Impact of ⁶⁸Ga-PSMA-11 PET on the Management of Recurrent Prostate Cancer in a Prospective Single-Arm Clinical Trial

DISCUSSION

For clinical impact, diagnostic tests need to translate into relevant changes in management. Analyses of the National Oncologic PET Registry (NOPR) demonstrated a change in management in 37% of cancer patients after ¹⁸F-FDG PET and resulted in ¹⁸F-FDG PET reimbursement for a wide range of indications in the United States (15). However, a subanalysis of the NOPR study revealed a somewhat lower rate of change in management for prostate cancer than for other entities, possibly because of low ¹⁸F-FDG uptake and limited lesion detection (16). Since NOPR completion, several novel radiotracers have been introduced for prostate cancer imaging. Of these, radiolabeled PSMA ligands have been studied extensively since their introduction. Recently, a high positive predictive value, detection rate, and interreader agreement were reported for ⁶⁸Ga-PSMA PET in a prospective multicenter trial (10). Here, we present a NOPR-like survey-based impact on management data, a secondary endpoint of this prospective study.

⁶⁸Ga-PSMA PET resulted in a change in management in more than half of patients undergoing ⁶⁸Ga-PSMA PET for localization of biochemically recurrent prostate cancer. Referring physicians frequently accepted the reported site of disease according to Q2 surveys. Subsequent management pathways were consistent with ⁶⁸Ga-PSMA PET disease locations; that is, local treatment was considered more often for local disease (54/126 patients, 44%), whereas systemic disease was associated more often with an intended change toward systemic or combination approaches (106/153 patients, 69%). Our findings demonstrate that the accuracy of ⁶⁸Ga-PSMA PET translates into a change in disease stage and management consistent with PET-positive sites of recurrent prostate cancer.

After ⁶⁸Ga-PSMA PET, the proportion of patients with unknown sites of disease declined from about two thirds to one third according to the referring clinicians. The ⁶⁸Ga-PSMA PET disease location was frequently accepted by referring physicians. Individual management pathways are diverse (Supplemental Fig. 5). However, changes demonstrate detectable patterns: patients without detectable disease by ⁶⁸Ga-PSMA PET more often experienced intended major deescalation toward active surveillance (47%), whereas patients with locoregional disease had an intended major transition toward focal therapy (56%). In cases of extrapelvic nodal disease (M1a), clinicians tended toward a major change to systemic therapy (65%). In patients with bone metastasis (M1b) or visceral metastasis (M1c), major systemic or local treatment changes were most common (43% and 33%, respectively).

Accurate localization of disease is a critical early step in the management of patients with biochemical recurrence of prostate cancer. Focal and salvage therapies need accurate target delineation. On the other hand, the presence of distant metastases may trigger additional or alternative systemic therapy (3). Therefore, the updated European Association of Urology guidelines recommend ⁶⁸Ga-PSMA PET in biochemical recurrence after radical prostatectomy if the results will influence subsequent treatment decisions (3). In this study, major changes occurred most often in patients with a PSA of 0.5 to less than 2.0 ng/mL. However, an impact on subsequent treatment decisions occurred also in patients with undetectable or extensive disease. We further demonstrate that detectable management pathways follow guideline recommendations: focal or salvage therapy is offered for local disease, and systemic treatment is recommended in cases of metastatic spread (3). Whether ⁶⁸Ga-PSMA PET–induced management changes translate into survival benefits remains unknown. Prospective studies with long-term follow-up are required to answer this question. With this intent, trials investigating ⁶⁸Ga-PSMA PET–guided therapy are currently under way (17,18).

A previous study reported management changes based on surveys and chart review in an initial UCLA cohort (n = 101) of the presented study (5). Systematic chart review confirms that intended management changes frequently differ from implemented changes based on subsequent diagnostic tests, tumor board decisions, or patient preference (5). However, even when considering subsequent modification, the overall proportion of patients experiencing a major implemented management change remains high (5). In our expanded cohort (n = 382), survey-based implemented management differed from intended management in 22% of patients overall; discrepancy was somewhat higher in patients with an intended management change (38%). The proportion of management change was similar in the biochemical failure cohort of a recent Australian multicenter study finding altered management in 62% of patients (6). Similarly, Müller et al. found a 60% management change in a retrospective cohort of recurrent prostate cancer and, of note, a high response rate to subsequent focal therapy (19). Overall, the impact on management was higher than reported in a recent metaanalysis of 1,163 patients at primary diagnosis and biochemical recurrence, with a change in management occurring in 54% of patients (95%CI, 47%–60%) (9). In this study, we report in more detail how management pathways are associated with PET stage, indicating that referring physicians have high confidence in ⁶⁸Ga-PSMA PET findings.

One hundred fifty diagnostic tests were prevented by ⁶⁸Ga-PSMA PET, according to the survey response. Most of these were CT scans (43 cases) or bone scans or ¹⁸F-NaF PET/CT (52 cases). The decision to omit these diagnostic tests is in line with several studies that demonstrated superior accuracy for ⁶⁸Ga-PSMA PET when compared with one or a combination of the prevented diagnostic instruments for prostate cancer localization (8,12,20,21). Specifically, ⁶⁸Ga-PSMA PET demonstrated superior detection sensitivity when compared head-to-head with bone scanning or the recently approved ¹⁸F-fluciclovine, especially at a PSA of 2 ng/mL or less (20,21). Although more diagnostic tests were prevented than triggered, the addition of ⁶⁸Ga-PSMA PET increases the total diagnostic work-up. On the other hand, at the time of enrollment, referring physicians had little experience with ⁶⁸Ga-PSMA PET, and some of the diagnostic tests, including biopsies (44/382, 12%), were encouraged by the study protocol for lesion validation. Histopathologic validation resulted in a positive predictive value of 84% for ⁶⁸Ga-PSMA PET both on a per-patient basis and on a per-region basis (10). As availability improves, by an increasing number of clinical trials or an anticipated approval of PSMA ligand PET, additional tests, especially potentially burdensome biopsies, may be ordered less frequently in the future clinical setting.

Although this study benefits from a large cohort, missing questionnaires are a limitation to our study. More specifically, Q1 and Q2 were completed for 60% of patients, and all 3 questionnaires were available for only 32% of patients. A greater likelihood that proponents of new imaging technologies would reply may have introduced a responder bias. Furthermore, information on implemented management was not confirmed by file review, and a potential discrepancy between intended and finally implemented management, reported previously (5), was not resolved. The low Q3 rate may be due to the late request to respond, that is, 3–6 mo after ⁶⁸Ga-PSMA PET—disconnected from the PET report and outside typical clinical timelines. Also, a more frequent Q3 response for closely monitored or high-risk patients might have led to an overestimation of the management implementation rate. On the other hand, similar patient characteristics between the intended and implemented management cohorts (Table 1) indicate no relevant selection bias. Only a small proportion of patients were African-American. This underrepresentation may have led to a selection bias, and findings might not be entirely applicable to this ethnic group.