Superior outcomes were observed in men with intermediate-risk prostate cancer who received magnetic resonance (MR)-guided focused ultrasound (MRgFUS) focal therapy than patients in the same population were treated with radical prostatectomy or radiation therapy, demonstrate findings from a phase 2b study (NCT01657942) presented at the 2021 American Urological Association Annual Meeting.

“ExAblate MR-guided focal therapy using real-time MR thermometry preserves urinary incontinence and sexual function and it’s an effective for grade group 2 and 3 prostate cancer cancers are 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 focus ultrasound may enable men to consider a tissue preserving approach and defer or avoid radical therapy.”

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.”

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.

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

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

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

Patients with prostate cancer fared better following treatment with magnetic resonance-guided focused ultrasound focal therapy than with radical prostatectomy or radiation therapy, shows study presented at 2021 AUA Annual Meeting.


 Men with Intermediate-Risk Prostate Cancer Experience Improved Sexual Function, Urinary Continence Following MRgFUS Therapy

Apalutamide (Erleada) was associated with high adherence rates and favorable prostate-specific antigen (PSA) response in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), suggest real-world evidence (RWE) presented at the 2021 American Urological Association Annual Meeting.

The analysis included data for 193 patients from routine urologic practice; investigators stratified results by Black vs non-Black patients. PSA response was defined as a minimum of 50% decline from baseline PSA; adherence was assessed using the medication possession ratio, defined as the number of days of supply within the entire exposure to therapy.

PSA response in the first 6 months after initiating apalutamide was observed in 83.5%, 86.5%, and 84.1% of patients in the overall (n = 176), Black (n = 29), and non-Black cohorts (n = 126), respectively, who had both pre- and post-index PSA measurements. At the 12 months, PSA response was reported in 86%, 93.1%, and 85.9% of patients in the overall (n = 178), Black (n = 29), and non-Black cohorts (n = 128), respectively.

Adherences rates were 93.6%, 90.1%, and 94.5% for patients in the overall (n = 193), Black (n = 33), and non-Black cohorts (n = 138), respectively.

“Apalutamide, a next-generation androgen receptor inhibitor, in conjunction with androgen deprivation therapy was approved by the [FDA] for [patients with] nmCRPC based on the results of randomized SPARTAN clinical study [NCT01946204],” said Benjamin H. Lowentritt, MD, FACS, director of Minimally Invasive Surgery and Robotics, and director of the Prostate Cancer Care Program at Chesapeake Urology in Towson, Maryland. “However, the effectiveness [of the agent] in real-world practice needs further evaluation.”

In the SPARTAN study, patients treated with apalutamide (n = 806) had a median metastasis-free survival of 40.5 months vs 16.2 months for those who received placebo (n = 401; HR, 0.28; 95% CI, 0.23-0.35; P < .001), meeting the primary end point of the study and leading the FDA approval.2 PSA response was an exploratory end point of the study.

Investigators reported that 89.7% of patients treated with apalutamide had a PSA response.

 “Our real-world study showed that PSA response to apalutamide and continuous androgen deprivation therapy was robust and consistent with that in the SPARTAN study,” Lowentritt said.

To conduct the analysis, investigators used electronic medical records collected as part of routine clinical care from 95 US-based urology practices with dispensaries. PSA response and treatment patterns were evaluated from the index date—the first apalutamide dispensation among patients with non-metastatic CRPC—to the end of data availability (October 4, 2019), switch to another first- or second-generation antiandrogen, or death.

Baseline characteristics were evaluated in 12 months preceding the index date.

In this retrospective longitudinal cohort design, 193 patients with non-metastatic CRPC were treated with apalutamide; 33 (17%) were Black, 138 (72%) were non-Black, and 22 (11%) had an unknown racial background. Among the 3 cohorts, most patients (76%) were aged 71 to 90 years.

Evaluated patients had 2 apalutamide prescription fills and 12 months of prior prostate cancer management at baseline.

