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An Update on Radiographic Imaging for Detecting and Staging Prostate Cancer, Evaluating Treatment Response, and as a Prognostic and Predictive Biomarker

Effective prostate cancer treatment relies on accurate disease detection and staging. For this reason, recent improvements in localized and whole-body imaging will transform management. The discussion regarding localized disease continues to focus on prostate MRI. For metastatic disease, there is a palpable excitement following the U.S. Food and Drug Administration (FDA) approval of PSMA PET diagnostic agents. These technologies are clearly disruptive. However, this disruption will lead to better informed treatment decisions and ultimately, better outcomes. This article provides an update on radiographic imaging for detecting and staging prostate cancer, evaluating treatment response, and as a prognostic and predictive biomarker.

Localized tumor detection

For patients with suspected or confirmed localized prostate cancer, multiparametric magnetic resonance imaging (mpMRI) plays a key role in risk stratification, diagnosis, and treatment planning, as is underscored by the recently updated American Urological Association (AUA) guidelines.1 mpMRI can detect localized prostate cancer in patients with negative systematic biopsies, whose tumors would otherwise be missed, and furthermore, we now have high-quality data supporting the use of mpMRI in biopsy-naïve patients, particularly those at risk of having more extensive or aggressive disease. In a recent prospective study of more than 2,000 patients with elevated prostate specific antigen (PSA) levels and MRI-visible prostate lesions, mpMRI-targeted prostate biopsy detected more tumors than systematic biopsy alone.2 However, mpMRI-targeted biopsy also can underestimate the clinical significance of some prostate tumors and thus is best used as an adjunctive rather than a stand-alone diagnostic tool.

The findings of some studies suggest that biparametric MRI detects prostate tumors as effectively as mpMRI,3,4 but there is not (yet) enough evidence to draw firm conclusions. It also is important to note that even a decade after the initial publication and subsequent updates of the Prostate Imaging Reporting and Data System (PI-RADS), the quality, accuracy, and standardization of MRI continue to vary substantially among practitioners and practice settings.5,6 There is optimism that with improved training, subspecialization, continuing education, standardized reporting, and artificial intelligence, quality will continue to improve.

In the future, prostate-specific membrane antigen (PSMA) PET/CT also may be used for the detection and evaluation of primary lesions of the prostate. In a recent retrospective study of 53 patients who were classified as intermediate or high risk, F-18-PSMA-1007-PET/CT was more accurate than mpMRI for staging seminal vesicle invasion, but mpMRI was more accurate for detecting extracapsular extension.7 Most recently, radiologists have begun developing and studying scoring systems such as PRIMARY, which incorporates both intra-prostatic PSMA PET/CT patterns and the intensity of tracer uptake to improve diagnostic accuracy.8 Early results are promising, although additional validation is needed.

Initial staging

We now have results from clinical trials of PSMA PET/CT with various tracers used for the initial staging of intermediate to high-risk patients. In the phase III proPSMA study, 302 patients with untreated biopsy-confirmed prostate cancer were randomly assigned to undergo either 68Ga-PSMA-11 PET/CT or conventional imaging with CT and bone scans. PSMA PET/CT was more sensitive and specific, showing 27% greater accuracy for detecting local and distant metastases.9 In the prospective OSPREY study, 18F-DCFPyL PET/CT showed a high positive predictive value (PPV) compared with gold-standard histopathology for the identification of pelvic nodal disease and distant metastases.10 Another large phase III study of 68Ga-PSMA-11 PET/CT showed a somewhat lower but clinically relevant PPV of 75.11 Both tracers are now approved by the FDA for the initial staging of suspected metastatic disease. The FDA also has recently approved two kits designed to help with the preparation of gallium Ga 68 gozetotide injection.

Such findings support the National Comprehensive Cancer Center (NCCN)’s current prostate cancer guidelines, which cite the greater sensitivity of PSMA PET/CT compared with conventional imaging and conclude that the latter is therefore not a “necessary prerequisite” for PSMA PET/CT.12 Nonetheless, it is important to keep in mind that PSMA PET/CT has been consistently less sensitive than histopathology in studies—there is still a gap between what can be seen under a microscope and what PET/CT can detect, even when targeted tracers are used. Consequently, while PSMA PET/CT is useful for the initial staging of prostate cancer, it is not a substitute for pelvic nodal dissection.

Restaging

For patients with biochemically recurrent prostate cancer (i.e., rising PSA after treatment of the primary tumor), PSMA PET/CT is more sensitive for detecting extraprostatic disease and for identifying sites of recurrence when compared with conventional imaging with CT, bone scan, and mpMRI.13-15 Furthermore, using PSMA PET/CT to restage patients alters treatment plans for many (64% in one study, including 80% with positive findings).16 Unsurprisingly, PSMA PET/CT is more likely to be positive in patients have shorter PSA doubling times, who comprise a subgroup of patients at higher risk for more extensive metastases.

