Beta and alpha radionuclide therapies (RNTs) are novel and effective treatment options for metastatic castration-resistant prostate cancer (mCRPC), as the survival benefit of chemotherapy and drugs that target androgen signaling is limited. Prostate-specific membrane antigens (PSMAs) are also effective targets for imaging and therapy because radioligands target PSMA epitopes. Several studies have investigated the effects of lutetium-177–labeled PSMA (¹⁷⁷Lu-PSMA) and actinium-225–labeled PSMA (²²⁵Ac-PSMA) RNT in patients with mCRPC, and they have shown promising treatment results.

¹⁷⁷Lu-PSMA Treatment Studies

An investigation carried out by Weineisen et al in 2015 treated 2 patients with mCRPC with multiple bone and lymph node metastases with 5.7 and 8.0 GBq of ¹⁷⁷Lu-PSMA. The treatment was well-tolerated and did not incur significant side effects. As a result, a larger study was carried out in 2019 by Heck et al, which utilized ¹⁷⁷Lu-PSMA in a test group of 100 patients with mCRPC. In this study, 319 cycles were given to each patient, with a median of 2 cycles per patient. The treatment results of this study were also well-tolerated with minimal serious side effects, and a prostate-specific antigen (PSA) response was reported in the majority of patients. The recent VISION trial investigated the use of ¹⁷⁷Lu-PSMA-617 in patients with mCRPC, and it was found to prolong progression-free survival and overall survival in patients when added to standard care.

²²⁵Ac-PSMA Treatment Studies

The first studies that investigated the effects of ²²⁵Ac-PSMA RNT were carried out in 2016 by Katochwil et al in 2 patients with mCRPC. The first patient was given 3 cycles of 9-10 MBq of [²²⁵Ac]Ac-PSMA-617 bimonthly, while the second patient was given 3 cycles of 6.4 MBq bimonthly. In the first patient, all previous PSMA-positive lesions were not visible on PSMA-positron emission tomography (PET)/computed tomography (CT) scans 2 months after the third administration, and PSA levels decreased from more than 3000 ng/mL to 0.26 ng/mL. In the second patient, partial response was seen on PSMA-PET/CT scans after 2 cycles. After 3 cycles, complete remission was achieved. Another study was conducted by Zacherl et al that utilized [²²⁵Ac]Ac-PSMA-I&T in 14 patients with mCRPC, with 11 of the patients having previously been treated with 177Lu-PSMA. A total of 34 cycles of [²²⁵Ac]Ac-PSMA-I&T were administered, and 50% of patients showed a PSA decline ≥50%, while 79% of patients showed any PSA decline.

¹⁷⁷Lu-PSMA-617 was approved by the US Food and Drug Administration for use in March 2022 and is an available treatment choice for patients with PSMA-positive mCRPC. While ²²⁵Ac-PSMA RNT has shown promising results, further developments in the treatment are needed before it can be used in clinical practice.

Reference

Advances in ¹⁷⁷Lu-PSMA and ²²⁵Ac-PSMA Radionuclide Therapy for Metastatic Castration-Resistant Prostate Cancer