Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial

Background Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium. Accordingly, we hypothesize that therapeutic targeting of androgen receptor signaling via degarelix, a luteinizing hormone-releasing hormone (LHRH) antagonist, will suppress COVID-19 infection and ameliorate symptom severity. Methods This is a randomized phase 2, placebo-controlled, double-blind clinical trial in 198 patients to compare efficacy of degarelix plus best supportive care versus placebo plus best supportive care on improving the clinical outcomes of male Veterans who have been hospitalized due to COVID-19. Enrolled patients must have documented infection with SARS-CoV-2 based on a positive reverse transcriptase polymerase chain reaction result performed on a nasopharyngeal swab and have a severity of illness of level 3–5 (hospitalized but not requiring invasive mechanical ventilation). Patients stratified by age, history of hypertension, and severity are centrally randomized 2:1 (degarelix: placebo). The composite primary endpoint is mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at 15 after randomization. Important secondary endpoints include time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a normal temperature, and the maximum severity of COVID-19 illness. Exploratory analyses aim to assess the association of cytokines, viral load, and various comorbidities with outcome. In addition, TMPRSS2 expression in target tissue and development of anti-viral antibodies will also be investigated. Discussion In this trial, we repurpose the FDA approved LHRH antagonist degarelix, commonly used for prostate cancer, to suppress TMPRSS2, a host cell surface protease required for SARS-CoV-2 cell entry. The objective is to determine if temporary androgen suppression with a single dose of degarelix improves the clinical outcomes of patients hospitalized due to COVID-19. Trial registration ClinicalTrials.gov NCT04397718. Registered on May 21, 2020

Preliminary results from a phase II trial of docetaxel before castration with degarelix in men with newly diagnosed metastatic prostate cancer.

116 Background: Randomized trials have demonstrated a survival advantage to administering docetaxel (D) shortly after initiation of androgen deprivation therapy (ADT) in men with newly diagnosed hormone sensitive metastatic prostate cancer (hsMPC). Clinical trials in breast cancer, research in prostate cancer cell lines, and pharmacokinetic analyses of D clearance in the castrate state, suggest increased efficacy of chemotherapy administered separately from hormone suppression. We proposed that treatment with D before ADT might improve outcomes in newly diagnosed hsMPC. Methods: In an ongoing phase II study (NCT03069937), men with newly diagnosed hsMPC were treated with 4 cycles of D (75mg/m2) every 21 days without ADT followed by 2 cycles of D concurrent with the LHRH antagonist degarelix (Deg) administered every 4 weeks. The Deg alone was continued for a total of 7 injections. Men were trial eligible with high or low volume disease by CHAARTED criteria. Bicalutamide was allowed for < 30 days before trial entry, but LHRH directed therapy was not permitted. The primary endpoint for this trial is percentage of men obtaining PSA < 0.2 ng/ml. Pre-specified secondary endpoints examined here after 4 cycles of docetaxel alone are safety, and efficacy defined by PSA (decrease by > 50%) and radiographic responses. Results: At time of this abstract, 50 patients have been enrolled to trial. Two patients withdrew after 1 cycle of D, and 4 patients have not yet completed 4 cycles. Of the 50 patients evaluable for safety, 6 (12%) had Grade 3 toxicities related to D. No Grade 4/5 toxicities were reported. Of patients who completed 4 cycles of D, 24/44 (55%) had a PSA response and 34/44 (77%) had PSA decline from baseline. All but two patients with declining PSA had stable or improved radiographic imaging. Six of the 44 patients (14%) had PSA progression (>25% increase) with D therapy, 3 of whom also had radiographic progression. Every patient with PSA response after 4 cycles D had PSA decline after 2 cycles. No patient with PSA decline after 2 cycles had PSA progression after 4 cycles. PSA response rate was stratified by baseline variables in table below. Conclusions: In hsMPC patients, 4 cycles D without ADT appears to be a safe and active therapy. Treatment with bicalutamide prior to the start of D predicts poorer PSA response. This result strengthens our hypothesis that sensitivity of hsMPC to taxane therapy may be enhanced if ADT is postponed. Baseline genomics will be analyzed, and we hope to correlate responses to D alone with later primary efficacy outcomes. Clinical trial information: NCT03069937. [Table: see text]

A randomized phase Ib/II study of nivolumab with or without BMS-986253 in combination with a short course of ADT in men with castration-sensitive prostate cancer (MAGIC-8).

