Phase 1 AcTION trial establishes RP2D for 225Ac-PSMA-617

Results from the AcTION phase 1 trial (NCT04597411)—the first prospective study of the alpha-emitting radioligand therapy (RLT) ²²⁵Ac-PSMA-617 in men with metastatic castration-resistant prostate cancer (mCRPC)—demonstrated a manageable safety profile up to 10 MBq, with no dose-limiting toxicities (DLTs) and no maximum tolerated dose (MTD) reached, alongside promising prostate-specific antigen (PSA) and radiographic responses across all 3 patient groups regardless of prior ¹⁷⁷Lu-PSMA-PSMA RLT exposure.¹

Louise Emmett, MD, PhD, MBChB, FRACP, a conjoint professor at St. Vincent's Public Hospital in Sydney, Australia, presented the data at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

Background

²²⁵Ac-PSMA-617 is an alpha-emitting prostate-specific membrane antigen (PSMA)-targeted RLT that uses the same ligand as beta-emitting ¹⁷⁷Lu-PSMA-PSMA-617 (lutetium Lu 177 vipivotide tetraxetan [Pluvicto]) but delivers higher linear energy transfer of 20-230 keV/µm, raising the probability of inducing DNA double-strand breaks.^2,3 Its moderate path length of 50 µm-100 µm limits radiation exposure to surrounding healthy tissues.^4-7 Prior retrospective data had suggested antitumor activity with alpha-emitting RLT, but prospective clinical evidence was limited.⁸ The AcTION trial was designed to determine the recommended phase 2 dose (RP2D) of ²²⁵Ac-PSMA-617 in PSMA-positive mCRPC with or without prior androgen receptor pathway inhibitors (ARPIs), taxane, or ¹⁷⁷Lu-PSMA-PSMA RLT.

Trial design and patient population

AcTION is an open-label phase 1 dose-escalation and expansion trial initiated in April 2021 across 2 international sites: St. Vincent's Hospital in Sydney, Australia, and Steve Biko Academic Hospital in Pretoria, South Africa. Eligible patients were men 18 years or older with confirmed mCRPC, ECOG performance status 0 to 2, and a positive ⁶⁸Ga-PSMA-11 PET/CT scan. Of 134 patients screened, 101 were treated.

Patients were enrolled into 3 groups based on prior treatment history: group A (n=34), prior taxane plus ARPI, naive to ¹⁷⁷Lu-PSMA-PSMA RLT; group B (n=27), taxane- and ARPI-naive, also naive to ¹⁷⁷Lu-PSMA-PSMA RLT; and group C (n=40), prior ¹⁷⁷Lu-PSMA-PSMA RLT, with no prior taxane or ARPI required. Doses of 4, 6, 8, and 10 MBq were evaluated, with at least 3 patients treated at the 4 and 6 MBq levels and 6 patients at each of the 8 and 10 MBq levels during dose escalation, followed by expansion to up to 10 additional patients at 8 and 10 MBq. Each cycle was 8 weeks in duration for up to 6 cycles. The primary end point was RP2D; secondary end points included safety and tolerability, confirmed PSA50 response rate, RECIST v1.1 response, and health-related quality of life.

Baseline characteristics reflected the differing treatment histories of the 3 groups. Median time since initial cancer diagnosis was 5.0 years in group A, 2.6 years in group B, and 7.2 years in group C. Median number of prior anticancer regimens was 3 in group A, 1 in group B, and 5 in group C. In group C, all 40 patients had received prior ARPI therapy, 90% had received prior taxane, and the median number of prior ¹⁷⁷Lu-PSMA-PSMA RLT cycles was 5, with at least 50% having demonstrated prior ¹⁷⁷Lu-PSMA-PSMA resistance. Bone metastases were present in nearly all patients across all groups (96%-100%); liver metastases were present in 17.6% of group A patients and 7.4% of group B and group C patients.

Patient disposition and exposure

Treatment completion rates differed substantially across groups, reflecting differences in disease burden and prior treatment history. In group B, 55.6% of patients completed all 6 cycles, with a median of 6 cycles received and a median treatment duration of 11.3 months. In groups A and C, the median number of cycles received was 3 in each, with median treatment durations of 5.5 months. Treatment discontinuation occurred in 52.9% of group A, 11.1% of group B, and 80.0% of group C patients, most commonly due to clinical or radiographic progression. AE-related discontinuations were infrequent across all groups.

