The potential oral therapy TRC253 was well-tolerated and showed effectiveness in a subset of patients with metastatic castration-resistant prostate cancer (mCRPC), according to results from the first part of a Phase 1/2a clinical trial.
The study, “An open label phase 1/2A study to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of TRC253, an androgen receptor antagonist, in patients with metastatic castration-resistant prostate cancer,” was presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the 2019 ASCO Annual Meeting Proceedings.
TRC253 is a small molecule developed by Tracon Pharmaceuticals that selectively blocks the androgen receptor (AR), whose activation is key for the growth of prostate cancer at all stages. Although prior therapies targeting the AR have prolonged the time to disease progression and, in some cases, the survival of people with mCRPC, treatment resistance is common and is due to changes such as AR mutations.
The treatment candidate, licensed from Janssen in 2016, was designed to address these resistance mechanisms by specifically targeting mutations in the AR binding domain, including the F877L mutation. It also suppresses signaling through the normal receptor.
A total of 22 men whose disease had progressed on Xtandi (enzalutamide, by Astellas and Pfizer), or Erleada (apalutamide, by Janssen) were enrolled into one of six groups of increasing daily doses of TRC253 (40–320 mg).
In the study, one man had the F877L mutation in the AR, which results in an altered binding domain in the receptor and in resistance to current medicines. This patient remained on treatment for 49 weeks and showed a partial response to TRC253.
Of the remaining 21 participants, 10 stayed on the study for a minimum of six months, received over six treatment cycles, and one showed a decrease in the prostate specific antigen — a well-established prostate cancer marker — greater than 50%.
TRC253-related adverse side effects included elevated levels of lipase (a pancreatic enzyme), fatigue, joint pain, diarrhea, and a lower platelet count. No treatment-related serious side effects were found.
Treatment with the 280 mg daily dose enabled achievement of the target exposures, which made the team select this dose for the ongoing Phase 2 trial.
Because the Phase 1 results suggested clinical efficacy, the Phase 2 protocol was changed to include an additional group to test TRC253 in mCRPC patients with a point mutation other than F877L. This second stage of the trial intends to have 15 patients with, and 30 without, the F877L mutation.
“We are pleased to have successfully completed the Phase 1 portion of the first-in-human study of TRC253 and look forward to the availability of Phase 2 data, which we expect in the second half of 2020,” Charles Theuer, MD, PhD, Tracon’s president and CEO, said in a press release.
Upon completion of the trial, Janssen will have the exclusive option to reacquire TRC253 for a $45 million fee, as well as royalties and other payments (up to $137.5 million) depending on the program’s success. If Janssen does not exercise this option, Tracon would have to pay up to $45 million in commercialization milestones, as well as a single-digit royalty.