Pienta KJ, Gorin MA, Rowe SP et al: A phase 2/3 prospective multicenter study of the diagnostic accuracy of prostate specific membrane antigen PET/CT with 18F-DCFPyL in prostate cancer patients (OSPREY). J Urol 2021; 206: 52.

Conventional imaging modalities such as ^99mTc-methylene diphosphonate bone scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) are suboptimal for detecting metastatic prostate cancer (PCa).^1–3 While ¹¹C-choline and ¹⁸F-fluciclovine are U.S. Food and Drug Administration-approved for positron emission tomography (PET) in men with suspected recurrent disease, neither imaging agent is approved for initial staging of PCa. Prostate-specific membrane antigen (PSMA)-PET/CT has the potential to improve the initial staging of PCa. ¹⁸F-DCFPyL is a PET ligand that targets PSMA with high affinity, enabling its use in diagnostic and therapeutic applications.^4–6 The OSPREY study evaluated the diagnostic performance of ¹⁸F-DCFPyL-PET/CT using a histopathology truth standard in men with either newly diagnosed PCa or known metastatic disease.⁷

Two distinct patient populations underwent ¹⁸F-DCFPyL-PET/CT: Cohort A, men with newly diagnosed high-risk PCa (clinical stage ≥T3a, or prostate specific antigen [PSA] >20 ng/mL, or Gleason score ≥8) planned for radical prostatectomy with pelvic lymph node dissection; and Cohort B, men with presumptive radiologic evidence of local recurrence or metastatic disease on whole-body bone scintigraphy or anatomical imaging (CT, MRI) and in whom lesion(s) were amenable to biopsy.

Baseline conventional images were obtained 4 to 6 weeks prior to ¹⁸F-DCFPyL-PET/CT and submitted to a central imaging laboratory for assessment. Both cohorts received 1 dose of 9 mCi (333 MBq) of ¹⁸F-DCFPyL intravenous injection, followed by PET/CT 1–2 hours thereafter; scans were submitted to the central imaging laboratory. Three independent board-certified nuclear medicine physicians blinded to clinical information and prior radiographic assessments evaluated the ¹⁸F-DCFPyL-PET/CT scans and biopsy images (for Cohort B patients). A separate blinded board-certified radiologist evaluated all baseline conventional images. Pathology specimens were evaluated locally by pathologists blinded to the imaging results. Cohort A nodal packets were analyzed. The number of positive pelvic lymph nodes (LNs) and size(s) of the largest metastatic foci were recorded. For Cohort B, biopsied tissue of at least 1 lesion identified on conventional imaging before ¹⁸F-DCFPyL-PET/CT was obtained and evaluated for the presence of PCa.

Diagnostic performance of ¹⁸F-DCFPyL-PET/CT was based on imaging results compared to histopathology. For Cohort A, determination of pelvic LN metastases with specificity and sensitivity at the patient level served as co-primary endpoints. Positive predictive value (PPV) and negative predictive value (NPV), detection of extra-pelvic (M1) disease, and detection of primary tumor within the prostate were secondary endpoints. No minimum size or standard uptake value criterion was used as a threshold for considering node positivity by PET/CT, while any confirmed microscopic disease was considered positive histopathology.

For Cohort B, the sensitivity and PPV of ¹⁸F-DCFPyL-PET/CT for extra-prostatic lesions were calculated, including analyses by region and PSA level. Since only presumptive PCa lesions were targeted for biopsy, specificity and NPV were not evaluated because of high prevalence of disease in this cohort.

Safety assessments included monitoring of adverse events (AEs) and serious adverse events (SAEs) occurring after ¹⁸F-DCFPyL administration through the date of surgery or biopsy, within 21±7 days post-biopsy.

Cohort A provided 80% power to test the null hypotheses for specificity at 80% and for sensitivity at 40% (co-primary endpoints). Formal hypothesis testing was not employed for Cohort B endpoints. Point estimates and 2-sided 95% confidence intervals were provided for all diagnostic performance parameters.

Patients were enrolled across 10 sites (United States: 8; Canada: 2). Of the patients 462 were screened; 77 were screen failures and 385 men were enrolled (Cohort A: 268; Cohort B: 117). Key baseline demographic and clinical characteristics for each cohort prior to PET imaging, and PET imaging details are described in the table.

