Hayley Virgil

Use of 18F-rHPSMA-7.3 PET prior to prostatectomy was associated with positive disease detection and also provided clinically important information, according to a recently reported study.

The data, from the phase 3 LIGHTHOUSE trial, were presented at the 

Society for Urologic Oncology (SUO) 23rd Annual Meeting

 by Brian F. Chapin, MD, associate professor of urology and fellowship director at MD Anderson Cancer Center, Houston, Texas.

Of the 296 patients included in the efficacy population, 7.8% to 13.0% had a 18F-rHPSMA-7.3 PET–positive pelvic lymph node according to 3 readers. Moreover, extrapelvic lesions were identified in 16% to 28% of patients in an extended population that included those who received 18F-rHPSMA-7.3 PET regardless of surgery (n = 352).

Brian F. Chapin, MD, associate professor of urology and fellowship director at MD Anderson Cancer Center, Houston, Texas, presented the data from the phase 3 LIGHTHOUSE trial.

Investigators noted that radiohybrid prostate-specific membrane antigen (PSMA)–targeting PET radiotherapeutic agents could be potentially labeled with 18F for use in diagnostic imaging or alpha-/beta-emitting radiometals for systemic radiation therapy. The LIGHTHOUSE trial assessed 18F-rHPSMA-7.3 PET, a novel, high affinity PSMA ligand that is currently being developed in the diagnostic imaging space for prostate cancer.

The study included patients with unfavorable-risk, high-risk, or very high–risk newly diagnosed disease set to undergo radical prostatectomy with regional pelvic lymph node dissection. PET/CT was performed 50 to 70 minutes following a 296 MBq (8mCi) intravenous dose of 18F-rHPSMA-7.3.

The images were interpreted by local readers prior to surgery and were subsequently sent for blinded independent evaluation by 3 central readers. Moreover, histopathology was performed with 30 days after PET.

The trial’s co-primary end points were patient level sensitivity and specificity in terms of detecting pelvic lymph node metastases. The prespecified threshold for sensitivity and specificity were 22.5% and 82.5%, respectively. The efficacy analysis population included patients who received 18F-rHPSMA-7.3 PET followed by surgery.

The trial did not meet the prespecified statistical threshold for sensitivity, which ranged between 23% to 30%. Investigators noted that sensitivity was higher for those with high-risk or very high–risk disease vs unfavorable intermediate-risk disease.

Moreover, specificity was between 93% to 97% and exceeded the threshold across all readers. Specificity was also high across all readers for both disease risk stratifications, measuring 93% or higher.

In terms of safety, investigators reported that in the safety population of 356 patients, 7.9% experienced a total of 33 treatment-emergent adverse effects (TEAEs), which were determined to not be serious. Of this population, 2.5% of patients experienced 10 TEAEs that were potentially related to 18F-rHPSMA-7.3 PET.

Three patients experienced injection site pain, and 1 patient each experienced peripheral swelling, diarrhea, nausea, hyperkalemia, arthralgia, dysgeusia, and hypertension.

1. Chapin BF. Diagnostic performance and safety of 18F-rhPSMA-7.3 PET in patients with newly diagnosed prostate cancer: results from a phase 3, prospective, multicenter study (LIGHTHOUSE). Poster presented at Society for Urologic Oncology (SUO) 23rd Annual Meeting; November 30-December 2, 2022; San Diego, CA. Poster 134.

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Specificity was between 93% to 97% and exceeded the threshold across all readers.

18F-rHPSMA-7.3 linked with positive prostate cancer detection in patients with newly diagnosed disease

A subgroup analysis of the phase 3 HERO trial (NCT03085095) presented at the SUO 23rd Annual Meeting showed that relugolix yielded positive safety and efficacy in advanced prostate cancer across all baseline testosterone levels.

In the population of 912 patients who had their baseline testosterone collected during the trial, a total of 147 patients—including 96 in the relugolix arm and 51 in the leuprolide arm—had a baseline level of less than 280 ng/dL—and 765—including 516 in the relugolix arm and 249 in the leuprolide arm—had a level of 280 ng/dL. Although the population had advanced age, most patients had testosterone levels that were within a normal range.

