The addition of the radiotracer fluciclovine to positron-emission tomography (PET) imaging for radiotherapy treatment planning led to superior failure-free survival compared with conventional imaging in men with prostate cancer who had undergone radical prostatectomy and were experiencing biologic recurrence of their cancer, according to the results of a phase III trial presented during the virtual edition of the 2020 American Society for Radiation Oncology (ASTRO) Annual Meeting.¹

The initial report from the phase III randomized EMPIRE-1 trial showed that 3-year disease-free survival rates were 75.5% for men whose treatment plan was based on fluciclovine PET imaging vs 63% for men whose treatment plan was based on conventional imaging. EMPIRE-1 is unique in that it studied the role of PET with cancer control as an endpoint.

“The decision to offer post-prostatectomy radiation therapy is complex. Failure rates [after surgery] are high, and more accurate imaging techniques are needed for treatment planning. Conventional imaging is limited,” explained lead author Ashesh B. Jani, MD, of Winship Cancer Institute of Emory University, Atlanta.

Ashesh B. Jani, MD

Several studies have shown that more advanced imaging techniques, including fluciclovine PET and prostate-specific membrane antigen (PSMA) PET, can reveal the presence of malignant lesions that are not found on conventional imaging, including bone scans, computed tomography (CT) scans, or magnetic resonance imaging (MRI).

“This research shows that integrating advanced molecular imaging [with fluciclovine PET] into the treatment planning process allows us to do a better job selecting patients for radiation therapy, guiding radiation treatment decisions and planning, and, ultimately, keeping patients’ cancer under control,” Dr. Jani said.

“This is the first study of its kind to look at the role of PET in influencing a cancer control endpoint. That is a very high bar for an imaging study.”

— David M. Schuster, MD

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“This is the first study of its kind to look at the role of PET in influencing a cancer control endpoint. That is a very high bar for an imaging study,” stated co–principal investigator of this study, David M. Schuster, MD, of Emory University.

Fluciclovine is approved by the U.S. Food and Drug Administration (FDA) as a radiotracer for the restaging of recurrent prostate and is included in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. However, it is not widely used as a standard for planning treatment in patients with recurrent prostate cancer. Other PET radiotracers are also under study in prostate cancer, including PSMA, which is not yet approved by the FDA.

Study Details

The EMPIRE-1 trial enrolled 165 men who had undergone radical prostatectomy but subsequently had a rising prostate-specific antigen (PSA) level, signaling the presence of more aggressive cancer. All patients enrolled in the trial underwent conventional imaging with bone scans, CT, or MRI for initial treatment planning that showed no cancer in the bones or outside the pelvis. Study participants were stratified for risk factors, including PSA level, the presence or absence of adverse features (extracapsular spread, seminal vesicle invasion, positive margins, or positive nodes) and intent to use androgen-deprivation therapy or not.

The men were then randomly assigned into two groups: the first group received radiation based on the conventional imaging, and the second group additionally underwent fluciclovine PET imaging, and treatment was planned based on PET findings.

The following PET findings changed treatment decisions accordingly: extrapelvic uptake = abort radiotherapy; pelvic nodal uptake = radiotherapy to the prostate bed and pelvis; prostate bed–alone uptake = radiotherapy to the prostate bed; no radiotracer uptake = radiotherapy to the prostate bed.

“This study is unique. Having a cancer control endpoint is rare. We hardwired treatment decisions into the study schema,” Dr. Jani explained.

Toxicity was reported during radiotherapy and every 6 months. Cancer control data were reported every 6 months.

Study Results

The primary endpoint was 3-year failure-free survival, and the patients whose treatment was planned via fluciclovine PET had a significantly higher rate: 75.5% vs 63% for those whose treatment was planned via conventional imaging results (P = 0.003)—an absolute difference of 12%. The superiority of fluciclovine PET imaging persisted at 4 years: 75.5% for the experimental arm vs 51.2% for the conventional arm (P < 0.001).

At a median follow-up of 3 years, provider-reported toxicity showed no significant differences between treatment arms for acute or late genitourinary or gastrointestinal toxicity. “This suggests that treatment to PET-directed volumes was tolerable,” Dr. Jani said. Patient-reported toxicity will be presented in the future.

“This is an important trial,” Dr. Schuster said. “The reason we did this research was because we were frustrated that we could not get better cure rates for patients with rising PSA levels after radical prostatectomy. We thought one of the factors involved may be the sensitivity of the imaging tests used to plan radiation therapy. We hoped this new PET test, with greater sensitivity to detect prostate cancer, would translate to a reduced failure rate as well. We believed there would be some effect, but we were pleasantly surprised by the strength of the findings.”

Drs. Jani and Schuster as well as their co-investigators will continue to explore more sophisticated imaging techniques in prostate cancer. The next study, EMPIRE-2, will randomly assign patients with rising PSA levels after prostatectomy to fluciclovine PET vs PSMA PET for treatment planning.

“EMPIRE-2 will build on the results of EMPIRE-1 using the newer kid on the block: PSMA. We want to see which of these radiotracers improves cancer control to a greater extent,” Dr. Schuster said. That study is already in progress and allows precise dose escalation to regions of PET uptake, he added.

Additional Commentary

Press conference moderator, Sue S. Yom, MD, PhD, of the University of California San Francisco, called this “a practice-changing study. The EMPIRE 1 study showed improved failure-free survival at 3 or 4 years by incorporating fluciclovine PET into treatment planning, resulting in an impressive absolute gain of 12% at the 3-year timepoint. This is a significant change [in survival] that is unexpected from an imaging intervention,” she said.

Dr. Yom continued: “It is rare to see that in a trial of imaging. I also thought it was interesting that no greater toxicity was observed with the use of a radiotracer. It was possible that fluciclovine PET would detect more disease and require more radiotherapy.”

“Fluciclovine is approved by the FDA for imaging of recurrent prostate cancer, but it is not routinely used for treatment planning yet,” she added. “EMPIRE-1 gives us the data to make that case.”

Dr. Yom offered a thought for the future. “It is possible that the new kid on the block—PSMA—may be more sensitive than fluciclovine, but we will have to see the results of the EMPIRE-2 trial.” 

DISCLOSURE: Dr. Jani has served as an advisor to Blue Earth Diagnostics. Dr. Schuster has received research grants through the Emory Office of Sponsored Projects from Blue Earth Diagnostics, Nihon MediPhysics, Telix Pharmaceuticals, Advanced Accelerator Applications, Fujifilm Pharmaceuticals USA, and Amgen and has served as a consultant to Syncona, AIM Specialty Health, Global Medical Solutions, Taiwan, and Progenics Pharmaceuticals. Dr. Yom has received research grants from Merck, Bristol Myers Squibb, and Genentech and has served as a consultant to Galera.

REFERENCE

1. Jani A, Schreibmann E, Goyal S, et al: Initial report of a randomized trial comparing conventional- vs conventional plus fluciclovine (18F) PET/CT imaging-guided post-prostatectomy radiotherapy for prostate cancer. 2020 ASTRO Annual Meeting. Abstract LBA 1. Presented October 26, 2020.