The mean baseline PSA levels for the overall (n = 190), Black (n = 33), and non-Black groups (n = 135) were 7 ng/mL, 10.5 nh/mL, and 5.6 ng/mL, respectively. PSA doubling times were reported for 90 (46.6%), 16 (48.5%), and 70 patients (50.7%), respectively, and the mean doubling times were 10.8, 10.2, and 10.1 months. The mean baseline testosterone for the overall (n = 146), Black (n = 22), and non-Black patient cohorts (n = 105) was 16.3 ng/dL, 15.1 ng/dL, and 17.3 ng/dL, respectively.

An additional efficacy end point was persistence rate, assessed as the proportion of patients who did not have a specific gap in treatment within a fixed period following the index date. At 6 months, 79.7%, 81.5%, and 80.6% of patients in the overall (n = 153), Black (n = 27), and non-Black cohorts (n = 108), respectively, did not have a gap in treatment over 45 days. Similarly, an over 90-day gap in treatment was not observed in 88.9%, 92.6%, and 87% of patients in the overall, Black, and non-Black groups, respectively.

A numerically higher proportion of Black patients were persistent at 12 months; specifically, 62.7%, 78.9%, and 58.6% of patients did not have an over 45-day gap in treatment in the overall (n = 102), Black (n = 19), and non-Black groups (n = 70), respectively. Correspondingly, an over 90-day gap in treatment was not observed in 69.6%, 78.9%, and 65.7% of patients in the overall, Black, and non-Black groups, respectively.

Lowentritt noted that although Black patients have higher incidence of prostate cancer, they comprised only 6% of the SPARTAN trial population.

“[This study provided] important information on real-word PSA responses in Black men, a population that is typically not well represented,” he concluded.

References
1.	Lowentritt B, Brown G, Kernen K, et al. Real-world effectiveness and treatment adherence of apalutamide in non-metastatic castration-resistance prostate cancer patients. J Urol. 2021;206(suppl 1):e58. doi:10.1097/JU.0000000000001969.08
2.	Smith MR, Saad F, Chowdhury F, et al; Spartan Investigators. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

Real-world evidence recently presented at the 2021 AUA Annual Meeting showed that high adherence rates and favorable prostate-specific antigen (PSA) response were observed in men with nmCRPC who were treated with apalutamide. 

Apalutamide Induces Impressive PSA Response and Solid Adherence Rates in Men with nmCRPC

Treatment with ≥ 2L cabozantinib (Cabometyx), compared with ≥ 2L axitinib (Inlyta) improved survival outcomes in patients with advanced renal cell carcinoma (RCC) who received prior VEGF-targeted therapy, according to a retrospective cohort study of data from Public Health England’s Cancer Analysis System (CAS), presented at the 2021 ESMO Congress.

The study analyzed outcomes of adults who were diagnosed with stage III or IV RCC between January 1, 2011 and December 31, 2018, with follow-up lasting until January 31, 2020. A total of 440 patients received cabozantinib treatment, while 1045 received axitinib.

Median duration of treatment was longer for those who received cabozantinib (5.52 months; IQR, 2.73-11.74) than those on axitinib (4.60 months; IQR, 1.45-12.36).

Patients on cabozantinib – a TKI inhibitor – also had numerically longer median overall survival (OS) than patients given axitinib. In the unweighted analysis, median OS for cabozantinib was 11.41 months (IQR, 5.65-27.32) compared with 9.60 months (4.54-20.32). Similar results were found in the IPW analysis, with average OS lengths of 11.24 months (IQR, 5.65-27.98) and 10.39 months (IQR, 4.70-20.03) for the cabozantinib and axitinib arms, respectively.

“Both agents have been approved in the U.K. as second or later line treatment options for patients with advanced RCC – axitinib since 2012, and cabozantinib since 2016,” said study author Janet Brown, MB BS, MSc, MD, FRCP, Professor of Translational Medical Oncology at University of Sheffield, in her presentation of the data.

Notably, patients in the cabozantinib arm tended to have a more recent diagnosis, with 65% receiving a diagnosis between 2016 and 2018. Conversely, 80% of those on axitinib were diagnosed before 2016. In the United States, cabozantinib was approved by the FDA in December 2017 for first-line treatment, based on findings from the CABOSUN (NCT01835158) trial, which showed improved progression-free survival over sunitinib (Sutent), at 8.6 months and 5.3 months, respectively.

