EAU 2023: State-of-the-Art Lecture When and How to Stage?

Monitoring therapy response in patients with mCRPC is important for optimizing treatment. Treatment decisions in mCRPC are based on clinical trials that have been using conventional imaging most of the time. Personalized medicine is widely discussed, but only intermittently implemented.

The current EAU guidelines recommend a baseline examination with a bone scan and CT abdomen/pelvis and state that the use of PET/CT scans for CRPC progression remains unclear and most likely not as beneficial as for patients with BCR or hormone-naive disease. Flares, PSMA upregulation and discordant results compared with PSA response have been described. At the 2015 APCCC conference, it was suggested that such conventional imaging should be repeated every 6 months, even in the absence of a clinical indication. Furthermore, treatments should not be stopped for PSA progression alone. Instead, two of the following three criteria should be fulfilled to stop treatment:

• PSA progression
• Radiographic progression
• Clinical deterioration

As of yet, the EAU currently recommends still using conventional imaging with a CT/bone scan when treatment modification is considered, and patients are restaged. It remains unclear if the use of PSMA-PET/CT in this setting improves outcomes. As such, until further data are available, MRI and PSMA-PET/CT should not be used outside of trials for treatment monitoring in metastatic patients.

It is recommended that the RECIST criteria be used to evaluate soft-tissue metastasis response, and the Prostate Cancer Working Group-3 criteria for bone lesions. It is important to note that CT cannot be used to monitor sclerotic bone lesions because bone sclerosis can occur under effective treatment and reflects bone healing. MRI may have use in this setting.

While the EAU guidelines primarily endorse conventional imaging given the uncertainty of improved outcomes with PSMA-PET/CT, there is ample evidence to suggest that PSMA-PET/CT has numerous advantages. As has been reported previously in the proPSMA trial, ⁶⁸Ga-PSMA-PET/CT has a:

• 27% greater accuracy compared to conventional imaging (92% [88-95] versus 65% [60-69]; p<0·0001).
• A higher sensitivity (85% versus 38%)
• A higher specificity (98% versus 91%)

Secondary to the improved sensitivity of PSMA-PET/CT, it does detect a larger number of metastases compared to conventional imaging. As such, there may be a stage/volume migration with use of this tool. To that end, Barbato et al proposed a quantitative PSMA-PET framework for disease volume assessment in mHSPC in 2021. 85 CT-based CHAARTED-low-volume and 20 CT-based CHAARTED-high volume patients were evaluated. A PSMA-total volume of ~40 ml was identified as the optimal cutoff between CT-based CHAARTED-low volume (non-unifocal) and high-volume disease (AUC: 0.86).²

One of the other sequalae of using PSMA-PET/CT has been the progressive disappearance of the M0CRPC state, which is defined based on conventional imaging. Among 200 patients with conventional M0CROC, PSMA-PET/CT was positive in 196 of 200 patients (98%).

But PSMA-PET/CT does not always upstage patients. In fact, Forlfi et al. demonstrated that among patients with mCRPC and reported visceral metastases on conventional imaging, PSMA-PET/CT downstaged 47% of patients, secondary to the improvement specificity in this setting.

Significantly, the next iteration of the PROMISE scoring system (PROMISE V2) is now available and will soon be published in European Urology. This scoring system takes into consideration the PRIMARY score as well as rating lesions by PSMA-expression score, which will have clinical implications for theranostics eligibility.

Although ⁶⁸Ga and ¹⁸F-DCFPyL have emerged as the two most popular tracers for PSMA-PET/CT, there are numerous other tracers available, including ¹⁸F-PSMA-1007 and ⁶⁸Ga-PSMA-I&T.

There are specific nuances to the interpretation of PSMA-PET by the tracer used, which includes increased false positive bone lesions in ¹⁸F-PSMA-1007 PSMA-PET/CT scans.

While routine use of PSMA-PET/CT is not currently endorsed for mCRPC patients, a recent study by Gafita et al. evaluated PSMA-PET/CT as a response biomarker for mCRPC patients receiving ¹⁷⁷Lu-PSMA therapy. Using response evaluation criteria in prostate-specific membrane antigen (PSMA) PET/CT (RECIP) and a composite response classification that combines responses by PSA measurements and by RECIP 1.0 (PSA + RECIP), the authors were able to use this framework to evaluate responders to ¹⁷⁷Lu-PSMA therapy at 12 weeks post-initiation of therapy.³

Additional evidence is accumulating that PET/CT response in mCRPC patients undergoing a repeat PET/CT following a baseline evaluation, can be a prognostic factor for progression-free survival.

In light of the current evidence, Professor Hadaschik concluded with the PSMA consensus statements:

• In the absence of clinical trials clearly answering open research questions, high-level consensus events are very important
• Use of PSMA-PET/CT should not be considered if no change in clinical management is expected
• PSMA-PET/CT criteria should categorize patients as responders or non-responders: categories of responders include patients with stable disease, partial response, and complete response.
• The use of PSMA-PET?CT response assessment should be implemented and evaluated in the context of clinical trials

1. Hofman et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020. 395, 10231, P1208-1216.
2. Barbato et al. PSMA-PET for the assessment of metastatic hormone-sensitive prostate cancer volume of disease. J Nucl Med. 2021.14;62(12):1747-1750.
3. Gafita et al. Novel framework for treatment response evaluation using PSMA-PET/CT in patients with metastatic castration-resistant prostate cancer (RECIP 1.0): an international multicenter study. J Nucl Med 2022. DOI: https://doi.org/10.2967/jnumed.121.263072.