Low-Risk and Favorable Intermediate-Risk Prostate Cancer

Currently, PSMA-PET imaging is not included in consensus recommendations for staging of low risk and favorable intermediate-risk PCa. ^, However, there are potential roles for PSMA-PET for these patients that are under investigation. A pivotal decision point for patients with low-risk or favorable intermediate-risk PCa is whether to pursue treatment or active surveillance (AS). In general, PSMA-PET maximum standardized uptake value (SUVmax) appears to associate strongly with International Society of Urologic Pathology (ISUP) grade group (GG). For patients eligible for AS, SUVmax and adverse features on PSMA-PET (eg, MR imaging occult lesions, evidence of extraprostatic extension, or seminal vesicle invasion) have been shown to predict for upstaging on additional targeted biopsy or final histology after RP. ^{, ,} A prospective study of 141 patients by Heetman and colleagues found that the number needed to scan for GG upstaging was 11 (based on targeted biopsy of PSMA-PET avid lesions with SUVmax ≥4). The optimal SUVmax cutoff remains unknown, however, as Roberts and colleagues showed that SUVmax ≥8 predicted GG ≥3 with a hazard ratio (HR) of 5.48 and associated with worse progression-free survival.

Integrating PSMA-PET SUVmax and multiparametric MR imaging (mpMRI) may provide additional guidance for patients eligible for AS. ^{, ,} A prospective trial of 296 men that enrolled biopsy-naïve patients reported that the sensitivity for detecting GG 2+ disease was improved from 83% to 97% when combining PSMA-PET (using SUVmax ≥4) with mpMRI. The findings have been adopted into version 2 of the prostate cancer molecular imaging standardized evaluation (PROMISE) framework for PCa staging. More broad incorporation of PSMA-PET into clinical workflows for patients eligible for AS will require additional prospective studies and validated nomograms. One such study is the CONFIRM trial, which will evaluate the proportion of men with newly diagnosed PCa no longer deemed appropriate for AS following PSMA-PET (in addition to mpMRI and biopsy). Overall, current use of PSMA-PET in this setting should be done with caution, as cost and insurance coverage remain important barriers for many patients.

Unfavorable Intermediate-Risk and High-Risk Prostate Cancer

The landmark trials that led to FDA approval of PSMA-PET for staging of newly diagnosed PCa included patients with unfavorable intermediate-risk and high-risk disease. ^{, , , 68} Ga-PSMA-11 was approved following 2 large multicenter trials. The phase 3 proPSMA study randomized 302 newly diagnosed men with high-risk features (at least one of prostate-specific antigen [PSA] ≥20 ng/mL, GG ≥3, or clinical stage ≥T3) to conventional imaging or PSMA PET-CT. Using a predefined reference standard (based primarily on confirmatory imaging and histopathology), the study showed that PSMA-PET outperformed conventional imaging in detecting nodal and distant metastases with greater sensitivity (85% vs 38%) and specificity (98% vs 91%). PSMA-PreRP was a single-arm prospective study of 764 patients, of whom 277 underwent RP and PLND to establish a standard of reference. ⁶⁸ Ga-PSMA-11 PET detected pelvic lymph node metastases with 40% sensitivity and 96% specificity.

Large prospective studies using ¹⁸ F-DCFPyL have shown similar performances to ⁶⁸ Ga-PSMA-11 PET for detecting pelvic lymph node metastases. ^, OSPREY was a phase 2/3 multicenter study with 2 cohorts: Cohort A enrolled patients with high-risk PCa intended for RP + PLND and Cohort B enrolled patients with suspected recurrence. Cohort A reported 40% sensitivity and 98% specificity, with higher positive predictive value compared with conventional imaging (87% vs 28%). The multicenter SALT trial also showed similar results, reporting 41% sensitivity and 94% specificity. The SALT trial, which used a ≥8% risk probability for LN metastasis for performing elective PLND, noted that the median size of nodes not detected on PSMA-PET was 1.5 mm, which led the authors to conclude that PSMA-PET may be inadequate to replace elective PLND for staging due to the presence of small metastatic deposits. More recently, the FDA approved ¹⁸ F-rhPSMA-7.3 for staging of newly diagnosed PCa based on the prospective LIGHTHOUSE study. While the reported specificity for detecting pelvic lymph node metastases was 93%, sensitivity ranged from 23% to 30% among 3 readers, which is lower than for other approved radioligands.