Characteristics between the cabozantinib and axitinib patient groups were otherwise balanced, with the average age being 62.5 years and 63.0 years, respectively. At diagnosis, 58.6% of patients in the cabozantinib cohort and 53.2% of those on the axitinib cohort had metastases, while 91.4% and 90.3%, respectively, had clear-cell histology. Regarding tumor size at diagnosis, 69.3% and 68.8% were 4.00 mm or smaller, in the cabozantinib and axitinib arms, respectively; 5.9% and 7.1% had tumors larger than 4.00 mm, and the remainder (24.8% and 24.1%) of patients had missing tumor sizes.

At diagnosis, 28.2% of patients given cabozantinib had an ECOG score of 0-1, compared with 20.4% of those on axitinib.

“Real-world evidence complements the results of randomized controlled trials,” Brown said. “This study demonstrates the potential for cabozantinib for conducting clinically relevant real-world research in England.”

Brown J, Harrow B, Marciniak A, McCarthy C, Cirneanu L, Protheroe A. Cabozantinib and axitinib after vascular endothelial growth factor therapy in patients with advanced renal cell carcinoma: a retrospective cohort study. Presented at: ESMO Congress 2021. September 16-21, 2021. Virtual. E-Poster 680P

Patients with advanced RCC who received prior VEGF-targeted therapy tend to have longer survival outcomes with cabozantinib than with axitinib.

UK Study of Real-World Data Shows Survival Benefit of Cabozantinib vs Axitinib in Pre-Treated RCC 

Patients with metastatic castration-resistant prostate cancer (mCRPC) who are obese report better disease specific and overall survival (OS) than patients who are overweight or normal weight, indicate findings from an analysis of three phase 3 clinical trials presented at the 2021 American Urological Association Annual Meeting.

“The BMI effect on cancer-specific mortality was also confirmed as a continuous and as a categorical variable,” said study coauthor Giuseppe Ottone Cirulli, MD, a urology resident of Vita-Salute San Raffaele University in Milan, Italy. “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 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/m2. 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/m2). A BMI of 30 kg/m2 or greater was considered obese.

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/m2 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/m2 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; 

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.

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

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

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

Obese men are more likely to have improved overall survival following treatment for mCRPC than man who are overweight or normal weight, analysis finds. 

Higher BMI Linked to Superior Survival in mCRPC

Patients and caretakers of patients with renal cell carcinoma (RCC) may lack adequate knowledge surrounding disease treatment, clinical trial enrollment, and the psychosocial impact of the cancer itself, a new survey says.

Results from the global survey were presented as a poster during ESMO Congress 2021.

“(This) indicates opportunities to improve communication about diagnosis, psychosocial impacts, and clinical trials, as well as biopsies, physical exercise, and patient engagement,” wrote Dr. Rachel H. Giles, chair of the International Kidney Cancer Coalition, and colleagues wrote in the poster.

Of note, kidney cancer is the seventhmost common cancer, although little is known about variations in patient experience and best practices in different countries.

The survey consisted of 35 questions focused on the diagnosis, management, and burden of RCC. It was distributed in 13 different languages to patients with kidney cancer and their caregivers between October 29, 2020, and January 5, 2021. The survey reached 2,012 (1,586 patients, 417 caregivers, 9 undisclosed) participants from 41 countries.

“The survey identified several actionable deficits,” according to the poster.

According to the survey, 42% of participants reported that the likelihood of surviving their cancer beyond 5 years was not explained, whereas 51% reported that they were involved as much as they wanted to be in developing their treatment plan. Fifty percent of younger-onset patients (< 46 years) did not know their tumor subtype and 56% experienced barriers to their treatment. Of the surveyed population, 74% took fewer than 3 months to obtain a correct diagnosis.

Regarding clinical trials and perspectives on biopsies, 41% of respondents indicated that no one discussed cancer clinical trials with them, 46% had a biopsy and 3% said they were not willing to undergo an additional biopsy if asked.

For physical activity, survey results that 45% of respondents were insufficiently active and 55% said that they very often or always experienced a fear of recurrence.

Several questions in the survey also focused on psychosocial effects of the disease. Nearly a quarter (26%) of respondents reported that they either very often or always experienced stress related to financial issues and 50% experienced disease-related anxiety very often or always. More than half of participants (52%) reported talking to their doctors or health care teams about their psychological well-being.

