Impact of Concomitant Cardiovascular Therapies on Efficacy and Safety of Relugolix vs Leuprolide: Subgroup Analysis from HERO Study in Advanced Prostate Cancer.

INTRODUCTION: Cardiovascular (CV) events are the leading cause of death in prostate cancer. Men with prostate cancer are likely to have CV risk factors and use CV-related concomitant medications. In the phase 3 HERO study, a 54% lower incidence of major adverse cardiac events was reported in men treated with the oral gonadotropin-releasing hormone (GnRH) receptor antagonist, relugolix, vs leuprolide. Herein, we characterize the impact of concomitant CV therapies on efficacy and safety in the HERO study. METHODS: In HERO, 930 men with advanced prostate cancer (APC) were randomized 2:1 and treated with relugolix (120 mg orally once daily; after single 360 mg loading dose) or leuprolide (injections every 3 months) for 48 weeks. Subgroups analyzed included men who received antihypertensives, antithrombotics, or lipid-modifying therapies (LMAs), as well as the most common drug classes (> 10%) and single most common agent within each class. Assessments included sustained testosterone suppression to castrate levels (< 50 ng/dL) through 48 weeks and safety. RESULTS: Antihypertensives, antithrombotics, and LMAs were utilized by 52.7%, 39.1%, and 39.6% of men in HERO, respectively. In the main subgroups, point estimates for sustained castration rates were generally consistent with overall estimates of relugolix and leuprolide observed in the overall population. Sustained castration rates were also mostly consistent for men taking the most common drug classes and individual agents in each class (losartan [n = 103]: relugolix, 95.4% vs leuprolide, 80.6%; amlodipine [n = 229]: 97.2% vs 85.5%; metoprolol [n = 88]: 95.7% vs 86.9%; acetylsalicylic acid [n = 259]: 97.0% vs 92.1%; clopidogrel [n = 43]: 96.4% vs 86.7%; simvastatin [n = 78]: 98.0% vs 87.3%). Incidence and types of adverse events (AEs) among men who received these medications were mostly consistent with overall population results, with some increases in grade ≥ 3 and fatal AEs. CONCLUSION: Relugolix suppressed testosterone and was generally well tolerated when given with concomitant CV agents. TRIAL REGISTRATION: Clinical Trial ID NCT03085095. PRIOR PRESENTATION: Data presented at 15th Annual Genitourinary Cancers Symposium; February 17-19, 2022, San Francisco, CA, USA [Abstract 101, Poster board E11]. The published abstract from this presentation can be found at https://ascopubs.org/doi/10.1200/JCO.2022.40.6_suppl.101 .

Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. PATIENTS AND METHODS: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. RESULTS: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03). CONCLUSIONS: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.

Hereditary cancer risk assessment and genetic testing in the community urology practice setting.

OBJECTIVES: To evaluate the feasibility of integrating a hereditary cancer risk assessment (HCRA) process in the community urology practice setting for patients with prostate cancer (PCa). METHODS: In this prospective intervention, an HCRA process was implemented across six different community urology clinics between May 2019 and April 2020. The intervention included a process integration during which the workflow at each site was refined, a post-integration period during which HCRA was conducted in all patients with PCa, and a follow-up period during which healthcare providers and patients reported their satisfaction with the HCRA and genetic testing process. RESULTS: Among patients who completed a family history assessment during the post-integration period, 23.6% met guideline criteria for genetic testing. Of all patients seen at the clinic during the post-integration period, 8.7% completed genetic testing; this was a twofold increase over the period immediately preceding process integration (4.2%), and a sevenfold increase over the same period 1 year prior (1.2%). The majority of providers reported that the HCRA was as important as other regularly performed assessments (61.0%) and planned to continue using the process in their practice (68.3%). Most patients believed that the genetic test results were important for their future cancer care (84.7%) and had already shared their test results with at least one family member (63.2%). CONCLUSIONS: This study demonstrated that implementing an HCRA process in the community urology practice setting was feasible, generally favored by providers and patients, and resulted in an increase in the number of patients with PCa who completed genetic testing.

The Oral Gonadotropin-releasing Hormone Receptor Antagonist Relugolix as Neoadjuvant/Adjuvant Androgen Deprivation Therapy to External Beam Radiotherapy in Patients with Localised Intermediate-risk Prostate Cancer: A Randomised, Open-label, Parallel-group Phase 2 Trial.