Results of PSMA-PET staging can significantly impact treatment decisions. For patients deemed appropriate for definitive radiation therapy (RT), treatment fields and boost volumes can vary based on the extent of disease. For high-risk clinically node negative (cN0) disease defined on conventional imaging, RTOG 9413 showed that elective whole pelvis RT (WPRT) improved progression free survival (PFS) compared with prostate-only RT when given with neoadjuvant hormone therapy. However, it is unclear whether cN0 disease staged by PSMA-PET is sufficient to omit WPRT, even though PSMA-PET has a high negative predictive value ranging from 81% to 90%. ^{, ,} In fact, the randomized prostate-only or whole-pelvic radiation therapy in high-risk prostate cancer (POP-RT) trial showed improved biochemical failure-free survival with WPRT compared with prostate-only RT (when combined with 2 years of androgen deprivation therapy [ADT]), despite 80% of patients being cN0 based on PSMA-PET. This seems to suggest the importance of other risk factors in predicting imaging-occult pelvic disease for high-risk patients, and support findings from the SALT trial regarding limitations of PSMA-PET in the detection of small metastases. More frequently in the clinic, PSMA-PET findings lead to more comprehensive treatment volumes. A post hoc analysis of 73 patients treated on trial found that PSMA-PET positive nodes altered 32% of RT plans due to initial under-coverage of the clinical target volume.

While the use of PSMA-PET exposes issues with target coverage based on conventional imaging, the long-term impact of defining RT volumes and selecting type and duration of hormone therapy based on PSMA-PET has yet to be determined in a prospective randomized setting. While it may seem appropriate to determine therapy based solely upon this more sensitive imaging modality, there is currently a lack of evidence to support this approach. Therefore, guidelines continue to support offering definitive therapy for patients with cN0 or cM0 disease defined based on conventional imaging regardless of extraprostatic PSMA disease. The multi-institutional phase 3 trial PSMA-dRT intended to evaluate the impact of PSMA-PET on treatment outcomes, but closed early due to enrollment. A 2-year update with 54 patients randomized showed upstaging in 17% of patients with PSMA-PET, but no difference in PFS. Two phase 3 trials are currently enrolling: PATRON, which will randomize to PSMA-PET ( ¹⁸ F-DCFPyL or ¹⁸ F-PSMA-1007) versus conventional imaging ; and EMPIRE-II, which will randomize to PSMA-PET ( ⁶⁸ Ga-PSMA-11) versus fluciclovine-PET, following results of EMPIRE-I, which showed improved 3-year event-free survival using fluciclovine-PET over conventional imaging.

For patients deciding between RP with PLND and RT, PSMA-PET may assist with shared decision making. PSMA-PET improves existing predictive nomograms for predicting pelvic lymph node metastases, and PSMA-PET N1/M1 status is prognostic for biochemical recurrence (BCR) after surgery. Importantly, prediction of pathologic N1 status may alter the decision to take a surgical approach, given the increased toxicity associated with adjuvant RT and the potential clinical determinant in delaying RT among pathologic node positive patients. ^,

The role of follow-up PSMA-PET after definitive treatment of localized PCa is poorly defined. Existing data on PSMA-PET response and clinical outcomes are from retrospective work. Chen and colleagues conducted a multivariable analysis of PSMA-PET response in 75 high-risk patients treated with ADT plus docetaxel or abiraterone followed by definitive RT. They found that post-treatment SUVmax less than 8.5 was an independent predictor of biochemical PFS. However, change in SUVmax appears to depend on treatment type, making these findings difficult to generalize. For example, Onal and colleagues showed in an analysis of 71 intermediate-risk PCa patients that PSMA-PET complete metabolic responses occurred in 40% of patients receiving ADT + RT compared with 0% in RT alone. Further, the optimal timing of post-treatment PSMA-PET remains unknown, adding additional uncertainty to its application in identifying treatment response. Nonetheless, given that PSA and PSMA response do not appear to be highly concordant, there may be a role for PSMA-PET in routine follow-up once the relationship between post-treatment imaging changes and outcomes are better characterized.

