Prostate Cancer Diagnostics: Novel Approaches Are Leaving Conventional Imaging Behind

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Advances in molecular imaging are having a big impact on prostate cancer management and outcomes, according to Ashesh B. Jani, MD, the James C. Kennedy Professor in Prostate Cancer, Department of Radiation Oncology at the Winship Cancer Institute of Emory University, Atlanta. Dr. Jani described his own work with fluorine F-18–labeled fluciclovine/positron-emission tomography (PET) and other rapidly evolving approaches in this cancer at the 2021 Debates and Didactics in Hematology and Oncology conference, sponsored by Winship Cancer Institute of Emory University.1

Ashesh B. Jani, MD

Ashesh B. Jani, MD

“The decision to offer radiotherapy after prostatectomy is complex. Failure rates are high. Most decisions about radiation are based on conventional imaging, which is very limited. That’s why there’s a role for molecular imaging,” he said.

Toward that end, there have been some exciting developments over the past 2 decades:

  • Single-photon emission computed tomography: Capromab pendetide (monoclonal antibody prostate-specific membrane antigen [PSMA] intracellular target): Approved by the U.S. Food and Drug Administration (FDA) in 1999


—Fluorodeoxyglucose (F-18 FDG, glucose-based)

—Carbon C-11 acetate (fatty acid synthase)

—C-11 choline and F-18 choline (phospholipid cell membrane); C-11 was approved by the FDA (at the Mayo Clinic) in 2012

—F-18 fluciclovine (amino acid analog); invented at Emory and approved by the FDA in 2016

—Gallium Ga-68 PSMA and F-18 PSMA (PSMA receptor [extracellular]); approved by the FDA in 2020.

More recently, other novel compounds are entering the prostate cancer diagnostics space:

  • Ga-68 PSMA-11: Approved by the FDA in 2020 at the University of California Los Angeles and University of California San Francisco for primary staging and recurrence. There is currently no reimbursement by the Centers for Medicare & Medicaid Services for this agent.
  • DCFPyL: A radioactive tracer that targets PSMA. F-18 DCFPyL was approved by the FDA in 2021 for primary staging and recurrence. This is a second-generation PSMA with a longer half-life and advantages over Ga-68 PSMA-11.
  • rhPSMA: Radiohybrid PSMA ligand. F-18 rhPSMA has potential advantages: fluorinated, higher affinity, lower bladder uptake, lower blood pool. LIGHTHOUSE and SPOTLIGHT trial results are pending, and the timeline for its release is not known.

F-18 Fluciclovine: EMPIRE-1 Trial

Dr. Jani focused on the development, approval, and use of F-18 fluciclovine/PET, which was developed at Emory. It is a diagnostic imaging agent (ie, radiotracer) that is used along with PET scanning in previously treated men who develop elevated PSA levels. The hypothesis is that F-18 fluciclovine/PET will improve radiotherapy outcomes by identifying patients with extrapelvic disease for whom radiotherapy would be futile and by integrating PET information into the radiation field design and target definition.

Dr. Jani was co–principal investigator (along with David Schuster, MD) of the phase II/III open-label randomized controlled EMPIRE-1 trial, whose results were reported as a late-breaking abstract at the 2020 American Society for Radiation Oncology (ASTRO) Annual Meeting2 and in The Lancet.3 The study’s aim was to establish the role of F-18 fluciclovine/PET in influencing radiotherapy decision-making after prostatectomy and in altering radiotherapy target volumes.

EMPIRE-1 enrolled 165 patients with prostate cancer who had detectable PSA levels after prostatectomy and negative conventional imaging (no extrapelvic or bone findings). Patients were randomly assigned to receive radiotherapy directed by conventional imaging alone or conventional imaging plus F-18 fluciclovine/PET. In the group that underwent F-18 fluciclovine/PET, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. Treatment decisions and planning volumes were first based on standard imaging; then when the F-18 fluciclovine scan was performed, decisions were revised if needed.

Patients found to have extrapelvic uptake did not undergo radiotherapy. Those with pelvic nodal FDG uptake received treatment to the pelvis and prostate bed. Those with uptake in the prostate alone received radiotherapy to the prostate bed. In the absence of uptake, the de facto option was also treatment to the prostate bed.

The primary endpoint was unusual for an imaging trial: 3-year event-free survival. Events were defined as biochemical or clinical recurrence or progression of disease or initiation of systemic therapy. PET uptake and decision changes were also reported.

F-18 Fluciclovine: Impact on Treatment Decisions and Planning

Use of the F-18 fluciclovine scan led to changes in treatment decisions for 38 of 79 patients (35%) overall, “which is quite significant for an imaging test,” Dr. Jani noted. Radiotherapy field changes were made for 24 of the 75 patients (32%) who underwent radiotherapy.

PET uptake was observed in the following locations: outside the pelvis (4), pelvis with or without the prostate bed (27), prostate bed alone (32), and none (6). Specifically, for 45 patients slated for radiotherapy to the prostate bed alone, 14 were converted to radiotherapy to the prostate bed plus the pelvis. For 30 patients slated for radiotherapy to the prostate bed plus the pelvis, 10 were converted to radiotherapy to the prostate bed alone (P < .001).

“We went a step farther and examined how the PET information was integrated into treatment planning,” explained Dr. Jani. “We found that disease was captured on PET that would otherwise have been missed when planning the target…. PET changed our target volumes as well. We were able to treat patients in a way that does not impact most normal structures…. The rectum and bladder dose volume histograms were generally unaffected (although penile bulb dose was higher after inclusion of PET information).”

It was hypothesized that F-18 fluciclovine would improve outcomes by “reducing geographic misses,” he added.

