitors translates into prolonged survival (similar to the neoadjuvant chemotherapy setting), validation is required,” Dr. Sonpavde said.

AstraZeneca provided funding for the study. For full disclosures, see 

Author | Wayne Kuznar

Articles

Water vapor thermal therapy results found durable at 5 years

6-month progression is strong survival surrogate in mHSPC

RP leads to better survival vs radiation from time of metastasis

Neoadjuvant durvalumab feasible in muscle-invasive bladder Ca