ABSTRACT
PURPOSE: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzamides , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant , Receptors, Glucocorticoid , Humans , Male , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/therapeutic use , Phenylthiohydantoin/pharmacokinetics , Benzamides/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Nitriles/administration & dosage , Aged , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , Neoplasm Metastasis , Androgen Receptor Antagonists/therapeutic use , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/pharmacokinetics , Androgen Receptor Antagonists/adverse effects , Receptors, Androgen/metabolism , Treatment OutcomeABSTRACT
We report a rare case of primary intracranial alveolar rhabdomyosarcoma (ARMS) in the right temporal lobe of a 51-year-old male. ARMS is one of 3 histological subtypes of rhabdomyosarcoma that most commonly presents in older children and younger adults. To our knowledge, there have been no prior published reports of primary intracranial ARMS in adults. Known cases of intracranial ARMS in adults are due to central nervous system (CNS) metastases from the head and neck and extremities. Diagnostic workup did not reveal any primary source outside the CNS. Given that risk factors for ARMS have not been studied in adults, it is difficult to ascertain what aspects of this patient's clinical history may have contributed to his diagnosis. Interestingly, he had prior history of traumatic brain injury requiring evacuation of a right fronto-temporal intraparenchymal hematoma.
