The 2026 ASCO Annual Meeting highlighted growing momentum behind alpha‑emitting radioligand therapies (RLTs), particularly for metastatic castration‑resistant prostate cancer (mCRPC). Among the most anticipated presentations was the AcTION phase 1 study¹ evaluating dose escalation of ²²⁵Ac‑PSMA‑617, a targeted alpha therapy designed to deliver high‑energy, short‑path radiation directly to PSMA‑expressing prostate cancer cells.

AcTION is the first prospective dosage escalation study of ²²⁵Ac‑PSMA‑617, an alpha‑emitting, PSMA‑targeted RLT in patients with mCRPC. The study enrolled 101 men with progressive, PSMA‑positive disease across 3 clinically relevant cohorts:

• Group A: prior chemotherapy and androgen receptor pathway inhibitor (ARPI), no prior ¹⁷⁷Lu‑PSMA
• Group B: taxane/ARPI‑naive, ¹⁷⁷Lu-PSMA RLT naive
• Group C: prior ¹⁷⁷Lu‑PSMA RLT

Patients received 4 to 10 MBq intravenously every 8 weeks for up to 6 cycles, with dose‑limiting toxicities (DLTs) assessed over the first 6 weeks.

Safety Profile: No DLTs and No Grade 4/5 Treatment-Related Adverse Events

Across all dose levels and patient groups, no DLTs were observed, and the maximum tolerated dose was not reached.

The most common treatment‑related adverse event (TRAE) was dry mouth, reported in more than 90% of patients across all groups. Importantly, all cases were grade 1/2. Fatigue and anemia were also observed, with grade ≥3 anemia occurring in 14% to 18% of patients depending on cohort. Only 2 TRAEs led to discontinuation: grade 2 dry mouth at 8 MBq and grade 3 anemia at 10 MBq, both in group C (prior ¹⁷⁷Lu‑PSMA).

Renal impairment was infrequent and mostly low‑grade. No dose‑dependent safety signals emerged, supporting the tolerability of dose escalation up to 10 MBq.

Based on the Bayesian logistic regression model and absence of DLTs, 10 MBq was selected as the recommended phase 2 dose (RP2D) for all cohorts.

Efficacy: High Prostate-Specific Antigen (PSA) Response Rates, Especially in Treatment‑Naive Patients

The AcTION trial demonstrated promising antitumor activity across all groups, with particularly strong responses in taxane/ARPI‑naive patients (group B).

PSA50 Response Rates

• Group A (postchemotherapy/ARPI): 58.8%
• Group B (naive): 85.2%
• Group C (prior ¹⁷⁷Lu‑PSMA): 52.5%

PSA90 Response Rates

• Group A: 44.1%
• Group B: 81.5%
• Group C: 17.5%

These results suggest that ²²⁵Ac‑PSMA‑617 retains activity even in heavily pretreated patients, including those previously exposed to ¹⁷⁷Lu‑PSMA. However, the magnitude of response appears greatest when used earlier in the disease course—an insight that may shape future sequencing strategies in community oncology.

Median follow-up ranged from 7.5 to 13.2 months across cohorts, providing a meaningful early look at durability. Additional efficacy data are expected in future presentations.

Implications for Community Oncology

For community oncologists, the AcTION phase 1 results reinforce several key themes in the evolving RLT landscape:

1. Alpha-emitting RLTs are moving rapidly toward frontline consideration. The high PSA response rates in treatment‑naive patients raise important questions about whether alpha‑emitting agents should be integrated earlier, potentially before or alongside ¹⁷⁷Lu‑PSMA.
2. Safety appears manageable in real‑world settings. The predominance of grade 1/2 dry mouth and limited high‑grade hematologic toxicity suggest that community practices with experience administering ¹⁷⁷Lu‑PSMA may be well positioned to adopt alpha‑emitting RLTs.
3. Prior ¹⁷⁷Lu‑PSMA exposure does not preclude benefit. Group C’s PSA50 rate of 52.5% underscores the potential role of ²²⁵Ac‑PSMA‑617 as a salvage option.
4. Phase 3 trials are already underway. Two pivotal studies—AcTFirst (NCT06855277) and PSMAcTION (NCT06780670)—are now recruiting, signaling that alpha‑PSMA therapy may soon enter broader clinical practice.

Conclusion

The AcTION phase 1 study provides compelling early evidence that ²²⁵Ac‑PSMA‑617 is both tolerable and active across mCRPC patients who had previously received different therapeutic regimens. With an RP2D established at 10 MBq and phase 3 trials in progress, alpha‑emitting PSMA‑targeted therapy may become a significant addition to the therapeutic armamentarium for advanced prostate cancer.

Reference

1. AcTION: phase 1 study of [²²⁵Ac]Ac-PSMA-617 (²²⁵Ac-PSMA-617) in men with metastatic castration-resistant prostate cancer (mCRPC) with or without prior [¹⁷⁷Lu]Lu-PSMA (¹⁷⁷Lu-PSMA) radioligand therapy (RLT). J Clin Oncol. 2026;44(suppl 16). Abstract 5010. doi:10.1200/JCO.2026.44.16_suppl.5010