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American Urological Association Annual Meeting

Bacille Calmette-Guérin (BCG) plus N-803 (ALT-803) yielded promising responses and an encouraging safety profile in patients with BCG-unresponsive, non-muscle invasive bladder cancer (NMIBC) carcinoma in situ (CIS), according to updated data from cohort A of the phase 2/3 QUILT-3.032 trial (NCT03022825) that were presented during the 2021 American Urological Association Annual Meeting.

Results showed that the study met its primary end point, with a complete response (CR) rate of 72% (95% CI, 61%-81%), and a 58.6% (95% CI, 43.1%-71.2%) probability of maintaining a CR for at least 12 months. Additionally, at a median follow-up of 20.4 months, the median duration of CR was 19.9 months (95% CI, 7.8–not reached).

“Eighty-five percent of our patients avoided a cystectomy,” according to lead study author Karim Chamie, MD, associate professor of urology at the University of California, Los Angeles. “This intravesical administration is quite favorable, and quite familiar amongst those who normally treat patients with BCG-unresponsive bladder cancer.”

N-803 is an interleukin-15 superagonist that activates and proliferates endogenous natural killer and CD8-positive T cells without inducing T-regulatory simulation.

QUILT-3.032 enrolled 81 patients with histologically confirmed BCG-unresponsive NMIBC, with persistent or recurrent CIS within 12 months of receiving adequate BGC treatment. Patients were treated with 50 mg of BCG plus 400 mg of intravesical N-803 weekly for 6 weeks, followed by re-induction for re-induction and maintenance for up to 3 years.

The primary end point was biopsy confirmed CR at 3 and 6 months, with a lower bound 95% confidence interval of at least 20%. Secondary end points included duration of CR, cystectomy avoidance, and time to cystectomy. Furthermore, safety end points included incidence of serious adverse effects (AEs) and immune AEs.

Notably, the analysis included patients who achieved a CR at 3 months, as well as those who achieved a CR after rescue and reinduction at 6 months.

Those were enrolled were heavily pretreated patients with a median of 5.0 transurethral resections of a bladder tumor, and a median of 12.0 prior BCG instillations. Additionally, 42% of patients had received prior treatment with chemotherapy, and 17% were previously treated with checkpoint inhibitors, vicinium, interferon, etc.

Additional data showed that among patients who achieved an initial complete response at 3 months, there was a 64% (95% CI, 47.3%-77.3%) probability of maintaining that response at 12 months, and a 61% (95% CI, 43.2%-74.5%) probability of maintaining it at 18 months.

Notably, as of May 2021, the combination showed a 30% durable response at 18 months. Eighty-five percent of patients have not progressed to radical cystectomy through a data analysis as of this time point, as well.

In terms of safety, the combination was well tolerated, with no incidence of treatment-related serious AEs, immune-related AEs, or treatment-related AEs (TRAEs) that were grade 4/5 in severity. Grade 3 TRAEs occurred in just 2 patients and included urinary tract infection and arthralgia. The most frequent grade 1/2 AEs were dysuria (22%), hematuria (16%), and pollakiuria (19%).

In comparison to other FDA-approved treatments for this patient population, N-803 plus BCG significantly improved outcomes. Previous data with pembrolizumab (Keytruda) showed that the agent induced at CR rate of 41% at any time, and a median duration of CR of 16.2 months at 24.1 months follow-up. Similarly, valrubicin elicited an 18% CR rate, and a median duration of CR of less than 6 months. Moreover, the cystectomy-free rate for the two drugs was 63% and 76%, respectively.

Chamie K, Chang S, Gonzalgo M, et al. Phase 2/3 clinical results of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) carcinoma in-situ (CIS) patients (cohort A). Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD09-05.

Bacille Calmette-Guérin (BCG) plus N-803 yielded promising responses and an encouraging safety profile in patients with BCG-unresponsive, non-muscle invasive bladder cancer carcinoma in situ. 

N-803/BCG Combo Shows Promising Responses, Tolerability in BCG-Unresponsive Bladder Cancer

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) demonstrated high adherence rates and favorable prostate-specific antigen (PSA) response to apalutamide (Erleada) according to 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; 

< .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.2 “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.

Lowentritt B, Brown G, Kernen K, et al. Real-world effectiveness and treatment adherence of apalutamide in non-metastatic castration-resistance prostate cancer patients. 

. 2021;206(suppl 1):e58. doi:10.1097/JU.0000000000001969.08

Smith MR, Saad F, Chowdhury F, et al; Spartan Investigators. 

. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

Patients with nonmetastatic castration-resistant prostate cancer demonstrated high adherence rates and favorable prostate-specific antigen response to apalutamide according to real-world evidence presented at the 2021 American Urological Association Annual Meeting.

RWE Demonstrates Robust PSA Response and Treatment Adherence of Apalutamide in CRPC

Antibody titers and fold changes may prove to be a prognostic marker for the efficacy of nadofaragene firadenovec for the treatment of patients with bacillus Calmette-Guérun (BCG) unresponsive non-muscle invasive bladder cancer (NMIBC). Anirban P. Mitra, MD, PhD, presented a secondary analysis of a phase 3 study (NCT02773849) exploring these markers during the 2021 American Urological Association Annual Meeting.

Specifically, investigators hypothesized that anti-adenoviral antibody levels and fold change metrics could be as novel predictors of durable response to nadofaragene firadenovec. Based on response to the intravesical gene therapy, patients with peak titer levels that were greater than 800 and peak fold changes greater than 8 were determined to be favorable for response. Patients who did not meet both criteria were designated as unfavorable.

