Hayley Virgil

Simultaneous enzalutamide (Xtandi) and active surveillance reduced the risk of disease progression by 46% (HR, 0.54; 95% CI, 0.33-0.89; 

 = .02). compared with active surveillance alone in patients with low- and intermediate-risk localized prostate cancer.

The findings from the phase 2 ENACT trial (NCT02799745), which were published online in 

, also showed that the odds of a negative biopsy were 3.5 times higher when adding the androgen receptor pathway inhibitor to active surveillance.

The multicenter, open-label trial enrolled patients with low- and intermediate-risk disease from June 2016 to August 2020. Patients who enrolled on the study were randomized 1:1 to undergo treatment with enzalutamide at 160 mg and active surveillance for 1 year or active surveillance alone. Stratification factors included disease risk and type of follow-up biopsy.

The trial included patients who were 18 years or older with histologically confirmed low- or intermediate-risk disease within 6 months of screening who were eligible for active surveillance.

The primary end point was time to pathological or therapeutic disease progression, with secondary end points including negative biopsy results at 1 and 2 years, percentage of cancer-positive cores at 1 and 2 years, time to prostate-specific antigen (PSA) progression, and incidence of secondary serum PSA level increase at 1 and 2 years.

A total of 227 patients were randomized at 66 sites. Of those, 114 were treated with enzalutamide, with 74.6% completing 1 year of active surveillance, 61.4% completing 1 year of follow-up, and 50.9% completing a year of continued follow-up. Among those who were placed under active surveillance (n = 113), 70.8% completed 1 year of treatment, 45.1% completed 1 year of follow-up, and 36.3% completed a year of continued follow-up. All study periods were completed in 47.4% of patients in the enzalutamide arm and 35.4% of those in the active surveillance arm.

The most common reasons for discontinuation were disease progression and patient withdrawal. The study had a median follow-up of 492.5 days in the monotherapy arm and 270.5 days in the active surveillance arm. Additionally, 53.3% of patients had low-risk disease and 75.8% received follow-up biopsies.

A total of 28.1% of patients progressed in the enzalutamide arm compared with 37.2% of patients in the active surveillance arm. Median time to pathological/therapeutic progression was not reached in either group. Additionally, pathological/therapeutic progression was reported in 7.9% of patients in the active treatment arm compared with 23.0% of those in the active surveillance arm (odds ratio [OR], 0.3; 95% CI, 0.11-0.60; 

 <.01). Incidence of progression at 2 years was comparable between cohorts at 16.0% and 16.4%, respectively (OR, 0.9; 95% CI, 0.36-2.24; 

Additional findings from the trial indicated that 1-year odds of a negative biopsy significantly increased following treatment with enzalutamide compared with active surveillance (OR, 3.5; 95% CI, 1.76-6.92; 

 <.001). Despite a higher rate of negative biopsies at 2 years in the enzalutamide arm vs active surveillance, the difference was not statistically significant. The treatment arm also had a significantly lower mean rate of cancer-positive cores at 1 year vs active surveillance (difference in least squares mean, –10.07 [2.40]; 95% CI, –14.79 to –5.34; 

 <.001). The difference in cancer-positive cores between groups at 2 years was not statistically significant, although the enzalutamide had a statistically significant reduction of 6.7% (95% CI, −11.36 to −2.00) from baseline to year 2. Enzalutamide also significantly delayed time to PSA progression by 6 months compared with active surveillance (HR, 0.71; 95% CI, 0.53-0.97; 

The most common adverse effects (AEs) in the enzalutamide arm included fatigue (55.4%), gynecomastia (36.6%), nipple pain (30.4%), breast tenderness (25.9%), and erectile dysfunction (17.9%). A total of 88.4% of patients experienced drug-related AEs, 2.7% of which were serious and 7.1% resulted in treatment discontinuation. The majority of AEs in year 1 were grade 1 or 2 in severity. Grade 3 or higher AEs were reported in 9.8% of patients in the treatment arm with grade 3 fatigue being the only event reported in 2 patients. There were no grade 4 AEs and 1 reported grade 5 AE. Moreover, 5.4% of patients had grade 3 AEs that were considered drug related, with 1 event each of gait disturbance, gynecomastia, myocardial infarction, and syncope and 2 occurrences of fatigue.

