POSLUMA Solution for injection Ref.[109999] Active ingredients: Flotufolastat ¹⁸F

The relationship between flotufolastat F 18 plasma concentrations and image interpretation has not been fully characterized.

Distribution

Following intravenous administration, flotufolastat F 18 distributes to liver (15.8% of administered activity), heart blood pool (7.4%), and kidneys (3.2%) and is cleared from the blood.

Elimination

Metabolism

Flotufolastat F 18 does not undergo metabolism up to 50 minutes post injection.

Excretion

Elimination is by urinary excretion. Approximately 7% of the administered activity was excreted in the urine in the first 2 hours post-injection with approximately 15% excreted by 4.5 hours post-injection.

Animal studies to assess the carcinogenicity or mutagenic potential of flotufolastat have not been conducted. However, flotufolastat F 18 has the potential to be mutagenic because of the F 18 radionuclide.

No studies in animals have been performed to evaluate potential impairment of fertility in males or females.

14.1 Imaging Prior to Initial Definitive Therapy of Prostate Cancer

The safety and efficacy of POSLUMA were evaluated in LIGHTHOUSE (NCT04186819), a prospective, multicenter, open-label, single-arm study in patients with prostate cancer who were candidates for initial definitive therapy.

The study enrolled 356 patients diagnosed with unfavorable intermediate-risk (32%) or high-/very high-risk prostate cancer (68%) who were candidates for radical prostatectomy and pelvic lymph node dissection (PLND). Unfavorable intermediate-risk was defined as having any ≥2 intermediate risk factors [T2b-T2c, Gleason score 7, PSA 10-20], Gleason pattern 4+3=7, or ≥50% of biopsy cores positive for prostate cancer. High or very high-risk was defined as having T3 or T4 disease, Gleason score ≥8, primary Gleason pattern 5, and/or PSA >20.

All patients received a single dose of POSLUMA with an administered radioactivity (mean ± SD) of 307 ± 23 MBq (8.3 ± 0.62 mCi), followed by PET/CT scan from mid-thigh to base of the skull. Three central readers blinded to clinical information independently interpreted each scan for lesions considered positive for prostate cancer in pelvic lymph nodes, categorized by subregion and left and right laterality [see Dosage and Administration (2.5)]. Positive lesions in the prostate gland, lymph nodes outside the pelvis, soft tissue/parenchyma, and bones were also recorded.

A total of 296 patients (83%) underwent standard-of-care prostatectomy and template PLND and had sufficient histopathology data for evaluation of the pelvic lymph nodes. The mean age was 65 years (range 46 to 82 years); distribution by race was 82% White, 8% Black or African American, 0.3% other, and 10% unreported; and distribution by ethnicity was 5% Hispanic/Latino, 86% non-Hispanic/Latino, and 9% unreported. The median serum PSA was 8.4 ng/mL. The total Gleason score was 7 for 45%, 8 for 26%, and 9 for 25% of the patients, with the remainder of the patients having Gleason scores of 6 or 10. Approximately 24% of patients had pelvic lymph node metastases based on histopathology.

POSLUMA performance was evaluated against histopathology after matching by hemipelvis. Table 6 shows the results, such that at least one true positive hemipelvis region defined a true positive patient.

Table 6. Patient-Level, Hemipelvis Region-Matched Performance of POSLUMA PET for Detection of Pelvic Lymph Node Metastasis (N1) in LIGHTHOUSE:

CI= confidence interval

In exploratory analyses, there were numerical trends towards higher sensitivity among patients with PSA greater than or equal to the median value (8.4 ng/mL) and among patients with high-risk or very high-risk categorization.

POSLUMA-positive lesions outside of the prostate gland and pelvic lymph nodes (M1) were also evaluated. As a percentage of the 352 patients with an evaluable POSLUMA scan and of the 61 patients with at least one POSLUMA positive M1 lesion, 10% (95% CI: 7% to 13%) and 56% (95% CI: 42% to 68%), respectively, had at least one matching positive M1 lesion between the POSLUMA majority read and a reference standard consisting of other imaging evaluated by a separate consensus panel or histopathology.