Safety

There were no DLTs, and no MTD was reached in any group up to 10 MBq. There were no grade 4 or 5 treatment-related adverse events (TRAEs). Any-grade TRAEs occurred in 100%, 96.3%, and 97.5% of patients in groups A, B, and C, respectively. Grade 3 or higher TRAEs occurred in 23.5% of group A, 11.1% of group B, and 15.0% of group C patients. TEAEs leading to dose reduction occurred in 14.7%, 11.1%, and 12.5% of patients in groups A, B, and C, respectively. TEAEs leading to treatment discontinuation were rare: 2.9% in group A, 0% in group B, and 10.0% in group C.

Dry mouth was the most common AE, occurring in 97.1%, 96.3%, and 90.0% of patients in groups A, B, and C, respectively, and was exclusively grade 1 or 2 with no grade 3 or higher events across any group. There was no dose-related trend in dry mouth frequency or severity, and only 1 patient discontinued treatment due to dry mouth (group C, 8 MBq). Emmett noted that serial PSMA PET/CT imaging demonstrated progressive reduction in salivary gland activity across treatment cycles, consistent with the salivary gland origin of this toxicity. Not-recovered dry mouth was reported in 70.6% of group A, 92.6% of group B, and 55.0% of group C patients overall.

Other notable AEs included fatigue (52.9%, 14.8%, and 67.5% in groups A, B, and C, respectively), anemia (26.5%, 14.8%, and 40.0%), and nausea (26.5%, 11.1%, and 40.0%). Grade 3 or higher anemia occurred in 17.6%, 14.8%, and 15.0% of patients. Hematologic toxicities, including lymphopenia, neutropenia, and thrombocytopenia, were reported at low rates across all groups, and renal impairment was infrequent. Approximately 20% of patients in each group experienced a weight decrease. A single fatal AE of cardiac failure was reported in a patient in group A with an extensive cardiovascular disease history and was not considered treatment-related.

"Treatment-related AEs that led to dose reductions or to treatment discontinuations [were very rare]," Emmett said. "When you look at other hematologic toxicities, they were very low—very low levels of lymphopenia, neutropenia, and thrombocytopenia, very low levels of renal impairment."

Efficacy

PSA50 response rates—defined as a confirmed PSA decrease from baseline of at least 50%—were 58.8% overall in group A (72.7% at 10 MBq), 85.2% overall in group B (100% at 10 MBq), and 52.5% overall in group C (56.3% at 10 MBq). PSA90 response rates were 44.1% overall in group A (63.6% at 10 MBq), 81.5% overall in group B (90.9% at 10 MBq), and 17.5% overall in group C (18.8% at 10 MBq).

Among patients with RECIST v1.1–measurable disease, the overall response rate was 42.9% overall in group A (66.7% at 10 MBq), 33.3% overall in group B (40.0% at 10 MBq), and 41.7% overall in group C (60.0% at 10 MBq). The disease control rate was 71.4% in group A, 100% in group B, and 83.3% in group C overall. Representative PSMA PET/CT imaging demonstrated a substantial reduction in tumor burden: One group B patient achieved a 94% PSA reduction from 5.98 to 0.04 ng/mL by post-cycle 6 (week 53), and one group C patient with prior ¹⁷⁷Lu-PSMA-PSMA RLT achieved a 75% PSA reduction from 3.42 to 0.87 ng/mL post-cycle 3 (week 22).

"We did see increased treatment efficacy at the 10 MBq dosing, but not an increase in xerostomia," Emmett said.

RP2D and conclusions

The RP2D was established as 10 MBq every 8 weeks for up to 6 cycles in all 3 patient groups. Emmett noted that the data suggest that earlier treatment of mCRPC with ²²⁵Ac-PSMA-617 is associated with greater antitumor activity and improved tolerability, as evidenced by the superior responses and treatment completion rates observed in the taxane- and ARPI-naive group B relative to more heavily pretreated populations. ²²⁵Ac-PSMA-617 is currently being investigated in 2 phase 3 randomized trials: AcTFirst (NCT06855277) and PSMAcTION (NCT06780670).

REFERENCES

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