2.1 Radiation Safety – Drug Handling

PYLARIFY is a radioactive drug. Only authorized persons qualified by training and experience should receive, use, and administer PYLARIFY. Handle PYLARIFY with appropriate safety measures to minimize radiation exposure during administration [see Warnings and Precautions (5.3)]. Use waterproof gloves and effective radiation shielding, including syringe shields, when preparing and handling PYLARIFY.

2.2 Recommended Dosage and Administration Instructions

2.3 Patient Preparation

Instruct patients to drink water to ensure adequate hydration prior to administration of PYLARIFY and to continue drinking and voiding frequently for the first few hours following administration to reduce radiation exposure [see Warnings and Precautions (5.3)].

2.4 Image Acquisition

The recommended start time for image acquisition is 60 minutes after PYLARIFY injection. Starting image acquisition more than 90 minutes after injection may adversely impact imaging performance. Patients should void immediately prior to image acquisition. Position the patient supine with arms above the head. Image acquisition should start from mid-thigh and proceed to the skull vertex. Scan duration is 12 minutes to 40 minutes depending on the number of bed positions (typically 6 to 8) and acquisition time per bed position (typically 2 minutes to 5 minutes).

2.5 Image Display and Interpretation

PYLARIFY binds to prostate-specific membrane antigen (PSMA). Based on the intensity of the signals, PET images obtained using PYLARIFY indicate the presence of PSMA in tissues. Lesions should be considered suspicious if uptake is greater than physiologic uptake in that tissue or greater than adjacent background if no physiologic uptake is expected. Tumors that do not express PSMA will not be visualized. Increased uptake in tumors is not specific for prostate cancer [see Warnings and Precautions (5.1)].

2.6 Radiation Dosimetry

Radiation absorbed dose estimates are shown in Table 1 for organs and tissues of adult male patients from intravenous administration of PYLARIFY. The radiation effective dose resulting from administration of 370 MBq (10 mCi) of PYLARIFY to an adult weighing 70 kg is estimated to be 4.3 mSv. The radiation doses for this administered dose to the critical organs, which are the kidneys, liver, and spleen, are 45.5 mGy, 13.7 mGy, and 10 mGy respectively. When PET/CT is performed, exposure to radiation will increase by an amount dependent on the settings used in the CT acquisition.

5.1 Risk of Image Misinterpretation

Imaging interpretation errors can occur with PYLARIFY imaging. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. The performance of PYLARIFY for imaging of patients with biochemical evidence of recurrence of prostate cancer seems to be affected by serum PSA levels [see Clinical Studies (14)]. The performance of PYLARIFY for imaging of metastatic pelvic lymph nodes prior to initial definitive therapy seems to be affected by risk factors such as Gleason score and tumor stage [see Clinical Studies (14)]. PYLARIFY uptake is not specific for prostate cancer and may occur with other types of cancer as well as non-malignant processes and in normal tissues. Clinical correlation, which may include histopathological evaluation of the suspected prostate cancer site, is recommended.

5.2 Hypersensitivity Reactions

Monitor patients for hypersensitivity reactions, particularly patients with a history of allergy to other drugs and foods. Reactions may not be immediate. Always have trained staff and resuscitation equipment available.

5.3 Radiation Risks

Diagnostic radiopharmaceuticals, including PYLARIFY, expose patients to radiation [see Dosage and Administration (2.6)]. Radiation exposure is associated with a dose-dependent increased risk of cancer. Ensure safe handling and preparation procedures to protect patients and health care workers from unintentional radiation exposure. Advise patients to hydrate before and after administration and to void frequently after administration [see Dosage and Administration (2.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of PYLARIFY was evaluated in 593 patients, each receiving one dose of PYLARIFY. The average injected activity was 340 ± 26 MBq (9.2 ± 0.7 mCi).

The adverse reactions reported in >0.5% of patients within the studies are shown in Table 2. In addition, a hypersensitivity reaction was reported in one patient (0.2%) with a history of allergic reaction.

