The Prostate Cancer Foundation (PCF) hosted the 2023 ProsTIC PCF Global Webinar providing a contemporary overview of novel prostate-specific membrane antigen (PSMA)-targeted alpha emitting agents and new targets for prostate cancer. Dr. David Pattison presented a brief overview of 212Pb radioligand therapy for prostate cancer patients.
Dr. Pattison began by arguing that 212Pb, an alpha emitter, is the ideal radioligand therapy isotope. This isotope combines a half-life of 10.64 hours (matched to ligand half-life) with high linear energy transfer (LET) emissions for effective cancer cell killing and low toxicity from a simple decay series. The half-life of 10.64 hours has important implications for clinical administration purposes, limiting the surrounding biohazardous toxicity, particularly when compared to the beta-emitter 177Lu (t½= 6.7 days) and the alpha-emitter 225Ac (t½= 10 days).
Furthermore, from a production standpoint, 212Pb is reliably produced by AdvanCell in sufficient amounts, solving the challenge of reliable supply, which is currently a major limitation to the widespread administration of 225Ac and is anticipated to become a growing issue for 177Lu.
Dr. Pattison next provided an overview of 212Pb generators and the decay schema. 212Pb is generated from Thorium-228 (228Th). Once 212Pb is produced, it undergoes a beta decay to Bismuth-212 (212Bi) and then Polonium-212 (212Po), which gives off the stable 208Pb.
Another ‘attractive’ characteristic of 212Pb is its biodistribution. Compared to [177Lu]Lu-PSMA-I&T, [212Pb]Pb-ADVC001 shows a significantly improved tumor-to-kidney uptake ratio.1
In addition to the improved biodistribution profile, [212Pb]Pb-ADVC001 shows significantly improved tumor control and survival in mouse models, compared to [177Lu]Lu-PSMA-I&T. In a mouse model study, subjects were randomized to receive either:
- Non-radioactive ADVC001 (control arm)
- 177Lu-PSMA-I&T - 177Lu-PSMA-I&T
- 177Lu-PSMA-I&T - 212Pb-ADVC001
- 212Pb-ADVC001 - 212Pb-ADVC001
Mice that received the 212Pb-ADVC001 - 212Pb-ADVC001 combination had decreased tumor volume growth and had significantly improved survival rates, compared to the other combinatory arms.
There are ongoing studies evaluating the use of 212Pb alpha therapy in human subjects, with Delpassand et al. recently publishing the results of a phase 1, first-in-humans dose-escalation clinical trial that evaluated the targeted alpha-emitter therapy 212Pb-DOTAMTATE for the treatment of metastatic SSTR-expressing neuroendocrine tumors. This phase I trial included 20 patients with neuroendocrine tumors with 10 patients receiving the highest dose of 2.50 MBq/kg/cycle. Treatment was generally well-tolerated with the most common treatment-emergent adverse events being nausea, fatigue, and alopecia. No serious treatment-emergent adverse events were related to the study drug, and no subjects required treatment delay or a dose reduction. From an efficacy standpoint, an objective radiologic response of 80% was observed for the first 10 subjects treated at the highest dose of 2.50 MBq/kg/cycle.2
TheraPb will evaluate [212Pb]Pb-ADVC001 in patients with metastatic prostate adenocarcinoma. This phase I/II dose escalation and toxicity study will have similar inclusion criteria to its namesake trial, TheraP:
- Male >18 years
- mCRPC with prior androgen receptor-targeted therapy and a taxane-based chemotherapy (or contraindicated)
- Progressive disease per the Prostate Cancer Working Group-3 (PCWG3) criteria and a serum PSA >20 ng/ml
- [68Ga]Ga-PSMA-11 SUVmax >20 at a site of disease and SUVmax >10 at all measurable (>10 mm) disease sites
- ECOG performance status 0-2 and a life expectancy >12 weeks
- Adequate hematologic, renal, and liver function profiles
Exclusion criteria will include:
- Sarcomatoid, spindle cell, or neuroendocrine small cell tumors
- Any prior treatment with 177Lu or 225Ac-PSMA-based radioligand therapy
- Sjogrens syndrome
- FDG positive and minimal PSMA avidity (FDG > PSMA or PSMA SUVmax <10)
- Other systemic malignancy
This trial will employ a 3 + 3 dose escalation design with a maximum of 18 patients receiving up to four cycles of [212Pb]Pb-ADVC001. The primary outcomes will be:
- Determining the dose-limiting toxicity (DLT)
- Determining the maximum tolerated dose level
Secondary outcomes will include evaluating the:
- Response as per the consensus statement on PSMA PET response and PCWG3/RECIST v1.1
- Clearance and cumulative activity of 212Pb in blood and urine at 10 minutes, one and four hours, and prior to release
- Incidence of treatment-related adverse and serious adverse events as per CTCAE v5, up to 10 months post-therapy.
Presented by: David Pattison, MBBS (Hones), MPH, Associate Professor, Deputy Director, Department of Nuclear Medicine and Specialised PET Services, Royal Brisbane and Women’s Hospital, Australia
Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 ProsTIC PCF Global Webinar held virtually on July 19, 2023
References:- Weineisen M, Schottelius M, Simecek J, et al. 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies. J Nucl Med, 2015; 56(8) :1169-76.
- Delpassand ES, Tworowska I, Esfandiari R, et al. Targeted α-Emitter Therapy with 212Pb-DOTAMTATE for the Treatment of Metastatic SSTR-Expressing Neuroendocrine Tumors: First-in-Humans Dose-Escalation Clinical Trial. J Nucl Med, 2022; 63(9): 1326-33