On Target
By Keith Loria  
Radiology Today
Vol. 24 No. 5 P. 14

Nuclear medicine and cutting-edge technology are vastly improving prostate cancer treatments.  

Radiology has transformed prostate cancer management several times over the past two decades. Before the 2000s, prostate cancer was detected by a doctor feeling a lump in the prostate or an elevated prostate-specific antigen (PSA) level on a blood test. Urologists would then biopsy the prostate gland under ultrasound guidance to look for cancer.

Since prostate cancer is frequently not visible on ultrasound, urologists would sample different areas of the prostate, hoping that one of the biopsies would randomly hit the cancer. Prostate MRI entered the scene in the early 2000s and exploded in the 2010s. Prostate MRI allowed radiologists to see whether prostate tumors were present, and, with technological advances, the MRI images could be fused to the ultrasound that urologists use when they perform a biopsy.

“They could now see and target the tumors rather than randomly sampling the prostate and hoping to biopsy the tumor,” says Brett Mollard, MD, a diagnostic radiologist in Michigan. “We’re actively witnessing a second revolution thanks to new imaging agents, known as radiotracers or radiopharmaceuticals, for PET.”

PET radiotracers began receiving FDA approval in 2012 (choline), with newer, better radiotracers receiving FDA approval in 2016 (fluciclovine) and 2021 (prostate-specific membrane antigen [PSMA]). PSMA was immediately adopted, diagnosing the spread of disease much earlier than all prior methods.

Andres Correa, MD, an assistant professor at Fox Chase Cancer Center in Philadelphia, has been following the work being done in Europe combining PSMA PET agents with prostate MRI.

“While MRI has significantly reduced the rate of negative biopsies and the diagnosis of low-risk prostate cancer, the imaging modality remains limited,” he says. “Up to 50% of patients with prostate imaging-reporting and data system (PI-RADS) 4 and 25% of patients with PI-RADS 5 lesions will have benign findings on targeted biopsy. I believe that the incorporation of PSMA agents into MRI screening will allow us to better define patients who need a prostate biopsy and further reduce the number of unnecessary prostate biopsies.”

The role of nuclear medicine in the diagnosis and treatment of prostate cancer is expanding. Traditionally, it was mainly limited to less precise scans to assess whether prostate cancer may have spread to bones.

Nuclear medicine’s resurgence as an imaging tool is largely due to advances in PET. Mollard says this is largely because PET cameras are capable of creating much better images than conventional nuclear medicine cameras (gamma cameras and SPECT cameras).

“PET cameras allow us to see smaller things that we weren’t capable of seeing with the older cameras,” he says. “Moreover, the more we learn about the genetics of specific cancers, the better we understand how to diagnose and treat them.”

Mollard notes that PSMA PET justifiably receives a lot of attention as it’s transforming prostate cancer management in two impactful ways.

“First, PSMA PET has emerged as the best imaging option for the detection of metastatic prostate cancer,” he says. “It detects more disease and much earlier in the disease process. It’s like inventing glasses that help you see prostate cancer— once you put on the glasses, you can suddenly see all of the cancer within the body that was previously invisible.”

He explains that PSMA PET currently has a role in initial staging of patients with high-risk disease (to detect early spread of cancer that is not detectable by CT, MRI, or bone scan alone) and when there is biochemical evidence of recurrence where there is an increase in PSA levels following surgery or radiation.

PSMA PET can detect the spread of disease at very early stages of disease recurrence or progression and throughout the entire body. This is incredibly important when it comes to treatment. In fact, a recent study published in 2020 showed that PSMA PET results changed management in 57% of cases.

“Second, PSMA can be used for both diagnosis and treatment,” Mollard says. “By switching the gallium-68 (Ga-68) or fluorine-18 (F-18) for lutetium-177 (Lu-177), PSMA can be converted from a diagnostic agent to a therapeutic agent. This process is known as theranostics. Lu-177 PSMA is taken up by the prostate cancer cells, where it emits radiation of a higher energy level than Ga-68 and F-18, which kills the cancer cells.”

For prostate and certain breast cancers, for example, the cancer cells express specific proteins on their surfaces that make them recognizable, similar to wearing a badge on your sleeve. Drugs can now be created that can see these “badges.”

“For nuclear medicine imaging, a radioactive element is added to the drug that acts like a tracking beacon or GPS,” Mollard says. “The radioactive drug finds and binds to the badges, and, with the right camera, we can take pictures of the radiotracers that show us exactly where the cancer cells are. For some drugs, the radioactive element can be swapped for a more powerful radioactive element that is actually capable of killing the cancer cells.”

Munir Ghesani, MD, chief of nuclear medicine at Mount Sinai Health in New York, calls targeted radiopharmaceutical nuclear medicine therapies “a game changer.”

“When used in the appropriate setting, they slow down progression of cancer, improve quality of life, and prevent complications from advanced cancer,” he says. “They have even shown to improve survival when compared with other therapeutic modalities in these settings.”

Ghesani says theranostics is a notable trend in cancer management. He says it essentially allows doctors to see what they will be treating and treat what they have seen.

