EAU 2023: Burning Questions in Oncological Urology: The Current and Future Role of PSMA-Based Theranostics in Men with Advanced Prostate Cancer

(UroToday.com) The 2023 European Association of Urology (EAU) annual congress held in Milan, Italy between March 10th and 13th, 2023 was host to an EAU Section of Oncologic Urology (ESOU) session addressing progress and controversies in urologic oncology. In her presentation, Professor Silkem Gillessen Sommer discussed the current and future role of PSMA-based theranostics in men with advanced prostate cancer.

Professor Gillessen began by noting that theranostics entails treating the “right” patient by image selection. This requires an appropriate cell surface target, with corresponding ligands, linkers, and isotopes.
illustration.pngWhat is the current evidence for theranostics in the prostate cancer treatment paradigm? Professor Gillessen highlighted the VISION trial, which was an international, randomized, open-label phase III study that evaluated 177Lu-PSMA-617 in men with PSMA-positive mCRPC (no PSMA negative lesions) who had previously received treatment with next-generation androgen receptor signaling inhibition (abiraterone, enzalutamide, etc) and one or two prior lines of taxane chemotherapy (NCT03511664). Additionally, patients must have had an ECOG performance status of 0-2 and life expectancy of at least 6 months. Following enrollment, patients were randomized in a 2:1 fashion to receive either 177Lu-PSMA-617 plus standard of care (SOC) or SOC alone. SOC treatments were at the discretion of the treating investigator; however, cytotoxic chemotherapy, immunotherapy, and radium-223 were explicitly excluded. Most patients received alternative androgen-directed therapies while others received palliative radiotherapy and glucocorticoids. Over a median study follow-up of 20.9 month (as of a data cut-off of 27 January 2021), treatment with 177Lu-PSMA-617 + SOC significantly improved overall survival by a median of 4.0 months (median OS, 15.3 vs 11.3 months; HR, 0.62 [95% CI: 0.52, 0.74]; p < 0.001, one-sided), compared to SOC alone, in the overall cohort of all randomized patients (n=831).1
Based on these results, the European Medicines Agency (EMA) approved 177Lu-PSMA-617, together with ADT, in prostate cancer patients previously treated with androgen receptor pathway inhibitors and a previous taxane.

When considering the role of 177Lu-PSMA-617 in the treatment paradigm of mCRPC patients, it is critical to consider prior treatments received in the mHSPC disease space. Professor Gillessen proposed four treatment paradigms based on the initial treatment received:

1. ADT alone for mHSPC
2. ADT plus docetaxel for mHSPC
adt_plus_doxe.png3. ADT plus ARPI for mHSPC adt_arpi.png4. Triplet therapy for mHSPC
While 177Lu-PSMA-617 is currently well-established in the 3rd line mCRPC treatment paradigm, numerous studies are evaluating this agent in earlier line settings. The PSMAfore trial (NCT04689828) is evaluating 177Lu-PSMA-617 in the pre-chemo, 2nd line setting. While results are not yet available, a press-release by Novartis stated that “PluvictoTM shows statistically and clinically meaningful radiographic progression-free survival benefit in patients with PSMA-positive metastatic castration-resistant prostate cancer”. Novel radioligands are currently in clinical development and testing, which is critical when we consider the recent logistic/production issues pertaining to PluvictoTM.
The most notable of these is 177Lu-PSMA-I&T (177Lu-PSMA-PNT2002), which is currently being evaluated in the 2nd line, post-ARPI mCRPC setting within the context of the SPLASH trial.
In addition, theranostics are being evaluated in the mHSPC, BCR, and pre-surgical treatment settings as well.

Finally, theranostics are also currently being evaluated in combination with other agents (e.g. immunotherapy, chemotherapy, PARP inhibitors, monoclonal antibodies, radionuclides such as 225Ac and 233Ra, and ARPIs) as demonstrated in the figure below.
Presented by: Professor Silke Gillessen Sommer, MD, Head of the Medical Oncology Department and Medical Scientific Director of the Oncology Institute of Southern Switzerland (IOSI) at the Ospedale San Giovanni in Bellinzona, Switzerland

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 European Association of Urology (EAU) Annual Meeting, Milan, IT, Fri, Mar 10 – Mon, Mar 13, 2023.

  1. Sartor O, de Bono J, Chi K, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med; 2021; 385:1091-1103