Androgen deprivation therapy and other therapies targeting the androgen pathway

Androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of PYLARIFY in prostate cancer. The effect of these therapies on performance of PYLARIFY PET has not been established.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of PYLARIFY in pediatric patients have not been established.

8.5 Geriatric Use

Of the 593 patients in completed clinical studies of PYLARIFY, 355 (60%) were ≥65 years old, while 76 (12.8%) were ≥75 years old. The efficacy and safety of PYLARIFY appear similar in adult and geriatric patients with prostate cancer, although the number of patients in the trials was not large enough to allow definitive comparison.

11.1 Chemical Characteristics

PYLARIFY contains fluorine 18 (F 18), radiolabeled prostate-specific membrane antigen inhibitor imaging agent. Chemically piflufolastat F 18 is 2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}ureido)-pentanedioic acid. The molecular weight is 441.4 and the structural formula is:

The chiral purity of the unlabeled piflufolastat F 18 precursor is greater than 99% (S,S).

PYLARIFY is a sterile, non-pyrogenic, clear, colorless solution for intravenous injection. Each milliliter contains 37 to 2,960 MBq (1 to 80 mCi) piflufolastat F 18 with ≤0.01 µg/mCi of piflufolastat at calibration time and date, and ≤ 78.9 mg ethanol in 0.9% sodium chloride injection USP. The pH of the solution is 4.5 to 7.0.

PYLARIFY has a radiochemical purity of at least 95% up to 10 hours following end of synthesis, and specific activity of at least 1000 mCi/µmol at the time of administration.

11.2 Physical Characteristics

PYLARIFY is radiolabeled with fluorine 18 (F 18), a cyclotron produced radionuclide that decays by positron emission to stable oxygen 18 with a half-life of 109.8 minutes. The principal photons useful for diagnostic imaging are the coincident pair of 511 keV gamma photons, resulting from the interaction of the emitted positron with an electron (Table 3).

11.3 External Radiation

The point source air-kerma coefficient for F 18 is 3.75 × 10-17 Gy m2/(Bq s). The first half-value thickness of lead (Pb) for F 18 gamma rays is approximately 6 mm. The relative reduction of radiation emitted by F 18 that results from various thicknesses of lead shielding is shown in Table 4. The use of 8 cm Pb decreases the radiation transmission (i.e. exposure) by a factor of about 10,000.

12.1 Mechanism of Action

Piflufolastat F 18 binds to cells that express PSMA, including malignant prostate cancer cells, which usually overexpress PSMA. Fluorine-18 (F 18) is a β+ emitting radionuclide that enables positron emission tomography.

12.2 Pharmacodynamics

The relationship between piflufolastat F 18 plasma concentrations and image interpretation has not been studied.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

No animal studies with piflufolastat have been performed to evaluate the potential impairment of fertility in males or females.

OSPREY

OSPREY enrolled a cohort of 268 men with biopsy-proven prostate cancer who were considered candidates for radical prostatectomy and pelvic lymph node dissection. These patients were all considered to have high risk disease based on criteria such as Gleason score, PSA level, and tumor stage. Each patient received a single PYLARIFY PET/CT from mid-thigh to skull vertex.

Three central readers independently interpreted each PET scan for the presence of abnormal PYLARIFY uptake in pelvic lymph nodes in multiple subregions, including the common iliac lymph nodes. The readers were blinded to all clinical information. While readers also recorded the presence of PYLARIFY PET-positive lesions in the prostate gland and outside the pelvis, those results were not included in the primary efficacy analysis.

A total of 252 patients (94%) underwent standard-of-care prostatectomy and template pelvic lymph node dissection and had sufficient histopathology data for evaluation of the pelvic lymph nodes. Surgical specimens were separated into three regions: left hemipelvis, right hemipelvis, and other. For each patient, PYLARIFY PET results and histopathology results obtained from dissected pelvic lymph nodes were compared by surgical region. PET results in locations that were not dissected were excluded from analysis.