Shore ND, Renzulli J, Fleshner NE, et al. Active surveillance plus enzalutamide monotherapy vs active surveillance alone in patients with low-risk or intermediate-risk localized prostate cancer [published online June 16, 2022]. 

Articles

The odds of a negative biopsy were 3.5 times higher when adding the androgen receptor pathway inhibitor to active surveillance. 

Enzalutamide treatment during active surveillance boosts outcomes in localized prostate cancer 

Aura Biosciences reported in a news release that the FDA has granted its Fast Track designation to belzupacap sarotalocan (AU-011) for the treatment of patients with non–muscle invasive bladder cancer (NMIBC).

Investigators plan to assess the agent’s safety profile, mechanisms of action, distribution, local necrosis, and proof of immune activation in a phase 1 clinical trial in the aforementioned patient population. The trial is set to begin in the second half of 2022, with initial findings anticipated in 2023.

“We are pleased that belzupacap sarotalocan has been granted Fast Track designation. We believe that, given that NMIBC presents such a high unmet medical need, the opportunity for more frequent interactions with Division of Oncology at FDA and the potential for Priority Review will be valuable as we advance further into clinical development in patients with NMIBC,” Mark De Rosch, PhD, FRAPS, chief operating officer and head of regulatory affairs at Aura, said in a press release.

Belzupacap sarotalocan is a virus-like drug conjugate that consists of a virus-like particle conjugated with an anticancer agent. It was selectively designed to seek out and eliminate cancer cells as well as encourage immune system activation and potentially yield prolonged antitumor immunity.

The fast track designation was designed to allow for the development of therapeutics in areas with significant unmet need and hasten the review process. If supported by clinical findings, belzupacap sarotalocan could be eligible for priority review in NMIBC. The agent has also previously received fast track designation and orphan drug designation by the FDA for chorodial melanoma, in which belzupacap sarotalocan is currently being assessed in a phase 2 trial (NCT04417530).

“NMIBC has no approved targeted therapies, and patients experience high levels of recurrence and progression, ultimately leading to cystectomy or the removal of the entire bladder,” Cadmus Rich, MD, chief medical officer and Head of R&D at Aura, said in a press release. “This milestone supports our goal to advance the development of belzupacap sarotalocan for patients with NMIBC in need of better and earlier targeted treatment options with the potential to help preserve the bladder.”

The phase 2 trial assessing the agent in primary indeterminate lesions and small choroidal melanoma has an estimated enrollment of 58 patients and will feature up to 7 experimental cohorts. The primary end point is tumor thickness growth rate over 52 weeks, with secondary end points including time to reach composite end point, time to reach disease progression, and change from baseline best corrected visual acuity at 52 weeks.

1. Aura Biosciences receives FDA fast track designation for belzupacap sarotalocan (AU-011) for the treatment of non-muscle invasive bladder cancer. News release. Aura Biosciences. June 30, 2022. Accessed July 1, 2022. https://bwnews.pr/3yAoEPt

Belzupacap sarotalocan is a virus-like drug conjugate that consists of a virus-like particle conjugated with an anticancer agent.

FDA grants Fast Track designation to novel therapy for NMIBC

Findings from a retrospective analysis showed that response to 177Lu-PSMA-617 (Pluvicto) was poor among patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumors had low/no PSMA expression.

For the analysis, which was presented at the 2022 Society of Nuclear Medicine & Molecular Imaging Annual Meeting, baseline PSMA-PET/CT scans were assessed by 1 reader who applied PET criteria from the phase 3 VISION trial (NCT03511664) and determine whether scans were eligible (VISION-PET-E) or a screening failure (VISION-PET-SF).