Metastasis-Directed Therapy

Oligometastatic mCSPC (omCSPC) is a state of limited volume disease often defined as ≤3 to 5 metastases, which appears to derive benefit from metastasis-directed therapy (MDT). This was first identified within the STOMP trial which randomized 62 patients with ≤3 metastases on 11-choline PET to observation versus MDT. This trial demonstrated MDT improved ADT-free survival from 13 to 21 months. The ORIOLE trial similarly randomized patients with ≤3 metastases to observation vs MDT, but used conventional imaging for staging. Importantly, patients on the ORIOLE trial underwent PSMA-PET imaging at diagnosis, but the investigators were blinded to the results. While the ORIOLE trial similarly demonstrated a benefit of MDT (6-month PFS 81% vs 39%), patients treated with MDT who had untreated conventionally occult, PSMA-PET avid lesions demonstrated significantly worse PFS (HR = 0.26, P =.006) than those with total PSMA-PET consolidation. These findings suggest the importance of highly sensitive staging imaging when identifying patients for MDT to ensure total disease consolidation can be achieved.

While both choline-PET and PSMA-PET offer improved sensitivity over conventional imaging, PSMA-PET appears superior for guiding total consolidative MDT. Mazzola and colleagues demonstrated that PSMA-PET-directed MDT was associated with improved 1-year ADT-free survival (89.6% vs 73.2%, P =.01) as compared with choline-PET-directed therapy. Deijen and colleagues similarly demonstrated PSMA-PET-directed MDT was associated with significantly longer median ADT-free survival (34.0 vs 14.7 months, P =.01) compared with choline-PET-directed MDT. This improvement is likely due to the increased detection of occult metastatic disease with PSMA-PET and consistent with the results of the ORIOLE trial.

In addition to increasing metastatic detection for total disease consolidation, PSMA-PET also appears to provide prognostic information. Sutera and colleagues reviewed 295 patients with metachronous omCSPC detected either on molecular (PSMA-PET, choline-PET, or fluciclovine-PET) imaging only or conventional imaging. Patients with molecular-only omCSPC were found to have better overall survival (OS) both from time of metastasis (HR = 0.13, P =.007) as well as from initial localized disease (HR = 0.12, P =.006). Further, molecular-only omCSPC was associated with fewer TP53 and more SPOP somatic mutations, indicating a less aggressive disease biology. Taken together, the results suggest that molecular-only omCSPC represents a more indolent disease state than those with metastases detectable on conventional imaging, rather than simply identifying patients earlier in their disease course. This difference in disease biology has potential to be leveraged for improved therapeutic precision in these 2 groups of omCSPC.

PSMA-PET not only holds promise for proper patient selection and prognostication within patients with omCSPC, but it may also be used as an indicator for treatment response to MDT. Greco and colleagues reported a single-institution phase II study evaluating PET response following MDT in oligometastatic disease across multiple histologies. This study included 147 patients with PCa (who underwent ⁶⁸ Ga-PSMA PET) and demonstrated change in SUVmax was associated with locoregional failure. More recently, an international multi-institutional review of men with omCSPC with pre-MDT and post-MDT PSMA-PET was reported. This work identified 131 patients with 261 treated metastases who underwent PSMA-PET approximately 6 months following MDT. Patients were classified as being PSMA responders (all lesions with at least 30% reduction in SUVmax) or PSMA nonresponders (at least 1 lesion with <30% reduction in SUVmax). Following stereotactic ablative radiation therapy (SABR), 70.2% of patients were classified as PSMA responders, who were found to have significantly improved median metastasis-free survival (MFS) of 39.9 versus 12 months ( P =.001) compared with PSMA nonresponders. Follow-up work with this cohort utilized machine learning incorporating both radiomic (pretreatment and post-treatment PSMA-PET) and clinical features was able to predict 2-year MFS with an accuracy of 75% to 80%.