In Cohort A (252 evaluable), ¹⁸F-DCFPyL-PET/CT had median specificity of 97.9% (95% CI: 94.5–99.4) and median sensitivity of 40.3% (28.1–52.5) among 3 readers for pelvic nodal involvement. The sensitivity endpoint was not met, as the lower bounds of the 95% CI (19.2–29.7%) did not reach the success threshold of 40%. Median PPV and NPV were 86.7% (69.7–95.3) and 83.2% (78.2–88.1), respectively. In a post hoc sensitivity analysis, ¹⁸F-DCFPyL-PET/CT was evaluated for detection of nodal metastases >5 mm in diameter based on the assumption that smaller tumor deposits are below PET detection limits.⁸ In this analysis, sensitivity and specificity both met the success criteria, and high PPV and NPV results were preserved (fig. 1).

Figure 1. 18F-DCFPyL-PET/CT diagnostic performance (median of 3 independent readers, relative to histopathology truth standard) in high-risk prostate cancer (Cohort A).

The median results of the 3 ¹⁸F-DCFPyL-PET/CT readers for detecting pelvic LN metastases were compared with CT or MRI; ¹⁸F-DCFPyL-PET/CT demonstrated 3-fold higher PPV (86.7% vs 28.3%), higher specificity (97.9% vs 65.1%) and slightly higher NPV (83.2% vs 77.8%), and similar sensitivity (40.3% vs 42.6%). At least 1 reader detected extra-pelvic lesions by ¹⁸F-DCFPyL-PET/CT in 12.3% (33/268) of high-risk patients, potentially upstaging them from M0 to M1 disease. Figure 2 exemplified this upstaging, with complete reader agreement.

Figure 2. ¹⁸F-DCFPyL-PET/CT upstaged patient with high-risk prostate cancer. This Cohort A patient was staged at baseline as T1cN0M0; his PSA was 13.68 ng/ml and his biopsy Gleason score was 4+5. CT (not shown) demonstrated no evidence of metastatic disease. Anterior and posterior bone scintigraphy showed changes of left hip arthroplasty and increased tracer uptake in anterior superior iliac spine (arrow) of uncertain significance, but was otherwise normal. ¹⁸F-DCFPyL-PET/CT showed multifocal osseous lesions involving spine, ribs, pelvis and right clavicle. On subsequent biopsy of transverse process of L3, osseous metastatic (M1b) disease was confirmed.

In Cohort B (93 evaluable), median sensitivity and PPV for extra-prostatic lesions were 95.8% (87.8–99.0) and 81.9% (73.7–90.2), respectively. Sensitivity and PPV across different baseline PSA levels were also evaluated. In men with low PSA (<2 ng/mL), sensitivity ranged from 88.9–100% and PPV ranged from 61.5–88.9% (fig. 3). An exploratory analysis showed that among 33 patients without distant metastasis on baseline conventional imaging, occult disease was detected in 57.6% (19/33) of patients on ¹⁸F-DCFPyL imaging.

Figure 3. Sensitivity and PPV (median of 3 independent readers, relative to histopathology truth standard) of ¹⁸F-DCFPyL-PET/CT in metastatic disease sites (A), by anatomical region (B), and across all PSA ranges (C) in men with recurrent or metastatic prostate cancer (Cohort B).

¹⁸F-DCFPyL was safe and well-tolerated. Of the 385 patients 51 (13.2%) experienced at least 1 AE; most frequent were dysgeusia (2.6%), headache (2.3%), and fatigue (1.3%). Seven patients (1.8%) experienced a SAE, none considered treatment-related.

While the co-primary endpoint for specificity was met, sensitivity of ¹⁸F-DCFPyL-PET/CT was not met in Cohort A. One explanation is that tumor foci <5 mm are below the PET/CT limit of resolution. Nonetheless, based on the high PPV of ¹⁸F-DCFPyL, clinicians can be confident that a ¹⁸F-DCFPyL-avid node, even if non-enlarged on conventional imaging, provides clinically meaningful information compared to currently available imaging modalities.

In men progressing post-therapy with suspected recurrent or metastatic disease, ¹⁸F-DCFPyL-PET/CT demonstrated high sensitivity and PPV in all sites of disease and across all PSA ranges.

The high PPV observed in both cohorts indicates that ¹⁸F-DCFPyL-positive lesions likely represent disease, supporting the potential utility of ¹⁸F-DCFPyL-PET/CT to stage men with high-risk PCa, and reliably detect disease in men with recurrent or metastatic PCa.