Reference
Giles RH, Maskens D, Martinez R, et al. Patient-Reported Experience of Diagnosis, Management, and Burden of Renal Cell Carcinomas: Results from a Global Patient Survey in 41 Countries. Presented at 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 671P

A global study revealed that patients and caregivers alike reported insufficient knowledge surrounding renal cell carcinoma.

Global Study Suggests More Informational Resources Needed for Renal Cell Carcinoma 

Although they may differ by genomic alterations, VHL-mutated and VHL wild type (ccRCC) may share overlapping clinical characteristics, suggest new study findings.

Findings from this study, which were presented at the 2021 ESMO Congress, demonstrate that this may have the potential to impact clinical trial treatment selection.

“Further study of ccRCC based on VHL mutations status in the clinical trial setting appears warranted,” Gennady Bratslavsky, MD, of SUNY Upstate University Hospital in Syracuse, New York, and colleagues wrote in the poster.

Researchers performed comprehensive genetic profiling in 948 patients with clinically advanced ccRCC to assess all classes of genomic alternation. Of these patients, 75% had VHL-mutated disease (median age, 62 years; 71% men) and 25% had VHL wild type ccRCC (median age, 63 years; 71% men).

Some of the significant differences in currently “untargetable” genomic alterations included higher TERT genomic alterations in patients with VHL wild type ccRCC (

 = .007) and higher frequencies of SETD2 in those with VHL mutated ccRCC (

 = .04). Patients with VHL mutated or VHL wild type ccRCC had similar frequencies of genomic alterations that could potentially be targeted except for MTAP deletions; these deletions were observed more frequently in patients with VHL wild type ccRCC (

Researchers also assessed patients with genomic alterations associated with immune checkpoint inhibitor efficacy. In these patients, PBRM1 genomic alterations were significantly more frequent in those with VHL wild type disease compared with VHL mutated disease (

 < .0001). Patients with ccRCC had low tumor mutational burden levels, with 1% to 2% of patients having levels above 10 mut/Mb.

Patients with VHL mutated ccRCC and those with VHL wild type disease often had low positive PD-L1 expression (1%-49% tumor cell staining). In addition, both groups rarely had high positive staining (≥ 50% tumor cell staining).

Bratslavsky G, Necchi A, Grivas P, et al. Comprehensive Genomic Profiling of 

Wild Type Clear Cell Renal Cell Carcinoma. Presented at 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 690P

Characteristics such as low positive PD-L1 expression and rare high positive staining were identified in both patients with VHL-mutated and VHL wild type clear cell renal cell carcinoma. 

Study Finds Similar Clinical Characteristics in VHL-Mutated and VHL Wild Type Clear Cell RCC

Darolutamide (Nubeqa) demonstrated a similar safety profile as placebo in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) continuing androgen-deprivation therapy (ADT), with comparable adverse event (AE) onset and occurrence rates, according to results from the ARAMIS trial presented during a poster presentation at the virtual 2021 ESMO Congress.

In the ARAMIS trial (NCT02200614), there was only a ≤2% difference in AE incidence of interest between the experimental and placebo group, and severity was low for both arms across 24 months. Fatigue was the only exception, with 12.6% of the darolutamide group who experienced the AE.

Notably, the incidence of rash was very low and nearly all cases of fatigue were reported early on in treatment. Most events were grade 1 or 2. The investigators noted that 

darolutamide poses a particular significance

 to the overall wellbeing of men with nmCRPC, given their potentially prolonged treatment time.

“Men with nonmetastatic castration-resistant prostate cancer are generally asymptomatic and may receive prolonged treatment with androgen receptor inhibitors (ARIs),” Christian Gratzke, MD, professor and chair in the Department of Urology at the Albert-Ludwigs-University in Freiburg, Germany, explained in a corresponding abstract presented alongside the poster. “Understanding the burden and time course of adverse events commonly associated with ARIs that may impact patients’ daily life will help inform optimal treatment selection for men with nmCRPC.”

