(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8th and June 11th, 2024 was host to a prostate cancer novel approaches and combination therapies session. Dr. James Buteau discussed novel approaches of combination PSMA-based radiopharmaceutical treatments for prostate cancer.
There are numerous ongoing trials of novel radioligand therapy combination approaches currently underway across the prostate disease spectrum.
Dr. Buteau highlighted three ongoing trials in the metastatic castrate-resistant prostate cancer disease space: VIOLET, LuCAB, and AlphaBet.
VIOLET (NCT05521412) is an ongoing phase I/II trial being conducted at the Peter MacCallum Cancer Centre in Australia evaluating Terbium-161-PSMA-I&T in mCRPC patients. While 177Lu-PSMA is an effective treatment that maximizes radiation to cancer cells while minimizing side effects,1,2 mCRPC eventually progresses even with a complete response to macroscopic disease. This recurrence may be secondary to micrometastases too small to receive a lethal dose from beta radiation alone.
A comparison of the physical characteristics of 161Tb and 177Lu is summarized below. While both agents have a similar half-life, 161Tb has a higher beta mean energy (154.3 keV versus 133.3 keV).
161Tb attaches to PSMA receptors and emits beta particles similar to 177Lu, killing larger sized tumors with abundant crossfire. 161Tb also emits additional Auger electrons that delivers higher concentrations of radiation over very short path-lengths, which may better kill micrometastases compared to 177Lu. As demonstrated in the histogram below, the absorbed radiation dose at both the single cell and cell cluster levels is higher with 161Tb, compared to 177Lu.
In VIOLET, the study investigators are hypothesizing that 161Tb-PSMA-I&T will be an effective treatment for mCRPC patients with an acceptable safety profile. In this prospective, single center, single arm phase I/II trial, 30 to 36 mCRPC patients with disease progression following ≥1 taxane (or medically unsuitable) and a 2nd generation anti-androgen (e.g., abiraterone or enzalutamide) with evidence of PSMA-positive disease and no FDG PET discordant disease will receive up to 6 cycles of 161Tb-PSMA-I&T intravenously every six weeks with phase I dose escalation and phase II dose expansion cohorts planned.
The primary outcomes are maximum tolerated activity and safety. The secondary outcomes are absorbed radiation dose, anti-tumor activity, and patient-reported outcomes.
AlphaBet is a phase I/II trial evaluating the combination of Radium-223 + Lutetium-177 PSMA-I&T in mCRPC patients. 90% of patients with advanced prostate cancer develop bone metastases that can lead to pain, fractures, and spinal cord compression. 223Ra is a bone-specific calcium mimetic that emits high energy alpha radiation that may be better suited for targeting micrometastatic cancer cells in the bone. There is pre-clinical evidence to support the combination of 223Ra and 177Lu-PSMA-617. In a LNCaP xenograft model, Scholz et al. demonstrated that this combination, compared to 223Ra or 177Lu-PSMA-617 monotherapy, is associated with improved PSA responses. As such, the AlphaBet study investigators hypothesized that the combination of 223Ra and 177Lu-PSMA-I&T may lead to deeper and more durable responses in humans as well.
In AlphaBet, 36 mCRPC patients will receive up to 6 cycles of 177Lu-PSMA-I&T 7.4 GBq intravenously every 6 weeks + 223Ra in a two-step dose escalation (28 kBq/kg – 55 kBq/kg, then in expansion at the determined safest dose) intravenously every 6 weeks.
The primary study objectives are to establish the ‘safe dose’ and to evaluate the anti-tumor activity. Secondary outcomes include side effects, survival outcomes, and patient-reported outcomes.
LuCAB is a phase I/II study of cabazitaxel in combination with 177Lu-PSMA-617 in mCRPC patients. Potential mechanisms of resistance to 177Lu-PSMA-617 include:
- Underlying PSMA-negative disease
- Tumor microenvironment related-sensitivity (low sensitivity with hepatic/visceral metastases, high sensitivity with nodal disease)
- Micrometastatic disease not receiving adequate radiation from 177Lu
- Underlying molecular factors which may confer radioresistance
Can cabazitaxel improve response rates and durability of treatment in mCRPC patients when combined with 177Lu-PSMA-617? LuCAB is recruiting 35 to 40 mCRPC patients with disease progression after docetaxel and a second-generation anti-androgen and who have PSMA-avid disease (SUVmax ≥15 and no FDG PET/CT discordant disease) to receive up to 6 cycles of 177Lu-PSMA-617 7.4 GBq intravenously six weekly plus cabazitaxel at escalating doses as illustrated below.
The primary study objective is to establish whether 177Lu-PSMA-617 and cabazitaxel can be combined and used at standard doses. Secondary outcomes include anti-tumor activity, patient-reported outcomes, and side effects.
Presented by: James Buteau, MD, FRACP, FRCPC, Nuclear Medicine Physician, Peter MacCallum Cancer Centre, Victoria, Australia
Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8th and June 11th, 2024
References:- Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804.
- Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021;385:1901-1103.