VISION-PET-SF criteria were defined by the following:

Lack of metastatic lesion with an uptake greater than the liver background, denoting low PSMA expression

Evidence of 1 or more metastatic measurable lesions

Moreover, VISION-PET-E criteria included the following:

1 or more PSMA-positive metastatic lesions

No PSMA-negative metastatic lesions, including bone with soft tissue component (1.0 cm or more), lymph node (2.5 cm or more), and solid organ (1.0 cm or more)

In the VISION-PET-SF population, investigators reported that PSA–progression-free survival (PSA-PFS) was shorter, and poorer outcomes were all noted for PSA responses and overall survival (OS). In particular, the median PSA-PFS was 4.1 months in the VISION-PET-E arm vs 2.1 months in the VISION-PET-SF arm (HR, 1.6; 95% CI, 1.1-2.5; 

-value = .023). Moreover, the median OS was 14.2 months compared with 9.6 months in the VISION-PET-E arm and VISION-PET-SF arm, respectively (HR, 1.4; 95% CI, 0.89-2.3; 

Any PSA decline was noted in 71.3% of patients in the VISION-PET-E arm vs 41.4% in the VISION-PET-SF arm (

 = .003). Moreover, a PSA decline of 50% or more was reported in 50.3% and 20.7% of patients in either respective arms (

A total of 304 patients with mCRPC were included in the analysis who had received 1 or more cycles of 177Lu-PSMA-617. Of these patients, 3 were excluded due to being lost to follow-up (n = 2) or missing a CT image (n = 1). From there, patients were assessed based on VISION PET criteria, of whom 272 were VISION-PET-E and 29 were VISION-PET-SF.

Outcomes included PSA-PFS, OS, PSA decline of 50% or more, and any PSA decline.

Notably, the cohort did not include pre-excluded patients via local site evaluation. Due to this, approximately 20% to 25% of patients in the unselected group would likely have failed screening via VISION PET criteria.

1. Hotta M, Gafita A, Czernin J, et al. Outcome of patients with PSMA-PET/CT screen failure by VISION criteria and treated with 177Lu-PSMA therapy: a multicenter retrospective analysis. 2022 Society of Nuclear Medicine & Molecular Imaging Annual Meeting; June 11-14; Vancouver, BC, Canada; abstract 3039.

177Lu-PSMA-617 is approved by the FDA for previously treated patients with PSMA-positive metastatic castration-resistant prostate cancer.

177Lu-PSMA-617 response poor in mCRPC tumors with low PSMA expression

Recently presented cohort 3 results from the phase 2 TROPHY-U-01 trial (NCT03547973) showed a 34% objective response rate (ORR) in patients with checkpoint inhibitor-naïve metastatic urothelial cancer undergoing treatment with second-line sacituzumab govitecan-hziy (Trodelvy) plus pembrolizumab (Keytruda).

The findings were presented at the 2022 Genitourinary Cancers Symposium in San Francisco, California.

At a median follow-up of 5.8 months, patients treated with the combination experienced an ORR of 34% (95% CI, 20.1%-50.6%), and an ORR of 38% among evaluable patients. One patient experienced a complete response (CR), 13 had partial responses (PR), and 11 achieved stable disease. Of those who experienced stable disease, 4 had stable disease for 6 months or more.

“These data support further evaluation of antibody-drug conjugate/checkpoint inhibitor combination [therapy] in metastatic urothelial cancer in the platinum-refractory setting and probably in earlier lines of therapy in a different patient population,” according to lead author Petros Grivas, MD, PhD, a physician at Seattle Cancer Care Alliance; clinical director of the Genitourinary Cancers Program and associate professor of the Division of Medical Oncology at the University of Washington School of Medicine; and associate professor of Clinical Research Division at Fred Hutchinson Cancer Research Center. “Additional follow-up for survival events and biomarkers are ongoing.”

As treatment options for patients with metastatic urothelial cancer remain limited and outcomes poor, investigators aimed to assess other safe and efficacious options to improve patient responses. Investigators theorized that antibody-drug conjugates and checkpoint inhibitors may be a valuable combination strategy capable of providing benefit to patients with metastatic disease.