“Most importantly,” Dr. Jani said, after a median follow-up of 3.5 years, the inclusion of F-18 fluciclovine/PET into postprostatectomy radiotherapy decision-making and planning significantly improved survival free from biochemical recurrence or persistence. The 3-year event-free survival was 63.0% in the conventional arm and 75.5% in the F-18 fluciclovine/PET arm—an absolute difference of 12.5% (P = .003). In adjusted analyses, randomization to the F-18 fluciclovine/PET arm was significantly associated with event-free survival (hazard ratio = 2.04; P = .0327).

Although not a predefined endpoint, the 4-year event-free survival was 51.2% vs 75.5% (P < .001). “We saw that this difference holds up with longer follow-up,” Dr. Jani commented. “It’s rare for an imaging study to be able to show a survival difference like this.”

“In fact, a cancer control endpoint—progression-free survival—is a high bar for an imaging study. Most studies focus on diagnostic accuracy, pathologic correlation, and decision changes…. Bone scans, CT, and MRI have not been held to this level of scrutiny,” he added.

Median survival was not reached in either arm, and toxicity was also similar, Dr. Jani continued. “Basically, it showed that when you treat these larger volumes, there’s no difference in acute or late provider-reported toxicity.” Patient-reported toxicities will be presented at the 2021 ASTRO meeting.

“EMPIRE-1 was the first such trial of PET over conventional imaging alone for post-prostatectomy radiotherapy,” Dr. Jani commented. “It paved the way for integration of novel PET radiotracers into radiotherapy decision-making.”

Targeting PSMA

The next generation of enhanced imaging targets PSMA, a type 2 transmembrane glycoprotein that is overexpressed on the cell surface of prostate cancer. Expression of PSMA increases progressively in higher-grade tumors, metastatic disease, and hormone-refractory prostate cancer.

Ga-68 PSMA has an advantage in detecting extraprostatic disease, especially at low PSA levels, whereas F-18 fluciclovine has an advantage over Ga-68 PSMA in detecting disease in the prostate bed, Dr. Jani stated.

To better understand the differences between these two radiotracers, the EMPIRE-2 trial is randomly assigning patients to undergo F-18 fluciclovine or Ga-68 PSMA. Although the study is similar to EMPIRE-1, a higher radiation dose will be delivered to sites of FDG uptake in EMPIRE-2. The study is quickly accruing, he reported, as the PSMA landscape is rapidly changing. “We want to finish this trial and answer our questions scientifically, before the widespread use of PSMA,” Dr. Jani commented.

Other Novel Approaches

MRI scanning is effective in soft-tissue delineation, and a growing body of evidence has found it useful in delineating the dominant intraprostatic lesion—which drives biology and predicts outcome—for targeting. The FLAME trial is showing that treatment with higher doses to areas of imaging-defined uptake may result in less biochemical failure and improved disease-free survival.4

Other studies are integrating PET information to help guide target fusion biopsies, both in initial staging and in the setting of recurrence. In the latter, Emory investigators have evaluated F-18 fluciclovine/PET or ultrasound fusion-targeted biopsy vs standard template biopsy in patients with biochemical failure after nonsurgical therapy, showing it is a “novel and viable strategy.” In a small 2019 study, this approach identified more recurrent prostate cancer using fewer cores than did template biopsy in the same patient.5 Up next, Loyola University, Chicago, investigators are integrating information from PET to target high-dose brachytherapy in patients with recurrence in the BEACON trial.

The newest compound for PET imaging is F-18 rhPSMA-7.3. It is being evaluated in two phase III trials by Blue Earth Diagnostics—LIGHTHOUSE ( identifier NCT04186819) and SPOTLIGHT (NCT04186845). The rhPSMA compound consists of a radiohybrid PSMA-targeted receptor ligand that attaches to and is internalized by prostate cancer cells. The compound may be radiolabeled with F-18 for PET imaging or with isotopes such as lutetium Lu-177 or actinium Ac-225 for therapeutic use.

LIGHTHOUSE will evaluate F-18 rhPSMA-7.3 in newly diagnosed prostate cancer, particularly looking at its sensitivity and specificity in detecting pelvic lymph node metastases compared with surgical pathology on a patient level. SPOTLIGHT will evaluate this compound in men with suspected prostate cancer recurrence based on elevated PSA levels following prior therapy. Its primary endpoints are the correct detection rate and positive predictive value of F-18 rhPSMA-7.3/PET, using histopathology or confirmatory imaging.

“Prostate cancer imaging is a very exciting area to be working in,” Dr. Jani concluded. “It’s a rapidly changing area, and, being a fierce optimist, I believe the best is yet to come.” 

DISCLOSURE: Dr. Jani has served as a consultant or advisor to Blue Earth Diagnostics.


1. Jani AB: Advanced imaging in the modern era of prostate cancer. 2021 Debates and Didactics in Hematology and Oncology. Presented August 1, 2021.

2. 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. Int J Radiat Oncol Biol Phys 108:1397, 2020.

3. Jani AB, Schreibmann E, Goyal S, et al: 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): A single centre, open-label, phase 2/3 randomised controlled trial. Lancet 397:1895-1904, 2021.

4. Kerkmeijer LGW, Groen VH, Pos FJ, et al: Focal boost to the intraprostatic tumor in external beam radiotherapy for patients with localized prostate cancer: Results from the FLAME randomized phase III trial. J Clin Oncol 39:787-796, 2021.

5. Fei B, Abiodun-Ojo OA, Akintayo AA, et al: Feasibility and initial results: Fluciclovine positron emission tomography/ultrasound fusion targeted biopsy of recurrent prostate cancer. J Urol 202:413-421, 2019.