Prostate-specific membrane antigen, or PSMA, has made headlines in the past several years with several important clinical trials demonstrating both diagnostic and therapeutic benefits. PSMA, a transmembrane glycoprotein, is frequently overexpressed in the prostate cancer epithelium, allowing it to serve as a target lesion for biomarkers for diagnostic or therapeutic purposes.1 Examples of therapeutic compounds include lutetium-177-PSMA-617 (177Lu-PSMA-617), which was reported on earlier in 2021 for its role in the treatment of patients with metastatic castration-resistant prostate cancer.
To review, when a biomarker-for diagnostic or therapeutic purposes-binds to the PSMA receptor, it triggers an endocytotic process that facilitates development of higher concentrations of the bound biomarkers inside the prostate cancer cells.2 On the diagnostic side, there are generally 2 classes of PSMA-based biomarkers that have been widely adopted into use: gallium-68 (68Ga)-PSMA-11 (also known as gozetotide) and fluorine-18 (18F)-based PSMA compounds.
The clinical impact of PSMA-based imaging has been documented by several studies, including a meta-analysis demonstrating that attaining a PSMA-based imaging study-especially in patients with suspected biochemical recurrence after primary therapy-can often lead to a change in the management approach. In a meta-analysis of 1,309 patients, Perera et al demonstrated that 68Ga-PSMA-11 scans had a 76% positivity rate for biochemical recurrence and led to a change in management 54% of the time.3 Despite many positive reports showing promising uses of 68Ga-PSMA-11, geographic availability remains a primary limitation because of its short 68-minute half-life, which restricts its ability to become commercially available and therapeutically viable in parts of the country where access is an issue.4
The primary alternative to 68Ga-PSMA-11 using the PSMA biomarker is the 18F class of compounds, which has slowly gained wide recognition. The CONDOR trial investigated the use of 18F-DCFPy (Pylarify®; piflufolastat positron emission tomography/computed tomography [PET/CT]) in patients thought to have biochemical recurrence after primary therapy (prostatectomy or radiation).5 Of the 208 patients enrolled in the trial, the authors reported a 63.9% change in management after Pylarify imaging, which is in line with the data in published reports of 68Ga-PSMA-11.5
At the 2022 American Urological Association Conference (AUA 2022), results of the phase 3 SPOTLIGHT study were presented that demonstrated the efficacy of 18F-rhPSMA-7.3 for diagnostic imaging in patients with prior localized therapy for prostate cancer who have concern about biochemical recurrence. The rhPSMA class is a subclass of PSMA compounds that allows for faster radiolabeling and decreased urinary clearance compared with 68Ga-PSMA-11.6,7 The latter point has been thought to be a significant impairment to image interpretation owing to the blurring of images produced by concentration of the compound within the urinary bladder.
Several other 18F-based PSMA ligands have been developed, including 18F-DCFPyL and 18F-rhPSMA-7. Proposed benefits of the 18F class of biomarkers, compared with 68Ga-PSMA-11, include its longer half-life (120 minutes), which facilitates simplified transport protocols, and therefore greater patient access, and makes higher quantities of production in cyclotrons (particle accelerators that produce radioactive isotopes) possible.6 Furthermore, 18F-based imaging is also thought to provide greater spatial resolution, leading to fewer blurring artifacts on the final imaging studies.
The SPOTLIGHT study (NCT04186845),8 which was reported at AUA 2022 and covered in a previous issue of GU Oncology Now, sought to explore the utility of 18F-rhPSMA-7.3 in the biochemical recurrence setting by identifying patients with increasing prostate-specific antigen (PSA) levels after primary treatment. All patients enrolled in SPOTLIGHT had negative results on conventional imaging, and all images were interpreted by 3 separate radiologists. The exploratory analysis demonstrated that obtaining 18F-rhPSMA-7.3 imaging at the time of concern for biochemical recurrence led to a 45% to 47% rate of upstaging. An interesting fact of note was that patients undergoing primary radiotherapy had higher rates of positivity in the prostate bed compared with those who underwent prostatectomy although their pelvic lymph nodes and extrapelvic regions were similar.
In a recent issue of European Urology, the authors of a double-blind phase 3 randomized controlled trial compared 68Ga-PSMA-11 with 18F-PSMA-11.9 In their introduction, they explain many of the limitations of 68Ga, including its short half-life and the cost of generating the compound. The trial, conducted out of Ghent University Hospital, Belgium, enrolled patients thought to have biochemical recurrence after primary therapy or prostate cancer confirmed by biopsy. Patients with limited renal function (serum creatinine >2 or estimated glomerular filtration rate <30) were excluded.
By design, all patients underwent both 18F-PSMA-11 and 68Ga-PSMA-11 scans. The primary endpoint was noninferiority of 18F-PSMA-11 compared with 68Ga-PSMA-11. The authors also investigated several secondary endpoints, including the number of positive PET scans, lesions suspicious for prostate cancer, and correlation of PET imaging with follow-up data. The trial had significantly more patients with concern for biochemical recurrence (n=66) compared to primary prostate cancer (n=19); however, other characteristics, including median age, were similar between the 2 groups.
In regard to the primary endpoint, the 2 imaging modalities had the same positivity rate (67%; 55 of 82 patients with positive scans). Secondary endpoints demonstrated no superiority of 18F- over 68Ga-based imaging, but the authors did note that 18F-PSMA-11 scans had a higher rate of equivocal lesions in the axial skeleton. Specifically, they noted that 18F-PSMA-11 scans demonstrated additional lesions in skeletal tissue in 9 patients and in lymph nodes in 4 patients. They attributed this to a known downside of 18F radioisotopes but explained that this hypersensitivity may be useful in detecting small positive lesions in patients with very low PSA values in whom clinicians might have concern for recurrence. The authors noted in their conclusion that this was the largest prospective phase 3 trial comparing 18F-PSMA-11 and 68Ga-PSMA-11 and suggested that 18F-PSMA-11 is a cost-effective alternative to 68Ga-PSMA-11 that achieves similar results.
Other ongoing clinical trials in progress will help elucidate the role of 18F-PSMA-11 in the management of prostate cancer. One trial of interest is an investigation into the role of 18F-PSMA scans in the primary localized treatment setting (NCT04461509). Another is a phase 2 trial being conducted at the University of Alberta, which is exploring the role of 18F-PSMA imaging in locoregional staging of patients undergoing radical prostatectomy for clinically significant prostate cancer (NCT05141760). These investigations and others will continue to provide valuable insights into the role and utility of PSMA-targeted imaging in the treatment of patients with prostate cancer.