Prostate-Directed Therapy

As previously mentioned, disease volume is also used to determine the role of prostate-directed therapy. The STAMPEDE arm H trial demonstrated an overall survival benefit with radiotherapy to the prostate for patients with low-volume but not high-volume de novo metastatic disease. Importantly, this definition was disease volume was based on conventional imaging. More recently, the PEACE-1, a 2×2 factorial design randomized trial, included radiotherapy to the prostate for patients with low-volume disease. This trial, however, similarly used a conventional imaging definition of disease volume. It, therefore, remains unclear if there is a differential benefit to prostate-directed therapy for patients with conventionally detected low-volume disease with PSMA-PET detected low-volume versus high-volume disease.

Predictive Value of Prostate Specific Membrane Antigen-PET and Patient Selection for Radioligand Therapy

Biomarkers based on PSMA-PET have been investigated in multiple retrospective and prospective studies involving RLT, including VISION, TheraP, LuPSMA. In order to develop a nomogram for predicting outcomes after PSMA-RLT, Gafita and colleagues conducted a multicenter retrospective study of 270 mCRPC patients in which they identified 6 variables as independent predictors of OS. Notably, the SUVmean of whole-body tumor burden, the number of lesions, and the presence of liver metastases remained significant on multivariable analysis. TheraP, a multicenter randomized phase 2 trial randomizing mCRPC patients to ¹⁷⁷ Lu-PSMA-617 versus cabazitaxel, reported whole-body tumor PSMA-PET SUVmean ≥10 was associated with greater PSA response and radiographic PFS (rPFS) for PSMA-RLT compared with cabazitaxel. ^, Although the cutoff of SUVmean ≥10 did not translate into a difference in OS within the ¹⁷⁷ Lu-PSMA-617 treatment arm in the updated analysis, SUVmean ≥10 was still prognostic for OS (HR: 0.58, 95% confidence interval [CI]: 0.40–0.83, P =.0033) after adjusting for randomized treatment. A secondary analysis of the VISION trial also showed that whole-body tumor SUVmean was the strongest imaging predictor of rPFS and OS after PSMA-RLT. These findings provide guidance for the optimal use of ¹⁷⁷ Lu-PSMA-617 in mCRPC patients as an alternative to cabazitaxel.

The presence of PSMA-negative lesions has also emerged as an important variable for predicting patient outcomes and for determining eligibility for PSMA-RLT. According to the phase III VISION trial, patients must have had at least one PSMA-positive metastatic lesion and no PSMA-negative lesions to qualify for treatment. Patients who did not meet the VISION inclusion criteria-either due to low PSMA expression or the presence of PSMA-negative lesions (defined as SUVmax less than or equal to liver background), had poor outcomes following PSMA-RLT. ^, Furthermore, discordance between fluorodeoxyglucose-PET (FDG-PET) and PSMA-PET uptake also portends worse outcomes. In a prospective study by Telli and colleagues, both ¹⁸ F-FDG and ⁶⁸ Ga-PSMA PET/CT scans were used to comprehensively assess tumor burden and heterogeneity in 52 mCRPC patients who received 2 to 6 cycles of PSMA-RLT. The study found that discordant imaging findings, where FDG uptake exceeded PSMA uptake in the majority of lesions (defined as FDG > PSMA disease), were associated with poorer OS and shorter PFS. Similarly, discordant findings on bone scintigraphy, where ^99m Tc-HDP uptake was higher than PSMA uptake in most bony lesions (defined as bone scan > PSMA disease), were linked to shorter PFS. Michalski and colleagues further corroborated these findings, reporting significantly lower median OS in patients with at least one FDG+/PSMA-lesion at baseline PET/CT (6.0 ± 0.5 months, 95% CI: 5.0–7.0 months) compared with those without any FDG+/PSMA-lesions (16.0 ± 2.5 months, 95% CI: 11.2–20.8 months).