Researchers analyzed the AEs most associated with antigen receptor inhibitors to provide patients with optimal treatment selection information. Kaplan-Meier estimates were utilized to analyze the incidence of AEs across the first 24 months. Time interval-specific analysis determined new event rates per each scheduled study visit.

Participants were randomized 2:1 to either receive darolutamide or placebo while continuing treatment with androgen deprivation therapy. The darolutamide group included 995 men, while the placebo group included 554.

Observed AEs across the darolutamide and placebo arms, respectively, included falls (0.2% vs 0.7%), fractures (0.4% vs 0.5%), mental impairment (0% vs 0.4%), hypertension (1.7% vs 1.1%), and rash (0.7% vs 0.2%).

Fatigue was reported by 12.6% of the men who received darolutamide, and by 8.3% of the placebo arm. Nearly half of all men who reported fatigue experienced it during the first month (5.9% vs 4.0%, respectively). The total rash incidences was 2.9% by 24 months. Half of all reported cases of rash appeared in the first 4 months, and almost all were grade 1 or 2. Serious AE incidence and initial onset were similar between the 2 groups.

Fatigue was shown to increase in cumulative incidence over time. In comparison, falls and fractures were mostly reported in the first month of treatment.

Hypertension onset was not specific to time interval. The number of cumulative incidences reported were similar across treatments. Although mental impairment was rare (<1% per treatment group), incidence occurrence was consistent across both groups.

While most cases of rash were grade 1 or 2, there were 2 patients who reported a grade 3 rash from the darolutamide group, and 1 patient who reported a grade 3 rash from the placebo group.

“The findings from this analysis confirm the safety profile of darolutamide showing a low incidence in a similar onset and cumulative incidence versus placebo,” Gratzke concluded.

Gratzke CJ, Fizazi K, Shore ND, et al. Time course profile of adverse events of interest and serious adverse events with darolutamide in the ARAMIS trial. Presented at: 2021 European Society Medical Oncology Congress; September 16-21, 2021’ Virtual. Abstract 630P.

Patients with nonmetastatic castration-resistant prostate cancer often undergo prolonged treatment periods, making the safety profile of therapies like darolutamide an important factor in optimum treatment selection. 

Addition of Darolutamide to ADT Shows Comparable Safety Profile Among Patients With nmCRPC

Yoga can promote an improved quality of life among patients with prostate cancer, show phase 2 trial findings presented at the 2021 AUA Annual Meeting. In addition, the meditative activity may result in antitumor immune responses and reduced inflammation in patients undergoing prostatectomy.

Yoga has a direct effect on the vagus nerve, which can shape how a person thinks, remembers, and feels. And patients with prostate cancer have a 20% to 30% incidence and prevalence of depression and anxiety.

In previous studies, yoga has demonstrated an improved quality of life for patients with cancer, as well as lower inflammation. Additionally, newer, emerging data has demonstrated that mindfulness exercises, such as yoga, can cause the frontal and limbic parts of the brain to structurally change.

“However, if you look at hierarchy of evidence, most data on immune benefits of yoga is from small series and case reports, no such data exists for prostate cancer. Given these findings of improvement in quality of life with yoga, we started looking at [the] role of yoga in prostate cancer,” said Dharam Kaushik, MD, associate professor in the department of urology at the University of Texas Health, San Antonio, during the presentation of the data.

The primary outcomes of this clinical trial [NCT02620033] was self-reported outcomes of quality of life at baseline, and 6 weeks. Secondary outcomes included immune cell status and cytokine levels, also at baseline and 6 weeks.

“We wanted to evaluate the quality of life from multiple vantage points, therefore we utilized 4 different quality of life questionaries,” Kaushik mentioned. Self-reported outcomes were assessed by the Expanded Prostate Index Composite (EPIC), Functional Assessment of Cancer Therapy-Prostate (FACT-P), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and Five Facets of Mindfulness Questionnaire (FFMQ).

The study consisted of 30 men who were newly diagnosed with localized prostate cancer and scheduled for a radical prostatectomy. Patients were randomized to either yoga (n = 15) or standard of care (n = 15). And patients in the yoga group, performed the activity for 60 minutes twice a week for 6 weeks before their prostatectomy and 3 to 6 weeks after.

