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Targeted Alpha Therapy for Prostate Cancer, the Next Generation of Alpha-Emitting Radiopharmaceuticals

It’s hard to believe that it’s been nearly a decade since the ALSYMPCA trial with radium-223 was published, showing an overall survival benefit for men with bone metastatic castration-resistant prostate cancer and symptoms.1  Radium-223 is an alpha-particle emitting radiopharmaceutical that incorporates into areas of osteoblastic activity, with subsequent induction of double-strand DNA breaks in neighboring tumor cells.  Although radium-223 has clear efficacy, one of the practical challenges of use is that prostate-specific antigen (PSA) level does not always decline in response to treatment and the association with clinical outcomes is poor.  As a result, it is sometimes difficult for patients and health care providers to determine if radium-223 is working well or not.


The newest radiopharmaceutical to join the regulatory approved ranks is 177Lu-PSMA-617, which has shown an overall survival benefit for patients with previously chemotherapy-treated metastatic castration-resistant prostate cancer in the VISION trial.2  177Lutetium (Lu) is a beta-emitting radionuclide that induces DNA strand breaks and cellular lethality.3  177Lu-PSMA-617, is unlike radium-223, as it is not an alpha-emitter, however, the construct has a small molecule targeting vector that binds to the highly-expressed prostate-specific membrane antigen (PSMA) on prostate cancer cells.

This setup is ideal for a combination of an alpha-emitting radiopharmaceutical with a targeting moiety for specific delivery and enhanced tumor cell kill.  The term “targeted alpha therapy” has been used to describe these types of constructs.  However, there are many considerations and potential for toxicity.  For example, in the case of PSMA, conjugation of the alpha-emitter with a PSMA-binding small molecule may lead to penetration to areas that might enhance toxicity, specifically in salivary glands or renal tubules.  Conjugation of the alpha-emitter with a monoclonal antibody might minimize such penetrative effects by nature of the size of the construct, however, prolonged circulation and half-life could lead to more myelosuppression for the patient.  Careful balance in preclinical and clinical development is necessary for success.  Looking beyond PSMA, as a target, should also be a key goal for the field.  We need to facilitate the development of the next wave of targeted alpha therapy that hones in on new targets, while carefully engineering unique targeting moieties, and testing various alpha-emitters for tumor cell kill.

There are multiple different targeted alpha therapies that have been tested in prostate cancer both pre-clinically and some have entered into the clinic.  211Astatine (At)-PSMA-pentanedioic acid has shown growth delay and improved survival outcomes in murine xenograft models.4  213Bismuth (Bi)-PSMA-617, is an alpha-emitter that uses the same small molecule that binds PSMA as 177Lu-PSMA-617.  It has been utilized in a patient with a significant response by both molecular imaging and PSA decline.5  227Thorium (Th)-PSMA-TTC is a PSMA-targeting monoclonal antibody conjugated with thorium as the alpha-emitter.  It has shown significant antitumor activity and tolerability in preclinical models.6  A clinical trial (NCT03724747) is listed as “active, not recruiting” with BAY2315497, a 227Th-PSMA-antibody-chelator conjugate, being studied alone and in combination with darolutamide in patients with metastatic castration-resistant prostate cancer.  Finally, 225Actinium (Ac)-PSMA-617 completed a dose finding clinical trial, showing significant antitumor efficacy and durability of response with xerostomia as the dose-limiting toxicity.7, 8

When reviewing the current portfolio of targeted alpha therapy clinical trials available on the U.S. National Library of Medicine clinicaltrials.gov website, actinium is the most comprehensively explored alpha-emitter.  Although PSMA is the most common target, other targets such as human kallikrein 2 and even neurotensin receptor 1 (NTSR1), specifically for neuroendocrine differentiated prostate cancer, are being evaluated.  Various small molecules and antibodies are being used for targeting.  Thorium is also being explored but is only currently active in a basket trial for HER2-expressing cancers, which occur in prostate cancer, but perhaps more so in urothelial cancers.  Please see below for additional details of the actively accruing clinical trials with targeted alpha therapy for patients with prostate cancer.

Actively accruing targeted alpha therapy trials for patients with prostate cancer

  • ACTION – ACTInium-J591 for PSMA-detected metastatic hOrmone-sensitive recurrent prostate CaNcer (NCT05567770)
  • 225Ac-J591 with pembrolizumab for metastatic castration-resistant prostate cancer (NCT04946370)
  • JNJ-69086420, 225Ac-labeled antibody targeting human Kallikrein-2 (hK2) for metastatic castration-resistant prostate cancer (NCT04644770)
  • TATCIST - 225Ac-PSMA-I&T for metastatic castration-resistant prostate cancer (NCT05219500)
  • 225Ac-FPI-2059 for NTSR1-expressing metastatic solid tumors (including neuroendocrine prostate cancer) (NCT05605522)
  • BAY2701439, a 227Th-labeled antibody conjugate to HER2-expressing advanced tumors (NCT04147819)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Parker C et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med 2013; 369:213-23.
  2. Sartor O, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med 2021; 385:1091-103.
  3. Fendler WP, et al. Establishing 177Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer. J Nucl Med. 2017; 58:1786-92.
  4. Kiess AP, et al. (2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy. J Nucl Med 2016; 57:1569-75.
  5. Sathekge M, et al. 213Bi-PSMA-617 targeted alpha-radionuclide therapy in metastatic castration-resistant prostate cancer.  Eur J Nucl Med Mol Imaging 2017; 44:1099-100.
  6. Hammer S, et al. Preclinical Efficacy of a PSMA-Targeted Thorium-227 Conjugate (PSMA-TTC), a Targeted Alpha Therapy for Prostate Cancer. Clin Cancer Res 2020; 26:1985-96.
  7. Kratochwil C, et al. 225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer.J Nucl Med 2016; 57:1941-4.
  8. Kratochwil C, et al. Targeted α-Therapy of Metastatic Castration-Resistant Prostate Cancer with 225Ac-PSMA-617: Swimmer-Plot Analysis Suggests Efficacy Regarding Duration of Tumor Control. J Nucl Med 2018; 59:795-802.