Although clinical trials cannot be directly compared, both the LuPSMA and TheraP trials excluded patients with discordant PET lesions (ie, FDG positive with no or low PSMA avidity) and resulted in PSA response of 64% and 66%, respectively. ^, This contrasts with the VISION trial, where PET-only screening resulted in a lower PSA response rate (46%). The advantages of using dual-tracer PET screening to select patients for PSMA-RLT warrant further investigation. Efforts are ongoing to develop dual-tracer criteria for PSMA-RLT eligibility and for predicting outcomes. Adnan and Basu have proposed a novel 6-tier integrated dual-tracer PET/CT scoring system, the “Pro-PET” score, which combines ⁶⁸ Ga-PSMA and FDG PET imaging to predict therapeutic outcomes and prognosis in mCRPC. There are ongoing studies to evaluate dual-tracer criteria prospectively, including the Triple-Tracer strategy against Metastatic PrOstate cancer (3TMPO) study.

Finally, the presence of liver metastases in mCRPC is associated with a poorer response to many forms of systemic therapy, likely due to the differentiated tumor microenvironment and intertumoral heterogeneity. Though this does not affect patient selection for PSMA-RLT, combination approaches or augmented PSMA-RLT may be considered to maximize the antitumor activity of RLT in the liver.

Assessment of Treatment Response

The evaluation of treatment response in mCRPC typically follows the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or the PCa Working Group Criteria 3 (PCWG3), using conventional imaging modalities such as CT and bone scans. ^, However, changes in PSMA expression detected on PSMA PET/CT scans after treatment offer a more sensitive and specific indicator of treatment response, surpassing traditional imaging in its ability to specifically target prostate cells. Despite its advantages, the role of PSMA PET/CT in routine clinical practice for response assessment remains less well-defined. Nevertheless, PSMA PET/CT progression criteria have been established for clinical trials, providing a standardized framework for evaluating treatment response in mCRPC patients. Two commonly used PSMA PET/CT reporting frameworks include the PSMA Reporting and Data System (PSMA-RADS) and the PROMISE framework. PSMA-RADS employs a 1 to 5 scale to assess the likelihood that tracer accumulations represent malignancy or benign processes. In contrast, the PROMISE framework offers a 3-tiered assessment, characterizing lesions, describing the metastatic extent, and quantifying tumor volume (PSMA-VOL) within molecular imaging regions, while considering organ-specific biological factors and their differential impact on patient outcomes. Several response assessment systems tailored to PCa and PSMA PET/CT imaging have been developed to evaluate treatment response in mCRPC. The Adapted PET Response Criteria in Solid Tumors (aPERCIST) is a standardized method specifically designed for assessing treatment response in PCa using PET imaging, typically with PSMA PET/CT.

Additionally, response assessment frameworks can be built on the PROMISE report. Two notable examples are the Response Evaluation Criteria in PSMA PET/CT (RECIP) and the PSMA PET Progression (PPP) criteria. RECIP evaluates changes in PSMA volume and the emergence of new lesions, making it particularly suitable for advanced mCRPC, while PPP focuses on individual lesions, making it more applicable to limited disease cases. A retrospective study by Shagera and colleagues specifically examined the potential use of PSMA-PET as an imaging biomarker for assessing and predicting outcomes in mCRPC patients treated with androgen receptor pathway inhibitors. The study compared 2 proposed PSMA response criteria—the European Association of Urology/European Association of Nuclear Medicine (EAU/EANM) criteria and RECIP 1.0. Both criteria demonstrated that PSMA responders had significantly longer median overall survival compared with nonresponders (54 vs 22 months). Although PSMA PET/CT shows promise as a response assessment tool in both clinical trials and routine practice, further prospective studies are necessary for validation.