Since prostate-specific membrane antigen (PSMA) became a standard-of-care therapy for patients with metastatic castration-resistant prostate cancer (mCRPC) in 2022, multiple agents showing potential to offer higher potency have entered the pipeline.

225Ac-J591, an alpha-emitter antibody-drug conjugate is 1 PSMA targeted therapy making headway, according to Jones T. Nauseef, MD, PhD. A phase 1 dose-escalation study investigating the agent in patients with mCRPC recently completed and is advancing to phase 2.¹

“There are a couple different ways to target PSMA. One is with a small molecule ligand, and the other one would be with a monoclonal antibody. J591 is our monoclonal antibody that has terrific targeting on cells that are expressing PSMA, and it helps with internalization into the cell. This monoclonal antibody is going to go throughout the body and with it carry actinium 225, and that is a potent radionuclide. With the antibody going to the sites where you want it to go, it will bring with its payload, which is radionuclide,” explained Nauseef, assistant professor of medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, and assistant attending physician at NewYork-Presbyterian Hospital, in an interview with Targeted Oncology™.

Results from the 24 patients with mCRPC included in the phase 1 study of 225Ac-J591 showed that the administration of a single fractionated cycle of 225Ac-J59l led to few high-grade adverse events. Moreover, preliminary efficacy was demonstrated with the drug in terms of prostate-specific antigen decline and changes in circulating-tumor (ct)DNA.

In the interview, Nauseef discussed how 225Ac-J591 achieves apoptosis, and findings from the phase 1 study, which he presented during the American Association (AACR) for Cancer Research Annual Meeting 2023.

TARGETED ONCOLOGY: Can you talk about the introduction of PSMA-targeted therapy in the prostate cancer space and the impact it has had?

Nauseef: The treatment of prostate cancers, specifically metastatic castrate-resistant prostate cancer, has changed so much in 25 years. [There has been] approval of drugs in many sectors, [including] AR pathway inhibitors, taxanes, targeted therapies, you name it. Most recently, with the approval of 177 Lu- PSAM-617, targeted radiotherapy is now reality in prostate cancer. This has come about because PSMA is just such a terrific target. Almost all of it is on prostate cells or prostate cancer cells. There are some in physiologic spaces, but otherwise, it makes for a nice target. The drugs that are now approved have had some real successes.

What can say about the agent 225Ac-J591 and the rationale for using it to treat patients with mCRPC?

There are a couple different ways to target PSMA. One is with a small molecule ligand, and the other one would be with a monoclonal antibody. J591 is our monoclonal antibody that has terrific targeting on cells that are expressing PSMA, and it helps with internalization into the cell. This monoclonal antibody is going to go throughout the body and with it carry actinium 225, and that is a potent radionuclide. With the antibody going to the sites where you want it to go, it will bring with its payload, which is radionuclide.

This is important. Patients with mCRPC can have cancer anywhere in their body, and you want to be able to target this. You can do that effectively with an antibody like J591 and bring with it a potent radionuclide. That’s one of the things that's so nice about the potency of this drug is that it has a short path length. Though you're delivering a high energy that even a single hit on a cell can result in double stranded DNA breaks and cell death, the path length is short, so your toxicity may be lower because the drug isn't going to get away from where you want it to be. This will be true anywhere that a patient has cancer. That is commonly in the bones and the lymph nodes, but also visceral sites of disease, such as the liver and lungs.

Can you explain about the study design and methods used in this study?

The data we presented was our phase 1 study of patients who did not have prior exposure to Lutetium-177-PSMA-617 in all patients with mCRPC. These patients were all the men had prior exposure to taxane-based chemotherapies, and half of them had received 2 or more prior androgen receptor signaling inhibitors, but everyone needed to have at least 1. This study design was modified 3 + 3 dose-escalation.

A key point to note about this study, in contrast to the VISION study [NCT03511664] that led to the approval of PSMA 617 is that PSMA PET imaging was done at baseline and was part of the screening criteria. But avidity or positivity on the scan was not required to be enrolled in the study. This is important because you could essentially take almost any patient with mCRPC and put them in this study and be able to generalize the results that we observed. In the dose-escalation, we had 3 cohorts, and after seeing what the toxicity was, we added a fourth cohort. That was how we established our recommended phase 2 dose.

What results did you present during AACR 2023?

Anytime we do a phase 1 study, everyone is interested in any evidence for preliminary efficacy. But the primary objective of these studies is to determine the dose-limiting toxicity, and the recommended phase 2 dose, and those things were established in our study.

Regarding the dose-limiting toxicity [DLT] period, we defined this period as the 8 weeks following the first dose of the drug, and the drug is given twice, once on day 1, once on day 15 in a dose intense fractionated regimen, during a single cycle. We looked specifically for DLTs related to neutropenia, thrombocytopenia, and then any-grade toxicity that would have delayed receipt of the second dose by greater than 2 weeks. In the dose-escalation, we observed at the highest dose, 2 DLTs. One patient had grade 4 thrombocytopenia, and that patient had prior exposure to PSMA 617 radioligand therapy. Then, a second DLT was in a patient with grade 2 thrombocytopenia that resulted in delay of the second dose by greater than 2 weeks. Following that, we did revise the protocol as mentioned and made an intermediate dose, a cohort 2.5 at 120 kg, delivered in 2 doses. In this group, 6 patients were treated and only 1 DLT was observed, which was grade 4 thrombocytopenia.

The grade 4 thrombocytopenia that I mentioned was transient and reversible. I saw this patient last month. His platelets are now back to normal, there were no high-grade non-hematologic toxicities, and fatigue and pain flare were common, but were all grade 1 or grade 2.

As far as efficacy goes, we observed very good efficacy regarding PSA change. Of the patients treated who were evaluable, we saw PSA declined in almost every patient with commonly PSA declines of 50% or 90%. Of those patients who had a PSA decline of 50%, 12 of the 16 were confirmed as PSA50, and 1 of those patients is still pending as confirmatory PSA.

We also saw good efficacy regarding circulating tumor cells. There were 14 patients that had CTCs at baseline, and at 12 weeks were available for change. Across the board we saw good responses.

Breaking that down into greater detail, most of the patients did have a CTC response. Almost 80% of patients had any CTC response of the patients who had variable CTCs at baseline. At 12 weeks, more than 50% had a 50% or greater decline in CTC count. There were also 5 patients who were unfavorable at baseline, and 2 of them converted to favorable. I think most excitingly, of the 11 patients who had detectable CTC as baseline, 6 of them became undetectable at 12 weeks, consistent with a good response.

What are the next steps with this research?

We've identified as the recommended phase 2 dose 120 KBq/kg given into fractions. We are proceeding with the phase 2 study with that dose.

There are important changes to highlight that will be occurring in the phase 2. One is the addition of a radioligand-specific patient-reported outcome. This is nice because we can observe whether the adverse event profile is different than it might be from chemotherapy or targeted agent or something on the AR signaling pathway. This patient-reported outcome was tailored specifically to radionuclide therapies. I think that's important to highlight and it makes us better able to take care of these patients as this becomes a more common modality. The second change is the introduction of dosimetry for alpha emitters. This will be done using multi-timepoint specification for Francium and Bismuth. Using dosimetry will allow us to measure and calculate the radioactivity dose received rather than just delivered, which I think is important as we move into using alpha emitters more commonly.

REFERENCE:

Nauseef JT, Sun M, Thomas C, et al. CT014 - Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer. resented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT-014.