BACKGROUND: External beam radiotherapy (EBRT) with neoadjuvant/adjuvant androgen deprivation therapy (ADT) is an established treatment option to prolong survival for patients with intermediate- and high-risk prostate cancer (PCa). Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was evaluated in this clinical setting in comparison with degarelix, an injectable GnRH antagonist. OBJECTIVE: To evaluate the safety and efficacy of relugolix to achieve and maintain castration. DESIGN, SETTING, AND PARTICIPANTS: A phase 2 open-label study was conducted in 103 intermediate-risk PCa patients undergoing primary EBRT and neoadjuvant/adjuvant ADT between June 2014 and December 2015. INTERVENTION: Patients randomly assigned (3:2) to 24-wk treatment with either daily oral relugolix or 4-wk subcutaneous depot degarelix (reference control). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of effective castration (testosterone <1.73nmol/l) in relugolix patients between 4 and 24 wk of treatment. Secondary endpoints included rate of profound castration (testosterone <0.7nmol/l), prostate-specific antigen (PSA) levels, prostate volume, quality of life (QoL) assessed using the Aging Males' Symptoms scale, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (30-item EORTC core questionnaire [EORTC QLQ-C30] and 25-item EORTC prostate cancer module [EORTC QLQ-PR25]) questionnaires, and safety. No formal statistical comparisons with degarelix were planned. RESULTS AND LIMITATIONS: Castration rates during treatment were 95% and 82% with relugolix and 89% and 68% with degarelix for 1.73 and 0.7nmol/l thresholds, respectively. Median time to castration in the relugolix arm was 4 d. During treatment, PSA levels and prostate volumes were reduced in both groups. Three months after discontinuing treatment, 52% of men on relugolix and 16% on degarelix experienced testosterone recovery (statistical significance of differences not tested). Mean and median QoL scores improved following treatment discontinuation. The most common adverse event was hot flush (relugolix 57%; degarelix 61%). Lack of blinding was a potential limitation. CONCLUSIONS: Relugolix achieved testosterone suppression to castrate levels within days and maintained it over 24 wk with a safety profile consistent with its mechanism of action. PATIENT SUMMARY: Oral once-daily relugolix may be a novel oral alternative to injectable androgen deprivation therapies.

Results of a Real-world Study of Enzalutamide and Abiraterone Acetate With Prednisone Tolerability (REAAcT).

BACKGROUND: The objective of this study was to evaluate differences in tolerability in patients with metastatic castration-resistant prostate cancer treated with enzalutamide (ENZA) or abiraterone acetate plus prednisone (AA+P). PATIENTS AND METHODS: This was a phase IV, prospective, open-label, multicenter, real-world study. Patients were prescribed ENZA or AA+P at the treating physician's discretion. Computerized tests of 4 cognitive domains (Cogstate), patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 [EORTC QLQ-30], Functional Assessment of Chronic Illness Therapy-Fatigue [FACIT-Fatigue], Functional Assessment of Cancer Therapy-Cognitive Function [FACT-Cog]), and patient/caregiver surveys were assessed at baseline and 2 months. Safety data were collected. RESULTS: Of 100 treated patients, 92 were evaluable (46/arm). Baseline characteristics were similar, with mild cognitive impairment observed in ∼20% of patients. The FACIT-Fatigue demonstrated a statistically significant worsening from baseline of -4.00 (95% confidence interval, -6.61 to -1.39) for ENZA compared with AA+P, -0.01 (95% confidence interval, -2.40 to 2.38). Overall, more adverse events (AEs) and more AEs of fatigue were reported with ENZA versus AA+P (52% vs. 36% and 26% vs. 8%, respectively). Grade 3/4 AEs were similar (4% vs. 6%). Unique neuropsychiatric AEs reported with ENZA included amnesia, cognitive disorders, memory impairment, and confusional state; those for AA+P included cerebrovascular accident, presyncope, and spinal cord compression. Clinically meaningful cognitive decline was seen in 4 patients on ENZA versus 1 patient on AA+P. However, the overall mean changes from baseline for the Cogstate tests, the EORTC QLQ-C30, and the FACT-Cog assessment were similar and showed no meaningful change. Caregiver survey responses noted more fatigue with ENZA and more moodiness with AA+P compared with patient responses. CONCLUSIONS: Although baseline values were similar, more fatigue and neurocognitive differences were observed with ENZA compared with AA+P.

Contemporary Management of Incident Prostate Cancer in Large Community Urology Practices in the United States.

