Phase 3 Multicenter Randomized Trial of PSMA PET/CT Prior to Definitive Radiation Therapy for Unfavorable Intermediate-Risk or High-Risk Prostate Cancer [PSMA dRT]: Study Protocol - Beyond the Abstract

Prostate cancer is the most common cancer in men, both in the USA and worldwide. One of the challenges is to stage the disease accurately and correctly before treatment. Of course, depending on where the disease is, patients will need to be treated differently. You need accurate tests and imaging techniques to locate the disease and to be sure you are giving the correct treatment for each disease stage. Staging is currently being done with conventional imaging, which includes computed tomography, bone scan, or MRI. They can have limitations, especially to stage disease that has spread out outside of the prostate.

Prostate-specific membrane antigen (PSMA) is overexpressed by prostate cancer cells in large amounts, which therefore makes it a very relevant target for prostate cancer imaging. New PET imaging agents that target PSMA have emerged and are now becoming widely available. PSMA PET imaging has higher sensitivity for extraprostatic metastatic staging and therefore can better select and classify patients for individualized therapy. We know that PSMA PET performs better than the current standard-of-care imaging techniques. PSMA PET/CT has a major impact on patient candidates for definitive RT by showing lesions outside the standard RT fields (Figure 1). However, we don’t know if its use translates into improved outcome – if having better imaging techniques with higher sensitivity actually makes a difference in terms of therapy results and cancer patient outcomes.

Figure 1
This research was originally published in JNM.
Calais J, Kishan AU, Cao M, Fendler WP, Eiber M, et al: Potential Impact of (68)Ga-PSMA-11 PET/CT on the Planning of Definitive Radiation Therapy for Prostate Cancer. J Nucl Med. 2018;59:1714-1721. © SNMMI.

Figure 1 legend: PSMA PET showed lesions (yellow) outside of the standard radiation therapy fields (prostate in orange, and pelvic LN in green) in 16.5% of patients included in a UCLA study. Radiation therapy would obviously fail in these patients. This provided the rationale to initiate this randomized phase 3 imaging trial powered for outcome.

This randomized trial tests this new imaging technique before definitive radiation therapy for prostate cancer. We’ll see if the patients who do not get the PSMA PET imaging technique before do better, equally or worse than patients who do get the PSMA PET imaging test before. It’s a randomized trial comparing two groups (Figure 2). The standard group is definitive radiation therapy as initially planned, as currently done under the standard-of-care setting versus the intervention group, definitive radiation therapy after the PSMA PET imaging. Maybe the PSMA PET imaging will show some disease that wasn’t seen by the conventional scans so the radiation oncologists can adapt their radiation fields or maybe PSMA PET imaging will show some disease already spread outside of the prostate that is not treatable using radiation therapy anymore. The radiation oncologist will therefore not treat these patients with radiation therapy, which changes the therapy management.

Figure 2: Study design

PSMA PET/CT may improve the success rate of curative intent radiotherapy in two ways. First, PSMA PET can be used not as a diagnostic tool but rather as a biomarker for patient selection. Patients with M1 disease by PSMA PET will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent definitive RT. PSMA PET M1 patients will thus not be included in the primary endpoint analysis. The primary objective of the trial is not to assess whether definitive RT will improve the oncological outcome of patients after PSMA PET-based staging. Rather, we will compare the success rate of curative intent definitive RT in patients who were selected with PSMA PET (M0) versus patients who were not selected (control group). Second, PSMA PET can help to personalize the radiotherapy plan (dose and target volumes definition).

Usually, imaging trials are designed for showing improved diagnostic accuracy and improved sensitivity. However, they are rarely designed for improved patient outcomes because it’s difficult to do. This is one of the rare imaging trials powered for outcome.

We have a limited time window to recruit the patients because of the approvals of PSMA PET agents (either  68Ga-PSMA-11 or DCFPyL). Insurance coverage of PSMA PET will also eventually set up and it will be difficult to randomize patients to the control group.

The second challenge is to obtain proper follow-up. The RT takes place at the treating radiation oncologist institution - if enrolled on the trial, the patient only comes to UCLA for the PSMA PET/CT only (if randomized to get it), and then goes back to his treating radiation oncologist either way. You cannot request formally that the patients randomized to the control group do not try to get or get a PSMA PET scan at another institution. If a patient gets randomized to the control group, they may want to try to get the PSMA scan at another institution, and then for us, it’s a dropout so the patient will be excluded from the study.

This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET/CT molecular imaging can improve outcomes in patients with PCa who received RT. In this trial the incorporation of PSMA PET/CT may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection as a biomarker and to personalizes the radiotherapy plan.

Written by: Jeremie Calais, MD, MSc, Director, Clinical Research Program, Assistant Professor, Nuclear Medicine and Theranostics, University of California, Los Angeles

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