Efficacy and safety of 225Ac-PSMA-617 targeted alpha therapy in metastatic castration-resistant Prostate Cancer patients

Abstract

Rationale: Despite the success of several standards of care treatment options in metastatic castration-resistant prostate cancer (mCRPC), a significant number of patients attain therapeutic resistance and eventually develop disease progression. Managing these patients are currently challenging. Hence, there is an unmet need for further efficient therapeutic options that induce anti-tumor activity and improve survival. The objective of this study was to assess the safety and therapeutic efficacy of ²²⁵Ac-PSMA-617 targeted alpha therapy (TAT) in mCRPC patients in real-world conditions. Methods: In this prospective study, we recruited patients with mCRPC who either were refractory to ¹⁷⁷Lu-PSMA-617 radioligand therapy (RLT) or did not receive previous ¹⁷⁷Lu-PSMA-617 RLT. Patients were treated with ²²⁵Ac-PSMA-617 TAT (100 KBq/Kg body weight) at 8-weekly intervals. The primary endpoint included the assessment of biochemical response by measuring the serum prostate-specific antigen (PSA) response rate as per the prostate cancer working group criteria (PCWG3). Secondary endpoints comprised the estimation of overall survival (OS), progression-free survival (PFS), molecular tumor response assessment (PERCIST 1 criteria), disease control rate (DCR), toxicity according to CTCAE v5.0, and clinical response evaluation. Results: A total of 28 patients were recruited for this cohort study among whom 15 (54%) received prior ¹⁷⁷Lu-PSMA-617 RLT and the remaining 13 (46%) patients were ¹⁷⁷Lu-PSMA-617 RLT naïve. The mean age was 69.7 years (range: 46-87 years). All patients, except one, had extensive skeletal metastases on baseline ⁶⁸Ga-PSMA-11 PET/CT scan; one patient had lymph node dominant disease and advanced primary prostatic tumor. The mean activity administered was 26.5 ± 12 MBq (range: 9.25 - 62.9 MBq) [715.5 ± 327 µCi, range: 250 - 1700 µCi] with a median of 3 cycles (range: 1 - 7 cycles). At 8^th week of post first cycle of ²²⁵Ac-PSMA-617 therapy (initial follow-up) and the end of the follow-up, >50% decline in PSA was observed in 25% and 39%, respectively. The median PFS and OS were 12 months (95% CI: 9 - 13 months) and 17 months (95% CI: 16 months - upper limit not reached), respectively. Molecular tumor response by PERCIST 1 criteria could be conducted in 22/28 (78.6%) patients, which revealed complete response in 2/22 (9%), partial response in 10/22 (45.4%) patients, 2/22 (9%) with stable disease, and 8/22 (36%) with progressive diseases. The disease control rate, according to the biochemical and molecular tumor response criteria, was 82% and 63.6%, respectively. Multivariate analysis revealed PSA progression as adverse prognostic indicator of OS, and any PSA decline as a good prognostic indicator of PFS. There was no Grade III/IV toxicity noted in this series. The most common side-effect was transient fatigue (50%) followed by grade I/II xerostomia (29%). Conclusion:²²⁵Ac-PSMA-617 TAT showed promising disease control rate, even when all other therapeutic options were exhausted, with low treatment-related toxicities.

Keywords: 225Ac-PSMA-617 therapy; Targeted alpha therapy; efficacy; mCRPC; safety; salvage treatment.

Figure 1

Flow chart depicting the treatment protocol and follow-up for ²²⁵Ac-PSMA-617 therapy.

Figure 2

(A) Waterfall plots depicting percentage change in PSA response post-first cycle ²²⁵Ac-PSMA-617 TAT. (B) Waterfall plots depicting percentage change in PSA response at the end of follow-up after ²²⁵Ac-PSMA-617 TAT. (the orange clour respresents patients with any PSA increase and the green colour depicts patients who experienced any percent PSA decline).

Figure 3

Flow chart depicting the biochemical and molecular imaging response rates in the prior ¹⁷⁷Lu-PSMA-617 RLT refractory group (Gr-I) and naïve groups (Gr-II).

Figure 4

Kaplan-Meier plots depicting the progression-free survival (A) and overall survival (B) of the patients in months.

Figure 5

Overall survival (A) and progression-free survival (B) in months according to the prior status on ¹⁷⁷Lu-PSMA-617 RLT.

Figure 6

Kaplan-Meier survival curves of prostate cancer patients treated with ²²⁵Ac-PSMA-617 TAT stratified by prognostic factors on multivariate analysis. (A) >25% PSA increase associated with overall survival. (B) Any PSA decline associated with progression-free survival.

Figure 7

A 79-year-old prostate cancer patient treated with hormonal and chemotherapy and refractory to prior ¹⁷⁷Lu-PSMA-617 presented with radiotracer-avid primary, lymph node, and extensive skeletal metastasis on pretherapy diagnostic ⁶⁸Ga-PSMA-11 PET/CT scan (A, B). After the 4^th cycle of ²²⁵Ac-PSMA-617 therapy, the interim ⁶⁸Ga-PSMA-11 PET/CT scan demonstrated complete resolution of the lesions (C, D) consistent with the complete molecular response.

Figure 8

A 84-year-old prostate cancer patient treated with hormonal and chemotherapy presented with radiotracer-avid primary disease and lymph node metastasis on pretherapy diagnostic ⁶⁸Ga-PSMA-11 PET/CT scan (A). After the 2^nd cycle of ²²⁵Ac-PSMA-617 therapy, the restaging ⁶⁸Ga-PSMA-11 PET/CT scan revealed a remarkable decrease in the uptake, size, and number of all lesions except for minimal residual disease in mediastinal lymph nodes (B). After further 5 cycles of ²²⁵Ac-PSMA-617 TAT, ⁶⁸Ga-PSMA-11 PET/CT scan demonstrated complete resolution of the lesions (C) consistent with the complete molecular response.