In cohort 3 of the registrational, open-label multicohort study, investigators enrolled up to 61 patients who were checkpoint inhibitor-naïve with progressive disease following treatment with platinum-based therapies. The cohort received sacituzumab govitecan at a dose of 10 mg/kg on days 1 and 8 every 21 days and 200 mg of pembrolizumab on day 1 every 21 days. Treatment continued until patients experienced unacceptable toxicity or disease progression. Patients needed to be 18 years or older with an ECOG performance status of 0 or 1. Additionally, a creatinine clearance of 30 mL per minute or higher and adequate hepatic function were required.

The study’s primary end point was ORR by investigator review, with key secondary end points including safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

The majority of patients were male (83%) and the median age was 67 years. Most patients were White (54%) and had an ECOG performance status of 1 (61%). In total, 49% and 27% of patients had a Bellmunt risk factor of 1 and 2, respectfully. Investigators also reported 49% of patients underwent neoadjuvant or adjuvant therapy with a median time from end of most recent prior systemic therapy to screening date of 1.6 months. In terms of best response to prior systemic therapy in the metastatic setting, 1 patient had a previous CR and 2 had a PR.

Additional findings from the study indicated that 63% of patients experienced tumor shrinkage and the clinical benefit rate was 61% (95% CI, 44.5%-75.8%). Patients had a median time to response of 2 months and the median DOR was not reached (95% CI, 2.80–not available). The median PFS was 5.5 months (95% CI, 1.7–not reached) and the median OS was not reached.

When examining ORR by subgroup, investigators reported that patients with or without baseline visceral metastases and liver involvement, had rates of 41.7% (95% CI, 15.17%-72.33%) and 31.0% (95% CI, 15.28%-50.83%), respectively. Additionally, for patients who had a Bellmunt risk factor of 0, 1, and 2, the ORRs were 40.0% (95% CI, 12.16%-73.76%), 35.0% (95% CI, 15.39%-59.22%), and 27.3% (95% CI, 6.02%-60.97%).

The most common any grade adverse effects (AEs) in cohort 3 were diarrhea (76%), nausea (59%), and anemia (56%), with grade 3 or higher AEs including neutropenia (27%), diarrhea (24%), anemia (20%), and leukopenia (20%).

The median duration of treatment was 4 months with sacituzumab govitecan and 3.5 months with pembrolizumab. Sixty-eight percent of patients permanently discontinued treatment and 32% were still being treated at the time of data cutoff. Patients who discontinued did so due to progressive disease (51%), withdrawal of consent (5%), and AEs (3%).

Grade 3/4 treatment-related AEs (TRAEs) occurred in 59% of patients, with 39% of patients discontinuing sacituzumab govitecan treatment because of TRAEs. The most common any grade TRAEs were diarrhea (71%), nausea (54%), and neutropenia (44%). Twenty-five percent of patients required a steroid to combat an immune-related AE, with 15% of patients requiring topical and 10% requiring oral steroids for diarrhea (n = 2), pruritis (n = 1), and maculopapular rash (n = 1). Investigators also reported that 29% of patients required granuloma macrophage colony–stimulating factor.

“[Other] TROPHY-U-01 cohorts are being assessed. We have cohort 2 looking at sacituzumab govitecan as a single agent after checkpoint inhibition and cohorts 4 and 5 evaluating sacituzumab govitecan in combination with cisplatin plus or minus avelumab [Bavencio] as induction therapy followed…avelumab [switch maintenance therapy],” Grivas concluded.

1. Grivas P, Poussel D, Park CH, et al. TROPHY-U-01 Cohort 3: sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) who progressed after platinum (PLT)-based regimens. 

. 2022;40(suppl 6):434. doi:10.1200/JCO.2022.40.6_suppl.434

“These data support further evaluation of antibody-drug conjugate/checkpoint inhibitor combination [therapy] in metastatic urothelial cancer in the platinum-refractory setting and probably in earlier lines of therapy in a different patient population,” says Petros Grivas, MD, PhD.

Hayley Virgil

Articles

Enzalutamide treatment during active surveillance boosts outcomes in localized prostate cancer

FDA grants Fast Track designation to novel therapy for NMIBC

177Lu-PSMA-617 response poor in mCRPC tumors with low PSMA expression

Combination sacituzumab govitecan/pembrolizumab shows efficacy and safety in metastatic urothelial cancer