by Dr. C.H. Weaver M.D. updated 6/2021
A new therapeutic approach that enables the targeted delivery of radiation to prostate cancer cells while limiting damage to the surrounding normal tissue appears to soon be available.1 177Lu-PSMA-617 is a type of precision cancer medicine that combines a targeting compound (ligand) with a cancer killing radioactive particle.2-4 177Lu-PSMA-617 binds to prostate cancer cells that express PSMA which is present in more than 90% of prostate cancer cells then delivers a dose of radiation triggering cancer cell death.5,6 The radiation from the radioisotope works over very short distances to limit damage to surrounding cells.7-9
In general, targeted radiation treatments consist of a radioactive isotope attached to a molecule that specifically targets tumor cells. In this case, the radioactive isotope is 177-lutetium (177Lu), an unstable form of the element lutetium, which shoots off high-energy beta particles when it decays. Beta particles kill cells by bombarding and breaking their DNA. PSMA-617 is a small molecule that specifically binds to PSMA (prostate specific membrane antigen), a protein that is present at high levels on 90-95% of prostate cancers, including most metastatic castration-resistant prostate cancers (mCRPC). PSMA is absent or present at very low levels on most other tissues in the body, a property that is important in limiting side effects of targeted therapies.
This new type of therapy is being developed for prostate cancer in many different forms (different isotopes attached to different PSMA-targeting molecules), and has received a significant amount of interest from the medical community due to exciting but anecdotal case reports over the past 15 years.12 Clinical trials now appear to both prove safety and confirm efficacy.
An early prospective, single-arm phase 2 clinical trial evaluated 177Lu-PSMA-617 in 30 men with mCRPC whose tumors express PSMA. All but two of the men had previously received and progressed after standard treatments. The men were treated with between one to four cycles of 177Lu-PSMA-617. Following treatment their PSA levels dropped by over 50% in 17 of the 30 (57%) patients treated, and by over 30% in 21 (70%) patients. Tumors stopped growing or shrank in many patients, including complete or partial tumor shrinkage in 14 of 17 (82%) patients who had metastatic tumors in lymph nodes and other non-bone sites on CT scans.
About the VISION Clinical Trial
The VISION clinical trial was designed to confirm the effectiveness and safety of 177Lu-PSMA-617. The trial compared 177Lu-PSMA-617 with standard of care in patients with PSMA PET-scan positive mCRPC and evidence of cancer progression after prior taxane, and androgen directed therapy (ADT) in 831 patients. The novel precision medicine both delayed prostate cancer progression and prolonged survival duration.11
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The addition of 177Lu-PSMA-617 to standard of care significantly delayed cancer progression-median time to cancer progression was improved from 3.4 months to 8.7 months with the addition of 177Lu-PSMA-617. Average survival duration was also significantly improved from 11.3 to 15.3 months.
Studies suggest that the treatment is well tolerated and the most common side effects included low-grade dry mouth (87% of patients) and low to high grade decreases in white blood cell (37% grade 1-2; 37% grade 3) and platelet counts (27% grade 1-2; 10% grade 3), anemia (13% grade 1-2; 13% grade 3), and pain (17% grade 1-2; 3% grade 3). Some patients also experienced low-grade dry eyes (17%), fatigue (50%), nausea (50%), vomiting (33%), anorexia (23%), and weight loss (10%).
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- Boyd M, Cunningham SH, Brown MM, et al. Noradrenaline transporter gene transfer for radiation cell kill by 131I meta-iodobenzylguanidine. Gene Ther 1999;6(6):1147–52
- Eder M, Schäfer M, Bauder-Wüst U, et al. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem 2012;23(4):688–97.
- Benešová M, Schäfer M, Bauder-Wüst U, et al. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J Nucl Med 2015;56(6):914–20
- Hupe MC, Philippi C, Roth D, et al. Expression of prostate-specific membrane antigen (PSMA) on biopsies is an independent risk stratifier of prostate cancer patients at time of initial diagnosis. Front Oncol 2018;8:623.
- Sant GR, Knopf KB, Albala DM. Live-single-cell phenotypic cancer biomarkers-future role in precision oncology? NPJ Precision Oncology 2017;1(1):21
- Current K, Meyer C, Magyar CE, et al. Investigating PSMA-targeted radioligand therapy efficacy as a function of cellular PSMA levels and intra-tumoral PSMA heterogeneity. Clin Cancer Res 2020;26(12):2946–55
- Hofman MS, Violet J, Hicks RJ, et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol 2018;19(6):825–33
- Sartor AO, Morris MJ, Krause BJ. VISION: an international, prospective, open-label, multicenter, randomized phase 3 study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2019;37(15 suppl):TPS5099
- Bander N, Milowsky M, Nanus D, et al. Phase I Trial of 177 Lutetium Labeled J591 a Monoclonal Antibody to Prostate Specific Membrane Antigen in Patients with Androgen Independent Prostate Cancer. Journal of Clinical Oncology. 2005; published ahead of print April 18, 2005.