麻豆传媒

ORLANDO -- An investigational radionuclide therapy targeting prostate-specific membrane antigen (PSMA) achieved biochemical responses in 70% of patients with castration-resistant prostate cancer (CRPC), and prostate-specific antigen (PSA) reductions in all but one patient, enrolled in a small preliminary clinical trial.

Overall, 22 of 23 patients had some degree of PSA decline in response to fractionated treatment with ²²⁵Ac-J591. PSA reductions of at least 50% occurred in 16 patients, and six patients had 90% reductions in PSA. In a subgroup of patients with circulating tumor cell (CTC) values, 79% had CTC responses and more than half had at least a 50% decline.

A single fractionated cycle of the therapy was associated with limited grade 3/4 adverse events (AEs), particularly thrombocytopenia, reported Jones Nauseef, MD, PhD, of the Weill Cornell Medicine Meyer Cancer Center in New York City, at the American Association for Cancer Research annual meeting.

"A single fractionated cycle of ²²⁵Ac-J591 was delivered with few high-grade AEs," said Nauseef. "The efficacy is supported by PSA responses, CTC changes, and objective response. The decline in PSMA-PET signal was concordant with the PSA responses."

Ongoing and planned studies of the agent include a phase I evaluation in patients previously treated with ¹⁷⁷Lu-PSMA (Pluvicto), studies of single-agent ²²⁵Ac, and combination strategies, he added.

The study added more evidence to the case for radionuclide therapy in CRPC, according to invited discussant Howard Scher, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"What we've learned from this presentation is that with a single fractionated dose [of ²²⁵Ac-J591], one can see a marked reduction in the adverse events, and efficacy was reported by changes in PSA, which is a favorable objective response that recently has been accepted as a regulatory endpoint and by circulating tumor cells," said Scher. "Intuitively, if a patient has tumor cells that are circulating throughout the body and that process is stopped, that patient will live longer. This has been shown in virtually every solid tumor."

The treatment landscape for CRPC changed "with the approval of PSMA-PET imaging followed by the approval of a therapeutic, which has actually been shown to improve outcomes and improve survival in well-designed phase III trials," he added.

The benefits of the PSMA-targeted therapies will likely expand as use of the agents move into earlier-stage disease, which is biologically less diverse as compared with CRPC and more likely to be treated, Scher said.

J591 is a humanized monoclonal antibody against PSMA. Linking the antibody to the beta emitter ¹⁷⁷Lu led to greater ligand retention as compared with the small molecule PSMA-617. In a , a single dose of ¹⁷⁷Lu-J591 achieved better results with a higher dose, including almost a doubling of median survival, but more than half of patients developed grade 4 thrombocytopenia, and 40% received platelet transfusions.

allowed use of higher doses that led to greater PSA changes with no increase in myelosuppression. Looking for ways to improve the results, investigators considered changing the radionuclide payload. They eventually settled on the alpha emitter ²²⁵Ac. A case report of two patients with metastatic CRPC treated with ²²⁵AC-PSMA-617 showed complete serologic and radiologic response.

During his discussion, Scher said the case report "changed the metrics for patients with metastatic castration-resistant prostate cancer. There is no systemic therapy that has been shown to do this. This was a signal to us that we could raise the bar in clinical trials to see whether we can get further benefit."

A yet-to-be published study of a single dose of ²²⁵Ac-J591 showed the therapy was safe, with no dose-limiting toxicities and substantially lower rates of grade 3/4 thrombocytopenia and xerostomia.

Nauseef reported findings from a phase I dose-escalation study of fractionated ²²⁵Ac-J591 in patients with no prior exposure to ¹⁷⁷Lu-PSMA-617. The primary objectives were dose-limiting toxicities and identification of the recommended phase II dose.

Patients had a median age of 73.5 and a baseline median PSA value of 25.78 ng/mL. Most of the patients had bone and lymph node metastases. A majority had received taxane chemotherapy, and half had received two or more androgen receptor signaling inhibitors.

No dose-limiting toxicities occurred during the study. Grade 3/4 AEs associated with fractionated dosing included thrombocytopenia (9% grade 3 and 13% grade 4), neutropenia (22% and 0%), and anemia (17% and 0%). No patient developed grade 3/4 nonhematologic AEs.

Nauseef reported that 95% of evaluable patients had some degree of PSA decline, including 50% declines in 70%, and 90% decreases from baseline in 26%.

The CTC analysis showed that 11 of 14 evaluable patients met response criteria, seven of 13 had at least a 50% decrease, and six of 11 changed from detectable to undetectable.

Nauseef said results from a separate cohort with prior treatment with ¹⁷⁷Lu-PSMA-617 will be reported in the near future.

Comment