There is a growing use and acceptance of prostate-specific membrane antigen (PSMA) targeted diagnostics and theranostics in prostate cancer. Undoubtedly, we have entered the PSMA era in prostate cancer.

PSMA Diagnostics for Staging

Three PSMA diagnostic agents have received FDA (Food and Drug Administration) approval over the past 5 years for staging and biochemical recurrence (BCR): Ga 68 PSMA-11 in 2020,^{1 18}F-DCFPyL in 2021,² and rhPSMA-7.3 in 2023.³ PSMA imaging is now regarded as a standard of care staging imaging modality for high-risk prostate cancer in both the NCCN (National Comprehensive Cancer Network) and AUA/American Society for Radiation Oncology 2022 guidelines. While it was hoped that PSMA staging positron emission tomography (PET)/CT would significantly improve nodal staging in prostate cancer, it is limited in its detection of small nodal disease. While trials have found impressive specificities ranging from 92% to 98%, PSMA PET/CT has failed to demonstrate significant improvement in nodal staging sensitivity. Prospective trials have found a sensitivity of 25% to 40% for nodal detection when compared to histopathologic confirmation.^1-3

Despite enthusiasm for PSMA imaging, questions remain as to how PSMA staging PET/CT should be effectively implemented into clinical practice. The existing evidence does not support omitting pelvic lymph node dissection in the setting of a negative PSMA PET/CT. Petersen et al evaluated Ga 68 PSMA-11 nodal staging accuracy compared to nodal histopathology and found the median size of true positive metastases to be 9 to 11 mm.⁴ Conversely, the median false-negative nodal diameter was 4 mm with nearly one-third of the positive lymph nodes on histopathology being < 2 mm, highlighting the size limitation to PSMA imaging.⁴ While highly specific, a negative PSMA scan is not sensitive enough to detect small nodal metastasis.

Furthermore, the clinical implications of a positive PSMA PET/CT in the setting of negative conventional imaging remain unclear. If nodal or bone metastatic disease are identified only on PSMA PET/CT, does this represent a unique biologic state in which local therapy remains a curative option? Conversely, would these findings exclude the patient from receiving potentially curative local therapy without level 1 evidence to support this change in management?

PSMA Diagnostics for BCR

In the setting of BCR, PSMA PET/CT is also recommended as the preferred imaging option. The positive predictive value of Ga 68 PSMA-11 in assessing biochemically recurrent prostate cancer is reported to be 84% to 92%.⁵ Likewise, for ¹⁸F-DCFPyL positive predictive values have been demonstrated at 89% and 92% for rhPSMA-7.3.^6,7 While advancements have been made in our interpretation of PSMA imaging, there is much to be explored in the treatment algorithm of the PSMA-positive conventional imaging–negative BCR patient. Pound et al have previously shown that the median time from BCR (without treatment) to identifiable metastasis on conventional imaging was 8 years.⁸ The median time to death was reported as an additional 5 years after the development of metastatic disease.⁸ The potential to identify metastatic disease at an earlier state necessitates the need to investigate novel treatment strategies to prolong survival (Figure 1). PSMA PET/CT will improve staging via stage migration; however, PSMA PET/CT will only facilitate improved survival if we effectively act on this early diagnosis of radiographic metastasis. As PSMA PET/CT expands, we expect the role of metastasis-directed therapies to expand in parallel.

PSMA Diagnostics for Tumor Localization Within the Prostate

Although there is potential for PSMA to improve tumor localization within the prostate, significant study is still needed. The phase 2 PRIMARY trial demonstrated that, in biopsy-naïve patients, the addition of PSMA PET/CT to multiparametric MRI (mpMRI) improves the sensitivity of significant prostate cancer detection (97% vs 83%).⁹ However, PSMA PET may not improve the specificity of cancer detection over mpMRI, leaving the challenge of false-positive findings.⁹ To standardize the reporting of intraprostatic PSMA PET/CT findings, the PRIMARY score has been developed, which mirrors the mpMRI Prostate Imaging Reporting and Data System but requires validation.

PSMA Theranostics in Localized Prostate Cancer

PSMA theranostics leverages the specificity of PSMA binding to prostate cancer and selectively delivers radiation at a cellular level. The VISION trial (NCT03511664) led to FDA approval of ¹⁷⁷Lu-PSMA-617 in the treatment of late-stage metastatic castration-resistant prostate cancer.¹⁰ This randomized phase 3 trial found that PSMA-bound β-emitting radionucleotides significantly improved overall survival.¹⁰ The NCCN and AUA/Society of Urologic Oncology 2023 guidelines reflected this change in care with recommendations to offer ¹⁷⁷Lu-PSMA-617 to metastatic castration-resistant prostate cancer patients with a positive PSMA PET scan and progressive disease despite standard of care therapy. Multiple trials now seek to bring this novel treatment class to earlier disease settings. The LuTectomy trial (NCT04430192, Peter MacCallum Cancer Center) was a phase 1 single-arm study that recently demonstrated the potential feasibility and safety of ¹⁷⁷Lu-PSMA-617 prior to radical prostatectomy in patients with high-risk localized prostate cancer.¹¹ Furthermore, in 2024, Chapin et al will open the Nautilus trial (NCT06066437, MD Anderson Cancer Center) as the first randomized, controlled, neoadjuvant PSMA theranostic trial. This trial seeks to evaluate the role of neoadjuvant ¹⁷⁷Lu-PSMA-617 with and without androgen deprivation therapy in high-risk prostate cancer (Figure 2). Future trials will continue to assess the potential role of theranostics in both the neoadjuvant and adjuvant spaces and may one day join the urologist armamentarium.

Conclusions

Great strides have been made in our understanding and utilization of PSMA diagnostics and theranostics. While PSMA is rapidly changing practice, prospective trials are needed to understand the implications of management changes based on PSMA PET findings. Additionally, PSMA theranostics are being evaluated in early disease settings and may one day be included in the management algorithm for localized or recurrent prostate cancer. While we have firmly entered the PSMA era, it is imperative that we prioritize prospective clinical trials to effectively implement PSMA into practice.