Survival outcomes of patients with metastatic castration resistant prostate cancer receiving 225Ac-PSMA-617 radioligand therapy

Introduction: Despite available treatment options, the outcomes of patients with metastatic castration resistant prostate cancer (mCRPC) remain dismal. ²²⁵Ac-PSMA-617 is a radioligand therapy (RLT) that delivers alpha-particle radiation to PSMA-expressing cells. In this study, we report the treatment outcomes and survival of this novel treatment modality in a series of patients with mCRPC who have exhausted the available line of therapies (LoTs).

Methods: Patients with mCRPC refractory to standard LoTs, including next-generation anti-androgen therapies, taxane-based chemotherapies, and ¹⁷⁷Lu-PSMA-617 therapy were included. The study was approved by the Institute Ethics Committee (IEC:518) and began enrolment in March 2018 and is currently ongoing. Eligible patients were treated with ²²⁵Ac-PSMA-617 TAT (100 - 150 KBq/Kg body weight) at every 8-week intervals. The primary outcome endpoint was overall survival (OS). Secondary endpoints included the assessment of biochemical response with sPSA, progression-free survival (PFS), and the assessment of adverse events graded according to the CTCAE v5.0.

Results: At the last follow-up, 63 patients met the inclusion criteria. Of these, 56 patients have completed at least two cycles of ²²⁵Ac-PSMA-617 TAT and were included in the study. The mean age was 67 years (range, 39-87 y) and patients received a total of 204 cycles of ²²⁵Ac-PSMA-617 RLT. Any PSA decline was noted in 91% of patients with 64% of patients having a decline ≥50%. With a median follow-up of 26 months, 55% of patients experienced disease progression, and 64% of them died from their disease.

The median OS was 15 mo (95% CI, 10-18 mo). In univariate analysis, >50% PSA decline (p-0.0318), liver metastases (p-0.054), and radiological progression (rPD) (p-0.0017) were predictive of OS whereas, in multivariate analysis, only rPD remained predictive in the Cox-proportional hazard model (HR: 3.042 (95%; CI: 1.424 to 6.497, p-0.004,). The median estimated OS for patients with a rPD was 10 mo (95% CI: 9 to 15 mo), whereas the median OS of those patients with no rPD was not yet reached at the date of the last follow-up visit [HR: 2.959; 95%CI: 1.502 to 5.832; 0.0017].

The estimated median PFS was 11 mo (95% CI, 8-21). In the multivariate analysis, any PSA decline and rPD proved predictive of PFS. The estimated median PFS for patients demonstrating any PSA decline was 16 months compared to only 3 months in patients who did not experience any PSA decline [HR: 8.497; 95%CI: 2.328 to 31.010; p-0.0012]. The estimated median PFS for patients with rPD was 7.5 mo compared to 21 months in patients who did not experience any rPD [HR: 3.638; 95%CI: 1.561 to 8.481; p-0.0028].

The most common treatment-emergent adverse events were fatigue (any grade 70%; ≥grade 3: 2%) which were transient and resolved without intervention prior to the next cycle of treatment. Xerostomia was observed as the second most common side-effect (grade 1/2: 32.6%; none: grade 3).

Conclusions: Our study demonstrates the safety and feasibility of ²²⁵Ac-PSMA-617 TAT in heavily pretreated patients with mCRPC with manageable treatment-emergent toxicities. These encouraging results of improved OS and PFS need to be confirmed with larger studies.