At month 12 following the first treatment with nadofaragene firadenovec, 47 patients were responsive to treatment and a total of 44 patients were nonresponders. On-treatment peak titer levels greater than 800 were reached in 89.4% of responders compared with 59.1% of nonresponders (

 = .001). Regarding peak fold change, 51.1% of responders had a peak fold change of at least 8 compared with 27.3% of nonresponders (

Further, the combination of markers was noted in 46.8% and 18.2% of responders and nonresponders, respectively (

“[Peak titer levels] were associated with the highest sensitivity, accuracy, and negative predictive value,” said Mita, a urologic oncology fellow at The University of Texas MD Anderson Cancer Center in Houston. “In addition, when we looked at peak fold changes with a cutoff of 8 this was also able to significantly distinguish between responders and nonresponders such that we then classified patients as ‘favorable’ if they had a combination of peak titer greater than 800 and a peak fold change greater than 8.”

Mita added that the marker combination was associated with the highest sensitivity and positive predictive value.

To conduct this analysis, investigators performed anti-adenoviral antibody assessment using a quantitative ELISA 1 to 24 hours prior to treatment at baseline and before each dose at 3, 6, 9, and 12 months or at the study-withdrawal visit. The assay assessed for both raw titers as well as fold change, which was calculated as the ratio of on-treatment antibody levels compared with baseline levels. The final treatment response was assessed at the trial’s primary end point of 12 months following the first dose or at the time of high-grade recurrence.

Patients enrolled to the trial received a single intravesical 75-mL dose of nadofaragene firadenovec (3 × 10

 The replication-deficient recombinant adenovirus is designed to deliver interferon–α-2b (INFα-2b) to the bladder epithelium. The therapy mimics viral infection, resulting in IFNα-2b production and subsequent tumor regression offering a novel treatment for patients whose tumors do not respond or recur after BCG.

In the absence of high-grade recurrence, patients received repeat dosing via catheter at 3 months, 6 months, 9 months, and 12 months; additional dosing was permitted at investigator’s discretion. The primary end point was complete response at any time. A total of 157 patients were enrolled and treated in the study and nonresponders were reported at 6 months (n = 21), 9 months (n = 8), and 12 months (n = 15).

The efficacy population included 151 patients and a complete response was observed in 59.6% (95% CI, 51.3%-67.5%) of patients at 3 months. The duration of response or high-grade recurrence-free survival was 7.31 months (range, 5.68-11.93).

The optimal titer threshold was determined based on the assessment of peak titers and peak fold change. For both responders and nonresponders, peak titers were achieved for most patients approximately 6 months after initiation of treatment; peak fold changes were also observed to occur by month 6. Therefore, investigators selected the optimal antibody titer level threshold to be 200 at baseline and 800 post treatment when maximizing the area under the receiver operating characteristic curve.

Mitra noted that baseline level (200) was not associated with a difference between responders and nonresponders; “however, a posttreatment cutoff of 800 was able to significantly distinguish between responders and nonresponders at 3 months and importantly also at peak titer levels.”

Most crossovers between low- and high-titer subgroups occurred in the first 6 months of treatment. After this time point the highest proportion of responders continued to have posttreatment titers greater than 800, further supporting the use of peak titers as a marker to predict durable response.

Finally, Mita presented an exploratory analysis of baseline titers levels as predictive markers for posttreatment titer level. Despite not being associated with durable response, low baseline titers were associated with low posttreatment titers (≤ 800). High posttreatment titers levels (> 800) were significantly associated with patients who had high baseline titer levels.

Specifically, for those with high posttreatment levels, the median baseline antibody level at 3 months was 400 (interquartile range [IQR], 200-1600) compared with 200 (IQR, 125-400) for those with low posttreatment titers (

For those who had high posttreatment titers at peak, the median baseline antibody level was 400 (IQR, 200-800) vs 200 (IQR, 1-400) for those with low posttreatment titers (

Mitra AP, Narayan VM, Boorjian SA, et al. Anti-adenoviral antibody levels predict nadofaragene firadenovec response in BCG-unresponsive NMIBC: results from a phase 3 trial. J Uro. 2021;206(suppl 3):e119-e120. doi:10.1097/JU.0000000000001977.02

Shore ND, Boorjian SA, Canter DJ, et al. Intravesical rAd-IFNα/Syn3 for patients with high-grade, bacillus Calmette-Guerin-refractory or relapsed non-muscle-invasive bladder cancer: a phase II randomized study. 

. 2017;35(30):3410-3416. Published correction in J Clin Oncol. 2019;37(24):2187.

Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. 

. 2021;22(1):107-117. doi:10.1016/S1470-2045(20)30540-4

Antibody titers and fold changes may prove to be a prognostic marker for the efficacy of nadofaragene firadenovec for the treatment of patients with bacillus Calmette-Guérun unresponsive non-muscle invasive bladder cancer. 

Elevated Antibody Titers May Predict Nadofaragene Firadenovec Durability in BCG-Unresponsive NMIBC

Obese men with metastatic castration-resistant prostate cancer (mCRPC) have better disease-specific and overall survival (OS) than overweight or normal weight patients, according to results from an analysis of three phase 3 clinical trials that were presented during the 2021 American Urological Association Annual Meeting.

“The BMI effect on cancer-specific mortality was also confirmed about 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/m2of 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/m2docetaxel 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 with metastatic castration-resistant prostate cancer have better disease-specific and overall survival than overweight or normal weight patients.

American Urological Association Annual Meeting | Conference

N-803/BCG Combo Shows Promising Responses, Tolerability in BCG-Unresponsive Bladder Cancer

RWE Demonstrates Robust PSA Response and Treatment Adherence of Apalutamide in CRPC

Elevated Antibody Titers May Predict Nadofaragene Firadenovec Durability in BCG-Unresponsive NMIBC

BMI Is a Significant Predictor for Survival in mCRPC