FDA Oks Phase 3 Trial of PT-112 in mCRPC Following Successful EOP2 Meeting
PT-112 monotherapy advances to phase 3 trial in metastatic castration-resistant prostate cancer after positive FDA end of phase 2 meeting.
US FDA
- Promontory Therapeutics is moving forward with a registrational phase 3 study of PT-112 monotherapy in metastatic castration-resistant prostate cancer (mCRPC).
- The FDA has agreed with the proposed dosing regimen, study design, end points, comparator, statistical framework, and patient population.
- The study will include an interim analysis, potentially allowing for earlier regulatory approval.
Following a constructive end of phase 2 meeting with the FDA, Promontory Therapeutics Inc. is advancing its development program for PT-112 monotherapy in patients with mCRPC.1 The successful meeting paves the way for the company to prepare and submit a registrational phase 3 study.
Notably, the FDA aligned with the proposed dosing regimen for the upcoming prospective, randomized controlled phase 3 trial, a decision that was informed by the data from the completed phase 2 study of PT-112 in mCRPC (NCT02266745). There was also an agreement in principle regarding the study design, end points of the trial, the proposed comparator, and the statistical framework.
The FDA also agreed with the company’s proposed patient population and their suggestion for an interim analysis. This introduces the potential for earlier drug approval, contingent on the interim results, before the full completion of the phase 3 trial.
Promontory Therapeutics will now focus on preparing the complete phase 3 study submission for final FDA review, incorporating the agency's guidance. The company also intends to engage with international regulatory authorities to discuss similar pathways.
Prostate cancer under the microscope: © heitipaves - stock.adobe.com
The foundation for this progress stems from a proof-of-concept and dose-optimization phase 2 study of PT-112 monotherapy in advanced mCRPC. The trial was conducted across sites in the US and France. This phase 2 trial included 3 randomized dosing arms of PT-112.
The open-label, multicenter, nonrandomized, dose-escalation study is being conducted in 2 parts: the dose-escalation phase to determine the maximum tolerated dose and the dose-expansion phase to evaluate its safety, tolerability, and pharmacokinetics (PK).2 The dose-escalation phase is complete and is no longer enrolling patients.
In the dose-expansion phase, 2 cohorts were evaluated. The first cohort (cohort A) consisted of patients with thymoma and thymic carcinoma, and the second cohort (cohort D) included patients with mCRPC.
Patients were required to be male, aged 18 years or older, and have histologically or cytologically confirmed adenocarcinoma of the prostate. Patients must have had evidence of mCRPC, where metastatic status is defined as having documented metastatic lesion(s) on either bone scan or CT/MRI scan, have received 3 or more prior intended life-prolonging therapies for metastatic disease, and have an ECOG performance status of 0 or 1. In addition, enrollment was open to patients with progressive disease, either measurable on physical examination or imaging by RECIST v1.1 or PCWG3 or by informative tumor marker(s) and adequate organ function based on laboratory values. If patients had a known history of brain metastases that were either treated or untreated, the disease must be stable.
Recent data highlighting immune response biomarkers were presented at the American Association of Cancer Research (AACR) 2025 Annual Meeting and provided insights into PT-112's mechanism of action.3 In a thymic epithelial tumors trial (n = 14; NCT05104736), peripheral immunome analysis revealed immune activation, marked by increased proliferative CD4-positive and CD8-positive T cells, activated natural killer (NK) cells, and PD-L1-expressing monocytes, alongside a decrease in naive CD4-positive T cells.
Serum analysis (n = 7) showed elevated pro-inflammatory cytokines, including IFN-γ and TNF-α, and reduced immunosuppressive factors. Limited tumor biopsy data (n = 3) indicated increased immune cell density and expression of activation markers. Further, in the broader mCRPC trial cohort (n = 74), 35% of patients exhibited marked T-cell clonal expansions, often with novel clones, and the overall median T-cell fraction significantly increased by 20% (P <.0005).
Experts can expect further insights into the preliminary clinical outcomes, which are scheduled to be presented at the upcoming American Society of Clinical Oncology (ASCO) 2025 Annual Meeting.1
