SNMMI 2021: Alpha Emitting PSMA Molecular Radiotherapy for mCRPC

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2021 annual meeting included a metastatic castrate-resistant prostate cancer (mCRPC) session and a presentation by Dr. Hossein Jadvar discussing alpha-emitting PSMA molecular radiotherapy in mCRPC. Dr. Jadvar notes that the lethal potency of alpha particles includes:

  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:

Jadvar_SNMMI21_Figure1.png

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 t1/2 of PSMA-617 in dose-limiting organs than the physical t1/2 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 t1/2 of 51.9 hours), and 212Pb (which is a beta nanogenerator of 212Bi with alpha decay to 208Pb and a t1/2 of 10.6 hours).3

Finally, Dr. Jadvar discussed the Terbium isotopes, which include 152Tb (Beta+), 155Tb (gamma), 149Tb (alpha, Beta+, t1/2 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
Presented by: Hossein Jadvar, MD, Ph.D., University of Southern California, Los Angeles, CA

Written by: Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the Society of Nuclear Medicine & Molecular Imaging 2021 virtual annual meeting

References:

  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.
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