OBJECTIVE: To characterize the contemporary management of prostate cancer patients in large community practices. The optimal management of incident prostate cancer has changed in the last decades to include active surveillance for a large number of men. At the same time, many community practices have merged into larger groups. The adoption of evidence-based guidelines is of increasing importance, but poorly understood in this newer practice setting. METHODS: We conducted a retrospective chart review of men ≤75 years old with very low, low, and intermediate risk incident prostate cancer diagnosed between December 1, 2012 and March 31, 2014, in 9 geographically distributed large urology practices. We used descriptive statistics and multivariable regression to assess predictors of primary management choice. RESULTS: 2029 men were in the study cohort. A majority were white (68.7%). Total of 45.7% had intermediate risk, 36.2% low risk, and 17.9% had very low risk disease cancer. Active surveillance (AS) was the initial treatment for 74.7% of men with very low risk disease, 43.5% of men with low risk disease and 10.8% of men with intermediate risk disease. The probability of choosing surgery vs radiation for men with lower and intermediate risk disease was 0.54 (95% confidence interval: 0.42, 0.65) and 0.59 (95% confidence interval: 0.48, 0.69), respectively. CONCLUSION: We found that the initial management of lower risk prostate cancer in large community urology practices largely followed clinical characteristics, widespread adoption of active surveillance, and equal use of surgery and radiation. However, some variation by practice suggested a need for further investigation and continued improvement.

Three-year Active Surveillance Outcomes in a Contemporary Community Urology Cohort in the United States.

OBJECTIVES: To determine the 3-year outcomes of men with prostate cancer managed with active surveillance (AS) in a cohort of geographically diverse community-based urology practices. AS is the management of choice for a majority of men with lower risk prostate cancer.1,2,3 Little is known about the contemporary "real-world" follow-up and adherence rates in the most common setting of urologic care, community (private) practice.4 METHODS: We retrospectively evaluated outcomes for men diagnosed between January 1, 2013 and May 31, 2014 with National Comprehensive Cancer Network (NCCN) very low, low and intermediate risk prostate cancer who selected AS in 9 large community urology practices. We used univariate and multivariate analyses to describe associations between race, age, insurance status, family history, comorbidity, clinical stage, Gleason score, NCCN risk-group, and PSA density with discontinuation of AS. RESULTS: Five hundred and forty-eight men on AS were followed for a median of 3.35 years. 89% (492) continued to follow-up with diagnosing practice. 32% (171) discontinued AS. On multivariate analysis, increasing NCCN risk classification (Hazard ratio [HR] 1.65, P = 0.02 and HR 2.09, P < 0.01 for low and intermediate risk vs very low risk) was significantly associated with discontinuation. Among those who discontinued AS, surgery and radiation were utilized equally (47% and 53%, respectively, P = 0.48). CONCLUSION: In this community-based cohort of men on AS, a minority was lost to follow-up and adherence to AS was similar to other reports. Disease characteristics more than sociodemographic characteristics correlated with adherence to AS, while surgery and radiotherapy were utilized equally among those discontinuing AS, both suggesting guideline concordant practice of medicine.

eRADicAte: A Prospective Evaluation Combining Radium-223 Dichloride and Abiraterone Acetate Plus Prednisone in Patients With Castration-Resistant Prostate Cancer.

BACKGROUND: Multiple castration-resistant prostate cancer (CRPC) therapies are approved by the United States Food and Drug Administration. Radium-223 dichloride (Ra-223) with abiraterone acetate plus prednisone have different mechanisms of action and distinct off-target side-effect profiles. We prospectively investigated their combined safety, tolerability, and patient-reported outcome measures. PATIENTS AND METHODS: eRADicAte, an investigator-initiated, phase II trial, studied 31 patients with metastatic CRPC, from 5 United States uro-oncology research sites. Patients completed 6 cycles of Ra-223 with concurrent abiraterone therapy. Quality of life and pain were assessed using the Functional Assessment of Cancer Therapy-Prostate and the Brief Pain Inventory-Short Form questionnaires and their subscales; we reported the number of subjects meeting standardized criteria for clinically meaningful improvements on each scale. Safety assessment included Eastern Cooperative Oncology Group performance status, laboratory changes, opioid use, radiographic responses, and adverse events (AEs). RESULTS: Twenty of 31 (65%) experienced positive clinically meaningful improvement changes on the Functional Assessment of Cancer Therapy-Prostate, and 25 (81%) of 31 on the Prostate Cancer Subscale. Eighteen (58%) of 31 demonstrated reduced pain intensity and 12 (39%) of 31 demonstrated reduction of pain interference in their lives. At baseline, subjects averaged 11.6 ± 2.8 bone lesions; at the end of treatment, subjects averaged 5.6 ± 2.4 bone lesions (P = .0002). The most frequent AEs were diarrhea (17%), nausea (17%), and fatigue (14%). There were 6 serious AEs; 1 led to study withdrawal. CONCLUSIONS: Patients experienced clinically meaningful improvements in quality of life and pain, without unexpected adverse toxicities. Phase III combination trials of Ra-223 with novel oral hormonal agents are ongoing to further evaluate radiographic progression and overall survival benefit.