FDA Grants Fast Track Designation to TRE-515 Plus Radioligand Therapy in PSMA+ mCRPC

FDA

The FDA has granted fast track designation to the first-in-class deoxycytidine kinase (dCK) inhibitor TRE-515 in combination with lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617) for the treatment of patients with prostate-specific membrane antigen (PSMA)–positive metastatic castration resistant prostate cancer (mCRPC).1,2

Eligible patients include those with prior exposure to agents such as androgen receptor pathway inhibitors or taxane-based chemotherapies.1

The regulatory decision was supported by results from Trethera’s ongoing, first-in-human phase 1 trial (NCT05055609) evaluating the agent as an oral monotherapy in advanced solid tumors, alongside preclinical evidence. Previously reported findings from the phase 1a dose escalation trial showed that TRE-515 was well tolerated and showed early signs of antitumor activity in a high-risk, heavily pretreated patient population.1,2

TRE-515 demonstrated a favorable safety and tolerability profile across all 5 planned dose-escalation cohorts, with no dose-limiting clinical or laboratory toxicities observed at doses ranging from 40 mg to 320 mg once daily.2 Among all 19 patients enrolled, adverse effects were limited, transient, and manageable. Two patients received continuous therapy for over 200 days and 2 others underwent treatment for over 100 days with acceptable safety profiles.

Across dose levels, 5 patients achieved stable disease per RECIST 1.1 criteria. The majority of these patients had been heavily pretreated with extensive metastases. Pharmacokinetic data showed predictable exposure, and exploratory analyses confirmed on-target activity.

“This designation marks a critical milestone in our mission to develop more effective, well-tolerated therapies for aggressive and treatment-resistant prostate cancers,” Kenneth Schultz, MD, chairman, chief executive officer, and president of Trethera, stated in a news release.1 “By combining TRE-515 with targeted radioligand therapy, we seek to accelerate precision medicine going beyond current standards of care and deliver meaningful, long-term benefits to patients.”

TRE-515 is a clinical-stage small molecule that selectively inhibits dCK, the rate-limiting enzyme of the nucleoside salvage pathway—one of 2 critical biosynthetic pathways responsible for generating deoxynucleotide triphosphates required for DNA synthesis and repair.1,2 Tumor cells in solid malignancies and aberrant immune cells in autoimmune conditions frequently exhibit heightened dependence on nucleotide biosynthesis to support uncontrolled proliferation. In contrast, most normal adult cells rely primarily on the de novo pathway and exhibit low dCK activity, suggesting a therapeutic window for selective targeting. By disrupting this metabolic vulnerability, TRE-515 aims to impair DNA precursor availability in rapidly dividing cells, thereby exerting antiproliferative effects with a potentially favorable safety profile.

Trethera is developing TRE-515 both as a monotherapy and in combination regimens for cancer and autoimmune indications. The agent is currently being evaluated in phase 1 clinical trials in advanced solid tumors.1

“I believe that TRE-515 has the potential to make a meaningful difference in the lives of prostate cancer patients and I am pleased that Trethera has received this fast track designation to expedite development,” Michael Jung, PhD, inventor of TRE-515 and cofounder of Trethara, added in the news release.“The chemical structure of TRE-515 was designed for a specific, on-target, binding to create an optimal drug profile.”

Jung is also a Distinguished Professor of Chemistry & Biochemistry and the Walter and Shirley Wang Endowed Chair in Medicinal Drug Discovery at UCLA.

Phase 1 Trial Design

The open-label, multicenter, nonrandomized phase 1 trial was designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TRE-515 in adult patients with histologically or cytologically confirmed solid tumors.3 Eligible patients had advanced, refractory disease for which no standard curative or palliative options were available or effective. Patients with known biomarkers of progression, such as prostate-specific antigen or CA-125, had biomarker status recorded. Notably, no limit was placed on the number or type of prior therapies. Additional eligibility criteria included measurable disease per RECIST 1.1 criteria or biomarker-evaluable disease in patients lacking measurable lesions; an ECOG performance status of 0 to 2; the ability to undergo PET imaging; and resolution of prior treatment-related toxicities to grade 1 or lower.

The dose-escalation portion was designed to enroll up to 46 patients across at least 5 sequential dose cohorts of TRE-515. TRE-515 was administered orally once daily in continuous 21-day cycles. A standard 3+3 dose escalation scheme was employed to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). In each cohort, 3 patients were initially enrolled and monitored through the full dose-limiting toxicity (DLT) evaluation period. Once the RP2D was established, 6 additional patients were planned to receive TRE-515 at that dose to further characterize safety and assess preliminary signs of antitumor activity. Treatment continued until radiographic disease progression per RECIST 1.1 criteria or the development of unacceptable toxicity.

The study’s primary end points were to evaluate safety and determine the maximum tolerated dose; secondary end points included establishing a RP2D, characterizing pharmacokinetics/pharmacodynamics, and assessing preliminary antitumor activity. Exploratory objectives included biomarker assessments related to target engagement.

“Prostate cancer is the second leading cause of cancer-related death in men. Although the treatment landscape continues to evolve, there is a high unmet need for additional precision medicine treatments and intelligently paired combination therapies to improve patient outcomes,” Johannes Czernin, MD, the cofounder of Trethara, as well as a professor and vice chair of the Department of Molecular and Medical Pharmacology at the David Geffen School of Medicine at UCLA, stated in the news release.1 “This TRE-515 FDA designation offers continued hope to the mCRPC community.”

“Trethera is working closely with the FDA to accelerate development and reimagine cancer care by combining radioligand therapy with TRE-515 to extend the lives of patients with prostate cancer and elevate current standards of care,” Jean B. DeKernion, MD, Trethera Director Emeritus and cofounder of the Specialized Program of Research Excellence in Prostate Cancer at UCLA, concluded in the news release.

References

1. FDA grants fast track designation for TRE-515 in combination with radiation therapy for the treatment of metastatic castration resistant prostate cancer. News Release. Trethera. July 9, 2025. Accessed July 9, 2025. https://trethera.com/news/fda-fast-track-tre-515-metastatic-prostate-cancer
2. Dose escalation portion of phase 1 solid tumors trial produces favorable results in heavily pretreated solid tumor patients. News Release. Trethera. March 15, 2023. Accessed June 9, 2025. https://trethera.com/news/dose-escalation-phase-1-solid-tumors-favorable-results
3. Open-label, dose-escalation with expansion to assess the safety, tolerability, and PK of TRE-515 in subjects with solid tumors. ClinicalTrials.gov. Updated May 22, 2025. Accessed July 9, 2025. https://www.clinicaltrials.gov/study/NCT05055609