“This is quite unlike other forms of therapies, such as chemotherapies,” he says. “This targeted approach allows us to preselect the patients who are most likely to benefit from the targeted radiopharmaceutical nuclear medicine therapies and then deliver these treatments while minimizing the side effects to normal tissues and organs.”

Engineered Radiopharmaceuticals
Also gaining prominence are radiohybrid PSMA (rhPSMA) compounds, engineered radiopharmaceutical agents with potential utility in both imaging and therapy, offering the possibility of precision medicine for men who have prostate cancer.

David E. Gauden, CEO of Blue Earth Diagnostics and Blue Earth Therapeutics, notes rhPSMA compounds may play an important role in the detection, localization, and treatment monitoring of prostate cancer, including informing therapy selection for patients who have prostate cancer and in the therapeutic radiopharmaceutical treatment of disease.

“The investigational PET diagnostic imaging agent 18F-rhPSMA-7.3 represents a new class of PSMA-targeted PET radiopharmaceuticals that is shown in clinical studies to have a high-affinity PSMA targeting mechanism of action,” he says. “18F-rhPSMA-7.3 binds to and is internalized by cells that express PSMA, including prostate cancer cells, the vast majority of which overexpress PSMA. It is labeled with the 18F radioisotope, which can enhance PET scan resolution to facilitate effective detection of disease.”

He cites the recent SPOTLIGHT study, a Phase 3, multicenter, single arm imaging study conducted in the United States and Europe to evaluate the safety and diagnostic performance of 18F-rhPSMA-7.3 PET imaging in men with suspected prostate cancer recurrence based on elevated PSA levels following prior therapy. The findings from a subgroup of men who had undergone primary treatment with radiation therapy, presented at the 2023 American Urological Association meeting, showed high detection rates by majority read for 18F-rhPSMA-7.3 across all regions.

“In particular, the finding that 43% (33/76) of this subgroup had distant extrapelvic recurrences has important implications for clinical management, as procedures such as salvage prostatectomy would be futile in those cases,” Gauden says.

The trial is important, he notes, because as many as 40% of patients who undergo radical prostatectomy and up to 50% of patients who undergo radiation therapy will develop local or distant recurrences within 10 years. The ability to determine the extent and location of recurrent prostate cancer is key for physicians and their patients.

“If approved by the FDA, 18F-rhPSMA-7.3 may provide valuable insights about diagnosis and care for patients with newly diagnosed or suspected recurrent prostate cancer across the care continuum, providing clinically valuable information to guide patient management,” Gauden says. “This, in turn, has the potential to spare certain patients from unnecessary or futile procedures and provide clinically valuable information prior to surgery that may result in management changes for these patients.”

Advancing Technology
In April, a group of physicians treated prostate cancer patients with Avenda Health’s new FDA-cleared, AI-backed prostate cancer technology at UCLA Health in Los Angeles. Using machine learning technology, Avenda Health’s Unfold AI platform provides physicians with the clearest picture yet of cancer within the prostate gland.

The platform analyzes patient-specific data from prostate imaging, biopsies, and pathology with deep-learning algorithms to create a patient-specific cancer estimation map. The 3D, AI-generated map visualizes the location of the cancer for physicians to use in treatment decision making and interventional planning.

“With a wide breadth of ablative options available, Unfold AI represents the first technology to improve tumor localization and patient selection,” says Wayne Brisbane, MD, an assistant professor of urology at UCLA Health. “I am hopeful that Unfold AI will be to intraprostatic staging what prostate-specific membrane antigen PET/CT has been for extraprostatic staging. Additionally, there are potential applications for surgery, radiation therapy, and patient decision-making.”

Most expect PET imaging and treatment to continue growing rapidly throughout the field of oncology.

Correa believes that the future of localized prostate cancer management will be one in which a growing number of patients will be managed with active surveillance, and physicians will be able to better define intermediate-risk cancers that require treatment, possibly treating them with focal options that minimize the quality-of-life altering side effects.

“I believe the key to better treatment selection is with prognostic biomarkers that are geared towards selecting patients into active monitoring categories and, importantly, allow for a longitudinal follow-up of the disease over time as the patient is followed in the monitoring program,” he says.

Mollard notes newer radiotracers will be discovered that are capable of targeting more cancers over time, which will positively impact diagnosis and treatment.

“Prostate cancer treatment is already at a great place, especially for local and regional disease, where five-year survival rates are already over 99%,” he says. “Over the next 10 years, I think the focus will remain on earlier and more accurate diagnosis/detection and discovering new drugs to treat metastatic prostate cancer.”

While targeted radiopharmaceutical therapies using beta particles already have a solid track record and are making remarkable improvements in the outcome of prostate cancer patients, Ghesani says there are emerging data on alpha particles, which may offer a greater benefit.

“In the coming years, targeted radiopharmaceutical therapies using alpha particles and various combinations of beta and alpha particles will be increasingly used in clinical care of prostate cancer patients, with even more profound impact in their outcomes,” he says.

— Keith Loria is a freelance writer based in Oakton, Virginia. He is a frequent contributor to Radiology Today.