The 48-week point estimated castration rates were notably higher among patients treated with relugolix vs leuprolide in each respective subgroup. In the relugolix arm, patients with a level of less than 280 ng/dL and 280 ng/dL or more had rates of 97.3% and 96.5%, respectively, vs 84.1% and 89.3% in the leuprolide arm. The sustained castration rates were 96.7% and 88.8% in the overall population, respectively.

“Relugolix in men regardless of their baseline testosterone level showed equal efficacy,” according to Kelly L. Stratton, MD, an assistant professor of urologic oncology in the Department of Urology and an adjunct assistant professor of medical oncology at the Stephenson Cancer Center at Ohio University Health, in an interview with CancerNetwork®. “The outcomes were similar between those who had normal or above, or below normal testosterone levels at baseline. There’s a thought that patients who come in with lower levels of testosterone may have worse outcomes, so we wanted to look at the ability to sustain castration in those 2 groups. It ended being that relugolix was effective in both groups.”

The HERO trial included a total of 930 patients with advanced prostate cancer who were randomly assigned 2:1 to receive either relugolix at a dose of 120 mg daily following a single loading dose of 360 mg or a 3-month leuprolide injection for 48 weeks. Patients who had a baseline testosterone level of less than 280 ng/dL or 280 ng/dL or higher were assessed in the subgroup analysis and included assessment of sustained testosterone suppression to castrate levels from day 29 to 48 weeks, early castration rates, prostate-specific antigen (PSA) levels, castration resistance-free survival (CRFS) at 48 weeks, and safety.

In the relugolix arm, 68.8% and 71.9% of patients in the low and high testosterone cohorts were 75 years or younger, respectively, with a median age of 72 years. The median PSA level in each respective cohort was 11.1 ng/mL and 11.8 ng/mL and the mean testosterone level was 228.5 ng/dL and 474.7 ng/dL, respectively. Additionally, most patients had metastatic disease at study entry (32.3% and 31.8%, respectively) followed by locally advanced disease (29.2% and 30.8%), and localized disease (29.2% and 28.3%).

In the leuprolide cohort, patients had median ages of 70 years and 71 years in the low and high testosterone groups, respectively, and 76.5% and 71.1% of patients were 75 years and younger. The median PSA was 12.5 ng/mL and 8.9 ng/mL in each respective group, and the mean testosterone levels were 227.6 ng/dL and447.3 ng/dL, respectively. This cohort primarily had metastatic disease (37.3% and 30.9%, respectively) followed by locally advanced disease (27.5% and 30.9%), and localized disease (25.5% and 11.2%).

Key secondary end points also appeared to favor those treated with relugolix vs leuprolide with the exception of CRFS, which was similar between treatment groups and subgroups.

Primary and select key secondary end points by baseline testosterone subgroup from a subgroup analysis of the phase 3 HERO trial (NCT03085095).

In the relugolix cohort, 24.0% of patients with a low testosterone level had grade 3 or higher adverse events (AEs), compared with 17.2% of those with a high level. Moreover, serious AEs occurred in 16.7% and 11.4% and fatal AEs occurred in 2.1% and 1.0%, respectively. The most common any grade AEs in each respective group included hot flash (52.1% and 54.8%, respectively), fatigue (30.2% and 20.2%), and diarrhea (14.6% and 11.6%). The low-level testosterone group had 2 events of grade 3 or higher hypertension while the high-level group had 8 events of hypertension and 4 events of hot flash.

In the leuprolide group, 21.7% of patients in the low testosterone group had high-grade AEs, compared with 20.5% in the high-level group. Moreover, 17.6% and 15.3% of patients, respectively, had serious AEs and 5.9% and 2.4% had fatal AEs. Common any grade AEs in this population included hot flash (56.9% and 51.8%, respectively), hypertension (27.5% and 8.4%), and fatigue (15.7% and 19.7%), with 1 event each of high-grade hypertension and 3 events of backpain.

1. Cookson MS, Tombal B, George DJ, et al. Impact of Baseline Testosterone Levels on Relugolix Efficacy and Safety: A Subgroup Analysis from the HERO Study vs Leuprolide in Men with Advanced Prostate Cancer. Presented at: Society for Urologic Oncology (SUO) 23rd Annual Meeting; November 30-December 2, 2022; San Diego, California. Poster 40.