Yoga “meaningfully” improved EPIC-sexual scores, FACIT-F, FACT general and FACT-P. In substratification, there were improvements in sexual, physical, and social well-being in the yoga group.

Additionally, participants in the yoga group demonstrated increased numbers of CD4+ (

There was also an increase in the natural killer cells IFNNK (

 = .041), “indicating a robust immune response,” Kaushik added.

Yoga also had an enhanced effect on antitumor activity, decreasing the numbers of regulator T-cells and myeloid-derived suppressor cells: CD11b+CD33+ (

There was also a decrease in cytokine cells including, G-CSF (

 = .032), which had shown to activate production endothelial cell and cytokines. Additionally, there was a decrease in MCP-1 (

 = .044), which are associated with proception against dementia, and FLt-3L (

 = .053) which has been linked to reducing chronic inflation, Kaushik mentioned.

The benefits demonstrated in this study require further investigation, the authors concluded in the abstract.

Kaushik D, Shah P, Mukherjee N, et al. A phase 2 randomized clinical trial of yoga in men with prostate cancer. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract LBA02-03.

Yoga has a positive impact on the vagus nerve, which influences how people think, remember, and feel, and therefore can improve the mental well-being of patients with prostate cancer. 

Yoga Encourages Antitumor Response, Boosts Quality of Life in Patients with Prostate Cancer 

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) may have a decreased immediate need for locally invasive procedures, as well as a minimized speed of deterioration in health-related quality of life (HRQOL ) after treatment with the androgen receptor inhibitor darolutamide (Nubeqa), suggest findings reported at the 2021 American Urological Association annual meeting.

For the study, investigators evaluated the effect of darolutamide on local symptom control. Specifically, they examined incidence and time to first prostate cancer-related invasive procedures, time to deterioration in health-related quality of life measures, and incidence of urinary and bowel treatment-related adverse events and their correlation with PSA decline from baseline to week 16 in patients receiving darolutamide.

Time to deterioration in HRQOL measures was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Prostate Cancer Module and the Functional Assessment of Cancer Therapy-Prostate (FACT-P) prostate cancer subscale.

In assessing incidence and time to first locally invasive procedures, “The results of these analyses showed that fewer patients receiving darolutamide, 4.7%, underwent locally invasive procedures, compared with patients receiving placebo, 9.6%,” said first author Neal D. Shore, MD, FACS, director of Carolina Urologic Research Center in Myrtle Beach, South Carolina. The most common procedures included catheterization, transurethral resection of the prostate, nephrostomy, and surgical excisions and resections.

Darolutamide also significantly prolonged the time to first prostate cancer-related locally invasive procedure compared with placebo (hazard ratio [HR], 0.42; 95% CI, 0.28-0.62).

“For the EORTC urinary symptom subscale, darolutamide significantly delayed the time to deterioration in quality of life for total urinary symptoms and for each individual question about urinary symptoms versus placebo,” Shore said.

The 4 questions that contributed the most to the delay in time to deterioration of HRQOL with darolutamide were:

• urinate frequently during the day (HR, 0.764; 95% CI, 0.648-0.902)

• urinate frequently at night (HR, 0.664; 95% CI, 0.559-0.790)

• pain when urinating (HR, 0.569; 95% CI, 0.441-0.734)

• urinary problems interfere with daily activities (HR, 0.748; 95% CI, 0.614-0.910).

Darolutamide was also found to significantly delay the time to deterioration of total bowel symptoms vs placebo (HR, 0.781; 95% CI, 0.664-0.918).

“For each of the 4 bowel symptom-related questions, darolutamide delayed the time to deterioration versus placebo with hazard ratios ranging from 0.87 to 0.91, but 95% confidence intervals were wide and crossed 1,” Shore said.

Regarding the FACT-P Prostate Cancer Subscale, darolutamide significantly delayed time to deterioration for total urinary symptoms as well as for each of the 3 urinary symptom questions. The time to deterioration in trouble moving bowels was not significantly affected by treatment with darolutamide, however (HR, 1.089; 95% CI, 0.0862-1.376).

In the overall study population, urinary retention occurred in 36 patients (3.8%) in the treatment arm vs 41 patients (7.4%) in the placebo arm. Dysuria occurred in 25 patients (2.6%) in the treatment arm vs 29 patients (5.2%) in the placebo arm.