TPS329 Background: Androgen deprivation therapy (ADT) is highly effective in castration-sensitive prostate cancer (CSPC) but is associated with significant side effects. Novel strategies to reduce ADT exposure and prolong disease control are needed. ADT initially induces a complex immune infiltrate within prostate tumors, suggesting that immunologic intervention may be more effective at the time of castration. Emerging data suggests that the cytokine interleukin-8 (IL-8) recruits immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment (TME) of many malignancies, including prostate cancer and serum IL-8 levels correlate with lack of response to anti-PD-1 therapy. We hypothesize that immunotherapy with nivolumab (a PD-1 inhibitor) with or without BMS-986253 (an IL-8 inhibitor) combined with degarelix (an LHRH antagonist) will be safe and promote an anti-tumor immune response that can prolong time to disease relapse in CSPC. Methods: This is a randomized, multicenter, two-arm, phase 1b/2 trial of patients with biochemically-recurrent or low volume metastatic CSPC and a rapidly rising PSA (≤12 months). 60 patients will receive immunotherapy with nivolumab or nivolumab plus BMS-986253 for 24 weeks. 16 weeks of ADT with degarelix will be added after 8 weeks of immunotherapy alone. The primary endpoints are safety and PSA relapse rate 10 months after the initiation of therapy. Secondary endpoints include relapse-free survival (RFS), time to testosterone recovery, rate of metastatic progression and change in PSA with immunotherapy alone. Correlative studies will quantify the systemic immune response through cytokine analysis and peripheral T cell profiling using serum and whole blood specimens collected from all enrolled patients. Pre- and on-treatment biopsies will also be obtained from the subgroup of patients with metastatic disease to further define changes in the TME using RNA-sequencing and quantitative multiplex immunofluorescence. The study is open with 1 patient currently enrolled at the time of submission. Clinical trial information: NCT03689699.

Quality of life differences for LHRH-antagonist versus LHRH-agonist in special patient groups with cardiovascular comorbidities and higher tumor burden in patients with hormone-sensitive prostate cancer (hsPCa).

153 Background: ADT with LHRH-agonists or LHRH-antagonists (degarelix, D) is the standard of care in advanced hsPCa. An analysis of ProComD from 2018 showed that D was more frequently used in patients with cardiac and peripheral arterial disease. Methods: In the ProComD, a two-arm, prospective non-interventional study, potential differences in comorbidity and other parameters such as baseline PSA and metastatic status on patient reported outcome between D and LHRH-agonists treatment were investigated. Results: Data on patients with a minimum follow-up period of one year (n = 285, D = 179, LHRH-agonist = 106) up to three years (n = 62, D = 40, LHRH-agonist = 22) were documented. Baseline criteria were generally similar except for disease T-stage (p = 0.0238), metastatic status (p = 0.0419) and PSA (p = 0.0041). The average age of patients was 74.1 years. Stage distribution: D vs LHRH-agonists, pT2 25.7/24.5%, pT3 24.1/34.9%, pT4 6.1/2.8%, unknown. 44.1/37.7%, cNX 49.7/44.3%, cN0 32.4/42.5%, cN+ 17.9/12.3%, cMX 27.4/25.5%, cM0 34.1/49.1%, cM1 38.6/25.5%. Global health status (EORTC) did not change over 12 months neither for D nor for LHRH-agonists. Differences in subscales between D and LHRH-agonists were observed for role functioning, cognitive functioning and, while QoL was unchanged under D, LHRH-agonists sig. reduced QoL (p = 0.073, p = 0.0368). Pain (marginal sig.) p = 0.0621) as well as analgesics (17.3% vs 1.1% at 3 months vs baseline) were reduced by D. Since baseline PSA differed sig., we specifically evaluated the subgroup of patients with a PSA > 50 ng/ml, where Global Health Status was found to be different between D and LHRH-agonists already at month 6 and at month 12 (p = 0.0331, p = 0.0232), favoring D. Conclusions: Our results indicate that Degarelix, with a different mode of action, is used in a different patient group (CVD and higher tumor stage as well as metastatic patients) compared to LHRH-agonists treatment. EORTC Global Health is similar to LHRH-agonists, but differences occur in subscales (role and cognitive functioning) as well as in subgroups (PSA > 50 ng/ml) in favour of the LHRH-antagonist. Clinical trial information: NCT02234089.