“The outcomes were similar between those who had normal or above, or below normal testosterone levels at baseline," said Kelly L. Stratton, MD.

Relugolix maintains benefit in prostate cancer, regardless of baseline testosterone level

Patients with cisplatin-ineligible muscle-invasive bladder (MIBC) experienced higher downstaging and improved survival when treated with neoadjuvant pembrolizumab (Keytruda) vs immediate radical cystectomy (IRC), experts report.

The findings were presented at the Society of Urologic Oncology Annual Meeting in San Diego, California.

In a population of 39 patients with cisplatin-ineligible MIBC who were treated with neoadjuvant pembrolizumab as part of the phase 2 PURE-01 (NCT02736266) and 313 patients who underwent IRC at Moffitt Cancer Center, overall survival (OS) was improved for the pembrolizumab group. Median OS that was not reached (NR) and 19 months, respectively (

Patients with cisplatin-ineligible muscle-invasive bladder cancer achieved improved downstaging and survival following treatment with neoadjuvant pembrolizumab (Keytruda) prior to radical cystectomy compared with immediate radical cystectomy.

Moreover, OS was also found to be prolonged in the propensity score matched analysis, with a median that was not reached in the pembrolizumab arm vs 21 months in the IRC arm (

 <.01). In fact, the IRC population experienced a worse OS in the Cox proportional hazards modeling compared with those treated with pembrolizumab. The response rate was improved in the pembrolizumab arm at 33% vs 13% in the IRC arm (pT0; 

Roger Li, MD, says, "There may be some opportunities for us to use combination treatments in the future as even more synergistic mechanisms of action to control the disease [emerge].”

“From this relatively small cohort, we have seen that neoadjuvant pembrolizumab given for patients with MIBC who are ineligible for chemotherapy did provide an [OS] benefit,” Roger Li, MD, a genitourinary oncologist at Moffitt Cancer Center, said in an interview with CancerNetwork®.

“There's a critical unmet need in the patients who are ineligible for chemotherapy with muscle-invasive disease, hence [why] we really need to develop efficacious treatments for these patients,” he added. “Certainly, this is an option but also along these lines, there may be some opportunities for us to use combination treatments in the future as even more synergistic mechanisms of action to control the disease [emerge].”

The study was conducted to that unmet need within the cisplatin-ineligible population, as pembrolizumab has previously demonstrated efficacy within the non-muscle invasive and metastatic bladder cancer populations.

Moreover, preliminary data from the PURE-01 trial indicated that pembrolizumab demonstrated efficacy in the neoadjuvant setting in the chemotherapy-eligible population. As such, investigators set out to compare pathologic response and survival benefit with neoadjuvant pembrolizumab vs IRC in the cisplatin-ineligible population.

OS in the study was assessed using the Kaplan-Meyer method, with comparisons conducted using log-rank functions.

The median age in the IRC cohort was 75.1 years vs 75.0 years in the pembrolizumab cohort and the majority of patients in both arms were male. No patients had an ECOG performance status of 2 or higher. Additionally, most patients in the IRC and pembrolizumab cohorts, respectively, had cT3 to 4N0M0 staging (69% vs 67%) and Pt4 or pTanyN-positive outcomes (41% vs 33%).

Rose KM, Naidu S, Bandini M, et al. Neoadjuvant pembrolizumab shows promise as effective systemic therapy prior to radical cystectomy for cisplatin-ineligible muscle-invasive bladder cancer. Poster presented at 2022 Society for Urologic Oncology (SUO) Annual Meeting; November 30-December 2, 2022; San Diego, CA. Poster 88.

OS was also found to be prolonged in the propensity score matched analysis, with a median that was not reached in the pembrolizumab arm vs 21 months in the IRC arm.

Higher downstaging, improved OS observed in patients with MIBC treated with neoadjuvant pembrolizumab

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]. 

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

Hayley Virgil

Articles

18F-rHPSMA-7.3 linked with positive prostate cancer detection in patients with newly diagnosed disease

Relugolix maintains benefit in prostate cancer, regardless of baseline testosterone level

Higher downstaging, improved OS observed in patients with MIBC treated with neoadjuvant pembrolizumab

Enzalutamide treatment during active surveillance boosts outcomes in localized prostate cancer