Both F-18 piflufolastat and Ga-68 PMSA -11 PSMA PET/CT are approved by the U.S. Food and Drug Administration (FDA) for the staging of suspected metastatic prostate cancer, as are the non-PSMA tracers C-11 choline, F-18 fluciclovine, and F-18 sodium fluoride. The PSMA-directed tracers appear to have the best performance, especially if PSA levels are low. At this point, the clinical value of the other non-PSMA diagnostic agents is questionable.

Finally, there is considerable interest in using PSMA PET/CT to guide metastases-directed therapy (MDT) for patients with oligometastatic or oligoprogressive disease. In a recent retrospective study of patients with castration-resistant oligoprogressive prostate cancer (up to 5 lesions on 68Ga-PSMA-PET/CT), stereotactic ablative body radiotherapy (SABR) appeared to prolong the efficacy of androgen deprivation therapy (ADT) and delay the need to start a next-generation systemic androgen receptor inhibitor.17 Findings were similar in a small phase 2 randomized study of patients with recurrent oligometastatic disease (up to three lesions on conventional imaging)—compared with observation only, SABR improved progression-free survival, while total consolidation of PSMA-avid disease was associated with about a four-fold decrease in risk of new lesions at 6 months.18 Hopefully, future studies will identify and validate useful biomarkers to guide the selection of patients for SABR.

Evaluation of treatment response

Clinicians evaluate treatment response in prostate cancer by periodically measuring PSA, performing radiographic imaging, and ascertaining patient-reported outcomes such as symptoms and quality of life. In clinical practice and most clinical trials, patient monitoring and evaluation for treatment response have mostly focused on the use of CT and bone scans.

Because PSMA PET/CT is considerably more sensitive than conventional imaging for detecting nodal and distant metastases, it is an intriguing modality for evaluating treatment response. A noteworthy recent step has been the development of the RECIP (Response Evaluation Criteria In PSMA-imaging) framework, which distinguish four response categories—complete response, partial response, progressive disease, and stable disease—based on the extent of PSMA ligand uptake and the presence or absence of new lesions compared with baseline PSMA PET/CT. In a retrospective study of patients who received 177Lu-PSMA therapy for mCRPC, interim staging with PSMA PET/CT and response classification by RECIP was prognostic for overall survival, and considering both RECIP and PSA measurements somewhat improved the identification of responders and progressors compared with considering PSA alone.19

Such approaches are intriguing, but it is important to emphasize that the use of PSMA PET/CT for response evaluation remains investigational and is not yet ready for prime time. For example, recent evidence suggests that ADT upregulates PSMA expression, which would likely increase the probability of false-positive PSMA PET/CT findings after antiandrogen treatment.20 We need to learn more about how various treatments affect PSMA receptor expression, and how this relationship might change over time before PSMA PET/CT can be used to evaluate treatment response in real-world settings.

PSMA PET/CT as a prognostic and predictive biomarker

Researchers also are studying questions such as the prognosis of patients with metastatic disease that is only detected on PSMA PET/CT, and how PSMA PET/CT results correlate with responses to various treatments or sequencing strategies. Recent findings suggest that baseline PSMA expression is associated with overall prognosis. In a large retrospective study of patients who underwent radical prostatectomy, increased PSMA intensity was prognostic for less favorable biochemical recurrence-free survival, while in an analysis of data from the phase 2 LuPSMA trial of patients with mCRPC, the intensity of PSMA radioligand uptake was a biomarker for overall survival, and in a composite study of patients enrolled in mCRPC PSMA imaging studies, high PSMA radioligand expression on SPECT or PET/CT was an independent prognostic factor for poor overall survival.21-23 However, more research is needed to clarify whether PSMA truly is associated with a more aggressive disease biology or whether correlative factors are at play.

Early data also indicate that PSMA PET/CT findings can help predict response to treatments such as salvage radiation therapy, 177LuPSMA, taxane-based chemotherapy, and radium-223.24-26 For example, in the TheraP ANZUP 1603 trial, higher PSMA uptake was predictive of a greater probability of favorable response to LuPSMA versus cabazitaxel, while high volume of disease on FDG PET was associated with a worse prognosis regardless of which of the two treatments patients received. This is another area that is not ready for prime time but findings like these do highlight the broad range of potential applications of PSMA PET/CT, not only for diagnosis and staging, but also for evaluating and predicting treatment response and refining overall prognosis. In the future, we can expect to see larger and more multi-institutional studies of these applications and, hopefully, clearer data on which PSMA-targeted radioligands are most useful, and in which settings. Note that the current FDA label for 177Lu-PSMA-617 specifies that an approved PSMA-11 imaging agent be used for lesion detection prior to therapy.

Finally, a crucial question will be how to assess and balance the various uses of PSMA PET/CT and other modalities of next-generation imaging against their financial costs to patients and healthcare systems, and how to make these imaging modalities available to as many patients as possible. Answering these questions will require more robust clinical data as well as research on optimizing healthcare resource utilization, ideally using large, nationally representative patient databases.

Written by: Phillip J. Koo, MD, Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center, Arizona

References:

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