Oncology
Prostate Cancer
Progress With Prostate-Specific Membrane Antigen: Current and Ongoing Trials
A session on next-generation theranostics at the 31st Annual Prostate Cancer Foundation (PCF) Scientific Retreat touched on current progress with prostate-specific membrane antigen (PSMA) and possibilities for the future.
Following these proceedings, featured expert Peter R. Carroll, MD, MPH, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Carroll’s clinical perspectives on this topic are presented here.
PSMA positron emission tomography (PET) has revolutionized the way we diagnose and manage prostate cancer. It is currently used for initial staging at the time of diagnosis in patients with higher-risk disease. It is also used at the time of relapse, and it clearly changes treatment paradigms.
The adoption of PSMA PET for initial staging has been rapid, replacing bone scan and computed tomography (CT) in higher-risk cases. This means that treatment can be more specific and more personalized, including intensification strategies based on the imaging characteristics. We still need to see what kind of an impact this will have on overall survival, and this will take some time to determine. We already see the impact in the treatment of metastatic disease, including the benefit of theranostics. I think that it will be interesting to learn how PSMA PET/magnetic resonance imaging (MRI) impacts detection and treatment paradigms. In my view, there is little doubt that we will see improvement, with the real question being: How much of an improvement will we see?
Like many newer modalities of disease assessment or intervention, the pattern is one that often begins with higher-risk cases and then gravitates to earlier stages of disease, often with similar or greater potential benefits.
There is less of a propensity for metastases in lower-risk disease, but there still may be benefits of using PSMA PET. Some patients with lower-risk disease may be candidates for focal ablative strategies, and, in an era when image-guided therapy (eg, focal therapy) is becoming very popular, you want to be sure that you adequately characterize the size, location, and stage of the primary tumor. Consensus guidelines do not, as yet, uniformly endorse these treatment strategies, but they are becoming very popular worldwide because they are associated with reduced morbidity. The key question is: How can you reduce infield recurrence rates? This is where we think that PSMA PET in addition to MRI may be better than MRI alone.
At the University of California, San Francisco (UCSF), we are involved in the MIRROR study, which looks at patients with confirmed favorable intermediate-risk disease. In this group, the presence of regional disease will be very low, but one of the aims is to see if PSMA PET/MRI can better detect lesion location and size, extraprostatic extension, seminal vesicle invasion, regional lymph node involvement, or distant metastases. PSMA PET combined with MRI may give you a better estimate of all compared with standard imaging (ie, transrectal ultrasound and MRI).
At the 31st Annual PCF Scientific Retreat, Louise Emmett, MD, MBBS, of the University of New South Wales, Australia, gave a scheduled talk titled “PSMA: What’s New in 2024?” during a session on next-generation theranostics. Dr Emmett et al have led the prospective PRIMARY clinical trials, exploring the additive value of 68Ga-PSMA PET/CT to multiparametric MRI in the diagnostic setting, publishing related work in 2024.
In the United States, similar work is being done. Although we currently still use the Prostate Imaging Reporting & Data System (PI-RADS), there are ways to integrate PSMA PET that help predict the presence and extent of disease. This has not yet been routinely incorporated, but I think that it will happen very soon. We need to reach a consensus. Tools such as the automated Prostate Cancer Molecular Imaging Standardized Evaluation (aPROMISE) may help standardize PSMA imaging assessment.
A related abstract from this year’s PCF Scientific Retreat by Jesus E. Juarez, MD, and colleagues at UCLA involved the integration of deep learning to predict metastatic progression based on PSMA PET imaging of the primary tumor, along with other variables. Researchers used PSMA PET scans, aPROMISE, conventional clinicopathologic data, and measurable imaging parameters in their models. This needs validation, but the idea is that you get both the imaging and a score based on all that artificial intelligence can “see” in addition to what is humanly visible. The image becomes a biomarker—not just a staging tool but also a biomarker.
