SNMMI 2021: Alpha Emitting PSMA Molecular Radiotherapy for mCRPC

1. A cross-fire effect, which is described as direct damage to multiple neighboring cells that is advantageous in heterogeneous and large tumors
2. Radiation-induced bystander effect, which is described as indirect DNA damage to cells surrounding irradiated cells
3. Abscopal effect, which is described as damage to remote cells due to radiation-induced immune response

PSMA is a type II transmembrane enzyme, located on secretory cells of the prostate epithelium, small bowel, proximal renal tubules, brain, and tumor neovasculature. PSMA is over-expressed in aggressive prostate cancer, however, 5-10% of prostate cancer tumors do not express PSMA. Current common iterations of PSMA PET include ⁶⁸Ga-PSMA-11, ¹⁸F-DCFPyL, and ¹⁸F-PSMA-1007.

The first alpha particle discussed by Dr. Jadvar was actinium-225, which has a low world quantity (~2 Ci), with impurities and high cost (~$1,200/mCi) making it difficult to support actinium-225 in large-scale clinical use. Early case reports/case series with ²²⁵Ac-PSMA-617 have demonstrated impressive radiologic responses, including patients with high-volume visceral metastases, and in patients after long-term ¹⁷⁷Lu-PSMA radioligand therapy.^1 225Ac-PSMA-617 has also been tested in the chemotherapy-naïve population, including 17 patients with advanced prostate cancer that were selected for treatment with ²²⁵Ac-PSMA-617 in 2-month intervals, with the initial activity of 8 MBq, then de-escalation to 7 MBq, 6 MBq, or 4 MBq in cases of good response.² Good antitumor activity assessed by serum PSA level and ⁶⁸Ga-PSMA-PET/CT was seen in 16/17 patients. In 14/17 patients, a PSA decline ≥ 90% was seen after treatment, including seven patients with undetectable serum PSA following two (2/7) or three cycles (5/7) cycles of ²²⁵Ac-PSMA-617. Additionally, 15 of 17 patients had a > 50% decline in lesions avidity for tracer on ⁶⁸Ga-PSMA-PET/CT including 11 patients with complete resolution of all metastatic lesions. As follows are waterfall plots showing PSA response at eight weeks after one cycle of ²²⁵Ac-PSMA-617 radioligand therapy, and showing best PSA response to ²²⁵Ac-PSMA-617 radioligand therapy:

The second alpha particle discussed by Dr. Jadvar was Bismuth-213, noting that ²¹³Bi-PSMA radioligand therapy typically includes 2 cycles of treatment with a cumulative 592 Mbq. Compared to ²²⁵Ac-PSMA-617, ²¹³Bi-PSMA-617 suffers from higher perfusion-dependent off-target radiation and longer biological t_1/2 of PSMA-617 in dose-limiting organs than the physical t_1/2 of ²¹³Bi, rendering this nuclide as a second choice radiolabel targeted alpha therapy for treating prostate cancer.

Both Astatine-211 and Thorium-227 have shown preclinical efficacy of a PSMA targeted conjugate alpha therapy in prostate cancer, but have yet to make significant strides in clinical trials. Lead isotopes have also generated pre-clinical interest, including ²⁰³Pb (gamma particle with a t_1/2 of 51.9 hours), and ²¹²Pb (which is a beta nanogenerator of ²¹²Bi with alpha decay to ²⁰⁸Pb and a t_1/2 of 10.6 hours).³

Finally, Dr. Jadvar discussed the Terbium isotopes, which include ¹⁵²Tb (Beta⁺), ¹⁵⁵Tb (gamma), ¹⁴⁹Tb (alpha, Beta⁺, t_1/2 4.1 hours), and ¹⁶¹Tb (beta^-, gamma, auger). Terbium is a rare earth element, which leads to challenges with production and chemical separation. In preclinical mouse models of ¹⁴⁹Tb-PSMA-617, tumor growth was significantly delayed in mice of the treated groups as compared to untreated controls (p < 0.05). Additionally, targeted alpha-therapy was most effective in mice injected with 2 × 3 MBq (Day 0 & 1) resulting in a median lifetime of 36 days, whereas in untreated mice, the median lifetime was only 20 days.⁴

Dr. Jadvar concluded his presentation of alpha emitters for PSMA molecular radiotherapy for mCRPC patients with the following future research propositions:

• There is a need for improving production, availability, accessibility, and cost, as well as improvement in chelation techniques
• Need for improvement in methods for pharmacokinetic and (micro)dosimetric modeling for robust comparison of alpha and beta therapies
• Evaluation of alpha/beta cocktails, earlier in the disease stage, and efficacy/toxicity in combination with or in sequence to other therapies
• Assess the comparative impact on outcomes such as OS, PFS, and quality of life

1. Ilhan H, Gosewisch A, Boning G, et al. Response to 225Ac-PSMA-I&T after failure of long-term ¹⁷⁷Lu-PSAM RLT in mCRPC. Eur J Nucl Med Mol Imaging. 2021;48:1262-1263.
2. Sathekge M, Bruchertseifer F, Knoesen O, et al. ²²⁵Ac-PSMA-617 in chemotherapy-naïve patients with advanced prostate cancer: A pilot study. Eur J Nucl Med Mol Imaging. 2019 Jan;46(1):129-138.
3. dos Santos JC, Schafer M, Bauder-Wust U, et al. Development and dosimetry of ²⁰³Pb/²¹²Pb-labelled PSMA ligands: Bringing “the lead” into PSMA-targeted alpha therapy? Eur J Nucl Med Mol Imaging. 2019;46:1081-1091.
4. Umbricht CA, Koster U, Bernhardt P, et al. Alpha-PET for prostate cancer: Preclinical investigation using ¹⁴⁹Tb-PSMA-617. Sci Rep. 2019 Nov 28;9(1):17800.