Clinical Summary:

• Design/Population: The phase 3 PROSTACT Global trial evaluating TLX591 (lutetium-177 rosopatamab) plus investigator-selected standard of care versus standard of care alone in patients with metastatic castration-resistant prostate cancer. Part 1 included 36 patients in a safety and dosimetry lead-in cohort.
• Key Outcomes: Early data demonstrated favorable dosimetry, prolonged tumor retention of radiation, manageable hematologic toxicity, and limited off-target radiation exposure to the kidneys and salivary glands. The study has successfully advanced into the randomized efficacy phase.
• Clinical Relevance: TLX591 represents a novel antibody-based PSMA radioligand approach that may offer advantages over peptide-based therapies through prolonged tumor residence time and reduced radiation exposure to sensitive normal tissues.

David Cade, MD, Telix Pharmaceuticals, Sydney, Australia, discusses the PROSTACT Global trial evaluating TLX591, an investigational PSMA-targeted radio-antibody drug conjugate for metastatic castration-resistant prostate cancer. Unlike currently approved peptide-based PSMA radioligands, TLX591 uses a monoclonal antibody platform designed to deliver radiation directly to tumor cells while limiting uptake in the kidneys and salivary glands.

Part 1 of the study demonstrated favorable safety and dosimetry characteristics, including prolonged retention of radiation within tumors, low rates of off-target organ exposure, and manageable hematologic toxicity. These findings supported progression into the randomized phase 3 portion of the trial, which will evaluate whether adding TLX591 to standard therapy improves radiographic progression-free survival and overall survival.

Transcript: 

Thank you for having me here, my name is David Cade, and I’m the Group Chief Medical Officer at Telix Pharmaceuticals Limited. As you can probably tell from the accent, I’m based in Sydney.

We’re talking about the ProstACT GLOBAL trial, which is a multicenter, international, randomized controlled trial evaluating a Telix pipeline candidate known as TLX591, which is the development name for lutetium-177 rosopatamab. The ProstACT GLOBAL study builds upon multiple prior phase 1 and phase 2 trials with this agent, in which we have studied it extensively in different groups of patients with metastatic castration-resistant prostate cancer.

What those earlier studies established is that this radiolabeled antibody-drug conjugate—and I emphasize that because it is quite distinct from the small-molecule radioligand therapies currently approved or in development for prostate cancer—has a unique mechanism of action. TLX591 is a radio-antibody drug conjugate. Rather than using a small molecule, it uses a monoclonal antibody to target PSMA-expressing prostate cancer cells while minimizing radiation exposure to sensitive organs such as the kidneys and salivary glands. Those earlier studies helped us characterize the safety profile of the agent, and based on those findings we have now advanced it into phase III development.

ProstACT GLOBAL is a phase 3 international trial being conducted across North America, Europe, China, Japan, Australia, New Zealand, and several other countries. The goal of the study is to evaluate TLX591 layered on top of conventional standard-of-care treatment. The standard-of-care backbone differs across regions. In North America, androgen receptor pathway inhibitors are most commonly used, whereas in some other regions docetaxel remains widely utilized. Investigators are allowed to select the appropriate standard-of-care backbone, and TLX591 is then added on top of that therapy. The objective is to determine whether the addition of TLX591 can improve radiographic progression-free survival and ultimately overall survival. At ASCO 2026, we are presenting results from Part 1 of the study.

Part 1 is a safety and dosimetry lead-in involving 36 patients. This portion was designed to assess the safety of combining TLX591 with different androgen receptor pathway inhibitors, as well as sequencing it with docetaxel, while also evaluating radiation dosimetry before proceeding to Part 2, the randomized expansion phase. One important point is that Part 2 has already begun in multiple countries. Patients are already being randomized to standard of care alone versus standard of care plus TLX591. 

As I mentioned, TLX591 is a radio-antibody drug conjugate. It uses a monoclonal antibody that specifically targets tumor-expressed prostate-specific membrane antigen, or PSMA, while avoiding significant uptake in normal tissues such as the salivary glands. It is also not filtered through the kidneys in the same way that small-molecule radioligands are. As a result, we do not see meaningful radiation exposure to those sensitive organs. The uptake, internalization, and residence time of this antibody-based therapy within prostate cancer cells is much longer than what is observed with small-molecule radioligands. Small molecules enter tumor cells, remain for a relatively short period of time, and are then cleared through the bloodstream and kidneys. By contrast, the antibody carries the radiation payload into the tumor cell and remains there for a prolonged period. This allows the radiation to continue delivering double-stranded DNA damage to the tumor over an extended duration.

When we perform post-treatment SPECT imaging, we can see that the radiation remains concentrated within the tumor for up to two weeks, rather than only a few hours or days. That is exactly what we want. Another practical advantage is that patients do not need repeated treatments over many months. The complete treatment course consists of only two fractions administered two weeks apart. This makes treatment relatively convenient and patient-friendly, as it is simply layered on top of whatever standard systemic therapy the patient is already receiving. 

Like all radioligand therapies, TLX591 has its own safety profile. The primary adverse events are hematologic. Platelet counts and neutrophil counts can decline, but when they do, they typically recover rapidly, usually within about two weeks, returning to grade 1 levels or normal ranges. In most cases, patients are not even aware of these changes. They generally do not feel different; the abnormalities are detected through routine blood testing. Importantly, patients do not typically experience dry mouth, long-term kidney injury, or many of the off-target toxicities associated with other radioligand approaches. What we see instead is a transient and manageable hematologic toxicity profile that resolves quickly. 

We had extensive discussions with the US FDA regarding the design of this study, as well as with experts in the field and major prostate cancer advocacy groups across North America. Together, we agreed that this two-part design was the most appropriate approach. Part 1 has now demonstrated that the treatment is feasible and that the safety and dosimetry profiles are manageable. That allows us to move confidently into Part 2, where the focus will be on the definitive efficacy endpoints—radiographic progression-free survival and overall survival. 

We are very excited to see those results mature in the coming years. Thank you very much.

Source: 

Barata P, Tincknell G, Gill DM, et al. Safety and dosimetry of 177Lu-rosopatamab tetraxetan plus SoC in patients with metastatic castration-resistant prostate cancer: Preliminary results from part 1 of phase 3 ProstACT Global study. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. LBA5009.