14.2 Imaging for Suspected Recurrence of Prostate Cancer

The safety and efficacy of POSLUMA were evaluated in SPOTLIGHT (NCT04186845), a prospective, multicenter, open-label, single-arm study in patients with biochemical evidence of recurrent prostate cancer.

The study enrolled 391 patients with suspected recurrence defined by either serum PSA of at least 0.2 ng/mL after radical prostatectomy (with confirmatory PSA level also at least 0.2 ng/mL) or by an increase in serum PSA of at least 2 ng/mL above the nadir after other therapies.

All patients received a single dose of POSLUMA with an administered radioactivity (mean ± SD) of 306 ± 22 MBq (8.27 ±0.61 mCi), followed by PET/CT scan from mid-thigh to base of the skull. Three central readers blinded to clinical information independently interpreted each scan by region for the presence and location of lesions considered positive for prostate cancer [see Dosage and Administration (2.5)]. The regions interpreted were grouped into three for primary analysis: prostate/prostate bed; pelvic lymph nodes; and other (including extra-pelvic lymph nodes, bone, and soft tissue/parenchyma).

A total of 389 patients had an evaluable POSLUMA PET scan. The mean age was 68 years (range: 43 to 86 years); distribution by race was 75% White, 16% Black or African American, 4% other, and 5% unreported; and distribution by ethnicity 5% was Hispanic/Latino, 87% non-Hispanic/Latino, and 8% unreported. The median baseline serum PSA level was 1.1 ng/mL with 60% of patients having a baseline PSA <2.0 ng/mL. Prior treatment included radical prostatectomy in 79% of the patients.

POSLUMA-positive interpretations were compared to a reference standard of either histopathology or other imaging (CT, MRI, Technetium 99m bone scan, or fluciclovine F 18 PET) obtained within 90 days of the POSLUMA scan using a lesion-to-lesion co-localization method and separate consensus panel. Reference standard information for negative interpretations was not collected.

At least one POSLUMA-positive lesion was detected by at least one reader in 366 patients (94%). Reference standard information consisted of imaging only (n=297) or histopathology (n=69). As a percentage of patients with an evaluable scan, 51% (95% CI: 46% to 56%) for reader 1, 48% (95% CI: 43% to 53%) for reader 2, and 49% (95% CI: 44% to 54%) for reader 3 had at least one matching positive region between the POSLUMA scan and the reference standard. Of all POSLUMA-positive regions, 46% (95% CI: 42% to 50%) for reader 1, 60% (95% CI: 55% to 66%) for reader 2, and 53% (95% CI: 48% to 58%) for reader 3 were categorized as positive by the reference standard.

Table 7 shows patient-level results from the majority read stratified by serum PSA level. Percent PET positivity was calculated as the percentage of patients with POSLUMA-positive lesions out of all patients with an evaluable PET scan. Percent PET positivity includes true and false positives and is not a measure of diagnostic performance.

Table 7. Patient-Level POSLUMA PET Results and Percent PET Positivity Stratified by Serum PSA Level in SPOTLIGHT by Majority Read (N=389):

PSA = prostate-specific antigen, PA = positive agreement, NPA = no positive agreement, CI = confidence interval
^a Imaging comprised of one or more of the following: CT, MRI, ^99mTc Bone Scan, fluciclovine F 18 PET

Variable Interpretation in Patients with Suspected Prostate Cancer Recurrence

POSLUMA reader agreement was evaluated for the three central readers and 389 patients. Inter-reader Fleiss ϰ was 0.41 (95% CI: 0.39-0.43). The three readers agreed on the presence or absence of positive lesions across all five evaluated regions in 118 patients (30% unanimity) [see Warning and Precautions (5.1)].

Given the level of inter-reader agreement observed overall, POSLUMA reader agreement was further evaluated by regional subgroup. The Fleiss ϰ for was 0.40 (95% CI: 0.33-0.46) in the prostate/prostate bed, 0.73 (95% CI: 0.67-0.78) in the pelvic lymph nodes, and 0.62 (95% CI: 0.58-0.65) across the other regions.