Now, in the metastatic space, we are seeing several trials that are combining 177Lu-PSMA radioligand therapy with other agents such as cabazitaxel, pembrolizumab, or, for those patients who carry a germline mutation, PARP inhibitors. 177Lu-PSMA causes single-strand breaks in the tumor cell DNA, and, when PARP is inhibited, it may lead to an accumulation of DNA damage that the cell cannot repair, ultimately causing cancer cell death. Further, the very interesting BULLSEYE trial is looking at 177Lu-PSMA radioligand therapy in people who have oligometastatic hormone-sensitive prostate cancer. So, again, that would be moving from third-line therapy to earlier therapy. Finally, actinium-225 is interesting, of course, because it is an alpha emitter, and it emits higher-energy alpha particles that typically have a shorter range.
I think that, moving forward, people will continue to develop and refine theranostics. The goal is to work toward a more precise, more targeted, more personalized treatment with fewer off-target effects and less morbidity.
Amin A, Blazevski A, Thompson J, et al. Protocol for the PRIMARY clinical trial, a prospective, multicentre, cross-sectional study of the additive diagnostic value of gallium-68 prostate-specific membrane antigen positron-emission tomography/computed tomography to multiparametric magnetic resonance imaging in the diagnostic setting for men being investigated for prostate cancer. BJU Int. 2020;125(4):515-524. doi:10.1111/bju.14999
Cereser L, Evangelista L, Giannarini G, Girometti R. Prostate MRI and PSMA-PET in the primary diagnosis of prostate cancer. Diagnostics (Basel). 2023;13(16):2697. doi:10.3390/diagnostics13162697
ClinicalTrials.gov. Lutetium-177-PSMA-617 in oligo-metastatic hormone sensitive prostate cancer (Bullseye). Updated October 30, 2024. Accessed November 6, 2024. https://clinicaltrials.gov/study/NCT04443062
ClinicalTrials.gov. PYLARIFY® PET/CT or PET/MRI in men with favorable intermediate risk (FIR) prostate cancer (MIRROR). Updated August 2, 2024. Accessed November 6, 2024. https://clinicaltrials.gov/study/NCT06074510
Emmett L, Papa N, Counter W, et al. Reproducibility and accuracy of the PRIMARY score on PSMA PET and of PI-RADS on multiparametric MRI for prostate cancer diagnosis within a real-world database. J Nucl Med. 2024;65(1):94-99. doi:10.2967/jnumed.123.266164
Emmett L, Papa N, Hope TA, et al. Beyond prostate imaging reporting and data system: combining magnetic resonance imaging prostate imaging reporting and data system and prostate-specific membrane antigen-positron emission tomography/computed tomography PRIMARY score in a composite (P) score for more accurate diagnosis of clinically significant prostate cancer. J Urol. 2024;212(2):299-309. doi:10.1097/JU.0000000000004010
Emmett L. PSMA: what’s new in 2024 [session 7: Next generation theranostics]? Session presented at: 31st Annual Prostate Cancer Foundation Scientific Retreat; October 24-26, 2024; Carlsbad, CA.
Juarez JE, Benitez CM, Rzechowski K, et al. Deep learning models built from PSMA PET of the primary tumor can predict synchronous and metachronous prostate cancer metastases [abstract]. Abstract presented at: 31st Annual Prostate Cancer Foundation Scientific Retreat; October 24-26, 2024; Carlsbad, CA.
Nickols N, Anand A, Johnsson K, et al. aPROMISE: a novel automated PROMISE platform to standardize evaluation of tumor burden in 18F-DCFPyL images of veterans with prostate cancer. J Nucl Med. 2022;63(2):233-239. doi:10.2967/jnumed.120.261863
Privé BM, Janssen MJR, van Oort IM, et al. Update to a randomized controlled trial of lutetium-177-PSMA in oligo-metastatic hormone-sensitive prostate cancer: the BULLSEYE trial. Trials. 2021;22(1):768. doi:10.1186/s13063-021-05733-4
Sollini M, Calais J, Chiti A, et al. Novel radiopharmaceuticals and future of theranostics in genitourinary cancers. Eur Urol. 2024 Oct 19;S0302-2838(24)02641-1. doi:10.1016/j.eururo.2024.09.036
Tward JD, Josephson D, Catana C, et al. A phase 4 open-label multicenter study of piflufolastat F 18 PET/CT or PET/MRI in men with newly diagnosed favorable intermediate risk prostate cancer: MIRROR. Int J Radiat Oncol Biol Phys. 2024;120(suppl 2):e592-e593. doi:10.1016/j.ijrobp.2024.07.1305
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