“The incidences of other urinary and bowel adverse events showed minimal differences of 2% or less between treatments,” Shore said.

In addition, for patients treated with darolutamide, greater prostate-specific antigen response was associated with a lower incidence of urinary retention and dysuria.

Specifically, patients receiving darolutamide who had a PSA decline of 90% or greater from baseline to week 16 had incidences of urinary retention and dysuria of 2.2% and 0.5% respectively compared with 5.1% for urinary retention and dysuria in patients with a PSA response of less than 50%.

“In conclusion, darolutamide was associated with a reduction in locally invasive procedures and delayed time to deterioration in patient health-related quality of life with respect to urinary and bowel symptoms. No increase in urinary and bowel-related adverse events compared with placebo confirms the favorable safety profile of darolutamide. These findings demonstrate that darolutamide had a positive effect on local disease recurrence and symptom control in patients with nonmetastatic CRPC,” Shore said.

1. Shore S, Stenzl A, Pieczonka C, et al. Impact of darolutamide on local symptoms in patients with nonmetastatic castration-resistant prostate cancer. Paper presented at the 2021 American Urological Association Annual Meeting; Sep

Researchers identified a slower rate of health-related quality of life deterioration, as well as an ability to postpone locally invasive procedures, in patients with nonmetastatic castration-resistant prostate cancer who received darolutamide. 

Darolutamide Postpones Need For Procedure, Slows Down Quality of Life Deterioration in Patients with nmCRPC

The FDA has granted full approval to pembrolizumab (Keytruda) for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) and are not deemed eligible for platinum-containing chemotherapy.

Pembrolizumab’s original indication had been granted an accelerated indication based off the tumor response rate and duration of response with continued approval remaining contingent upon certification of clinical benefit in confirmatory trials.

“While the treatment landscape has evolved, an unmet need remains for appropriate patients newly diagnosed with certain types of advanced urothelial carcinoma who are not eligible for platinum-containing chemotherapy,” Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, stated in a press release. “We are confident in the role [pembrolizumab] will continue to play for these patients who have few other treatment options and are working with urgency to advance studies to help more patients living with bladder and other types of cancer.”

Earlier this year, the drug was assessed by the FDA’s Oncologic Drugs Advisory Committee (ODAC) during an industry wide evaluation of accelerated approvals that had not yet met their post-marking requirements. ODAC members voted 5-3 to maintain the accelerated approval of pembrolizumab for the first-line bladder indication.

The following phase 3 KEYNOTE-361 trial, which evaluated pembrolizumab both as a monotherapy and in combination with chemotherapy for early treatment of patients with advanced or metastatic urothelial cancer and were fit to receive platinum-containing chemotherapy, did not achieve its pre-specified dual primary end points of overall or progression-free survival, in comparison with the current standard-of-care chemotherapy.

Pembrolizumab is also approved to treat patients with locally advanced or mUC following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy as well as for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer and are ineligible for or have chosen not to undergo cystectomy.

The humanized monoclonal antibody functions by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Patients receiving pembrolizumab should be monitored for potential immunotherapy-related adverse events (irAEs). Liver enzymes, creatinine, and thyroid function should be assessed at baseline and revisited throughout treatment.

For serious irAEs, corticosteroid therapy should be administered (1 to 2 mg/kg/day prednisone or equivalent) until the grade is diminished to grade 1 or less. Pembrolizumab should be withheld or discontinued if the steroids do not improve symptoms.

Some AEs occur at a 10% higher rate in pediatric patients compared with adults, including pyrexia (33%), vomiting (30%), leukopenia (30%), upper respiratory tract infection (29%), neutropenia (26%), headache (25%), and Grade 3 anemia (17%).

FDA approves updated indication for Merck's KEYTRUDA (pembrolizumab) for the treatment of certain patients with urothelial carcinoma (bladder cancer). News release. Merck. August 31, 2021. Accessed August 31, 2021. https://bwnews.pr/3zCgh3N


Pembrolizumab has been granted full approval as a first-line treatment for a select population of patients with bladder cancer. 


Genitourinary Cancer