clinical topic updates

Next-Generation Imaging in Curative-Intent and Metastasis-Directed Strategies

by Robert Dreicer, MD, MS, MACP, FASCO

Overview

Prostate-specific membrane antigen positron emission tomography (PSMA PET) continues to be widely adopted. Clinical trials including both PSMA PET and conventional imaging are likely to further guide the transition to the more sensitive modality.

Expert Commentary

Robert Dreicer, MD, MS, MACP, FASCO

Section Head, Medical Oncology
Deputy Director, University of Virginia Comprehensive Cancer Center
Associate Director for Clinical Research
Co-Director, Paul Mellon Urologic Cancer Institute
Professor of Medicine and Urology
University of Virginia School of Medicine
Charlottesville, VA

“A recent development that will hasten the transition to PSMA PET imaging is the FDA approval of lutetium Lu 177 vipivotide tetraxetan in metastatic castration-resistant prostate cancer and the requirement for PSMA uptake on a 68Ga PSMA PET/CT.”

Robert Dreicer, MD, MS, MACP, FASCO

There are currently 2 US Food and Drug Administration (FDA)–approved agents for PSMA PET imaging. One is gallium based and the other is fluoride based. Although there are some differences between the 2 forms, these differences are not considered to be clinically meaningful. Both forms of PSMA PET imaging are FDA approved in the assessment of patients with prostate-specific antigen (PSA) failure after definitive local treatment, as well as in staging patients who have high-risk localized disease. The gallium-68 (68Ga)–based agent has the additional approval as a companion diagnostic for use with lutetium Lu 177 vipivotide tetraxetan (formerly referred to as 177Lu-PSMA-617) for the treatment of progressive, PSMA-positive, metastatic castration-resistant prostate cancer.

A major challenge in the use of next-generation imaging is that, to date, virtually all studies that have led to the regulatory approval of new therapies for prostate cancer have used conventional imaging (computed tomography [CT] and bone scan)—not PSMA PET—in their response assessments. So, as we transition from a conventional imaging paradigm to a next-generation imaging paradigm, there is the potential to under- or overtreat in a variety of different prostate cancer clinical disease states. The potential for the undertreatment of locally advanced disease is an example. For instance, clinicians might withhold curative-intent therapy based on subtle extrapelvic findings on PSMA PET. 

In contrast, in patients with PSA recurrence following radical prostatectomy who have subtle findings on their PSMA PET imaging, there may be an inclination to assess these findings as “oligometastatic” disease and to offer either “metastasis-directed” therapy such as stereotactic body radiation therapy alone or with androgen deprivation therapy. Thus, there are many unknowns. Selected clinical trials are beginning to incorporate both conventional and next-generation imaging as part of their assessments, which may ultimately inform the field, albeit this will take some time to generate appropriate data.

As to the future of conventional imaging in advanced prostate cancer, I suspect that we will still be using CT/bone scans in patients for some time, for a variety of reasons. Some reasons are clinical (eg, patients with non–PSMA-expressing disease), while others are related to reimbursement, access, and availability. We would obviously like to minimize the need for multiple studies, for example, in patients with biochemical failure and PSMA PET imaging that is demonstrating uptake in bone or soft tissue. I am not sure that obtaining a bone scan in that scenario would add anything of value. A recent development that will hasten the transition to PSMA PET imaging is the FDA approval of lutetium Lu 177 vipivotide tetraxetan in metastatic castration-resistant prostate cancer and the requirement for PSMA uptake on a 68Ga PSMA PET/CT. 

The study of metastasis-directed therapies and research on oligometastatic prostate cancer both began well before the introduction of PSMA PET, and this work is still ongoing. Stereotactic body radiation therapy is a form of metastasis-directed therapy that is often considered. At my institution, we have tried as a urologic oncology group to develop an institutional strategy for the approach to these patients. Looking to the future, currently ongoing trials and new clinical trials will inform practice, but this is still very much a new frontier. Even the definition of oligometastatic prostate cancer is unsettled. From a practical perspective, this is currently an area for which the data to guide decision making remain extremely limited, coming from just a few studies that used different end points. Enrolling these patients in clinical trials is clearly the right thing to do; however, such trials may not always be available, and, ultimately, decisions are likely to be made on a case-by-case basis according to the clinician's best clinical judgment in accord with the patient’s goals of care.

References

Eder A-C, Matthias J, Schäfer M, et al. A new class of PSMA-617–based hybrid molecules for preoperative imaging and intraoperative fluorescence navigation of prostate cancer. Pharmaceuticals (Basel). 2022;15(3):267. doi:10.3390/ph15030267

Hofman MS, Emmett L, Sandhu S, et al; TheraP Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [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. doi:10.1016/S0140-6736(21)00237-3

Phillips R, Shi WY, Deek M, et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6(5):650-659. doi:10.1001/jamaoncol.2020.0147

Rauscher I, Karimzadeh A, Schiller K, et al. Detection efficacy of 18F-rhPSMA-7.3 PET/CT and impact on patient management in patients with biochemical recurrence of prostate cancer after radical prostatectomy and prior to potential salvage treatment. J Nucl Med. 2021;62(12):1719-1726. doi:10.2967/jnumed.120.260091

Schmidt-Hegemann N-S, Fendler WP, Buchner A, et al. Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy. Radiat Oncol. 2017;12(1):176. doi:10.1186/s13014-017-0902-0

Tagawa ST, Bander NH, Osborne JR. Evaluating the current role of PSMA PET: utility, availability, and challenges. ASCO Daily News. March 2, 2022. Accessed July 14, 2022. https://dailynews.ascopubs.org/do/10.1200/ADN.22.200864/full 

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