For the 252 evaluable patients, the mean age was 64 years (range 46 to 84 years), and 87% were white. The median serum PSA was 9.3 ng/mL. The total Gleason score was 7 for 19%, 8 for 46%, and 9 for 34% of the patients, with the remainder of the patients having Gleason scores of 6 or 10.

Table 5 shows PYLARIFY PET performance by reader through comparison to pelvic lymph node histopathology at the patient-level with region matching, such that at least one true positive region defines a true positive patient. Approximately 24% of the evaluable patients had pelvic lymph node metastases based on histopathology (95% confidence interval: 19%, 29%).

In exploratory analyses, there were numerical trends towards more true positive results among patients with total Gleason score of 8 or higher and among patients with tumor stage of T2c or higher relative to those patients with lower Gleason score or tumor stage.

CONDOR

CONDOR enrolled 208 patients with biochemical evidence of recurrent prostate cancer, defined by 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. The mean age was 68 years (range 43 to 91 years), and 90% of patients were white. The median serum PSA was 0.82 ng/mL. Prior treatment included radical prostatectomy in 85% of the patients.

All enrolled patients had conventional imaging evaluation (for most patients, CT or MRI) within 60 days prior to receiving PYLARIFY PET, and this evaluation was negative or equivocal for prostate cancer. All patients received a single PYLARIFY PET/CT from mid-thigh to skull vertex with optional imaging of the lower extremities.

Three central readers independently evaluated each PYLARIFY PET scan for the presence and location of positive lesions. Location of each lesion was categorized in one of 19 subregions that were grouped into 5 regions (prostate/prostate bed, pelvic lymph nodes, other lymph nodes, soft tissue, bone). The readers were blinded to all clinical information.

Depending on the reader, a total of 123 to 137 patients (59% to 66%) had at least one lesion that was identified as PYLARIFY PET-positive (Table 6, TP + FP + PET-Positive Without Reference Standard). The region most commonly observed to have a PYLARIFY PET-positive finding was pelvic lymph nodes (40% to 42% of all PET-positive regions) and the least common region was soft tissue (6% to 7%).

Depending on the reader, 99 to 104 patients with a PYLARIFY PET-positive region had location-matched composite reference standard information available (Evaluable Set, Table 6, TP + FP) that consisted of histopathology, imaging (CT, MRI, ultrasound, fluciclovine PET, choline PET, or bone scan) obtained within 60 days of the PYLARIFY PET scan, or response of serum PSA level to targeted radiotherapy. Reference standard information for PET-negative regions was not systematically collected in this study.

Table 6 shows patient-level performance results of PYLARIFY PET by reader, including location -matched positive predictive value [true positive / (true positive + false positive)], also known as Correct Localization Rate (CLR). For these results, a patient was considered true positive if they had at least one matching location positive on both PYLARIFY PET and the composite reference standard. In addition to calculating location-matched positive predictive value in the Evaluable Set (CLR), an exploratory analysis of positive predictive value in all scanned patients (Imputed CLR) was performed in which PYLARIFY PET-positive patients who lacked reference standard information were imputed using an estimated likelihood that at least one PET-positive lesion was reference standard positive, based on patient-specific factors.

An exploratory analysis of region-level positive predictive value using only PET-positive regions that had sufficient composite reference standard information to determine true positive or false positive status demonstrated results of 67% to 70% with the lower bound of the 95% confidence interval ranging from 59% to 63%.

The percentage of patients categorized as true positive in a location-matched analysis out of all patients scanned with PYLARIFY was an additional exploratory endpoint. Using the same imputation approach for PET-positive patients who lacked reference standard information as in Table 6 above, this value was 47% to 51%, with the lower bound of the 95% confidence interval ranging from 40% to 45%.

Table 7 shows patient-level PYLARIFY PET results from the majority read stratified by serum PSA level. Percent PET positivity was calculated as the proportion of patients with a positive PYLARIFY PET out of all patients scanned. Percent PET positivity includes patients determined to be either true positive or false positive as well as those in whom such determination was not made due to lack of composite reference standard information. The likelihood of a patient having at least one PYLARIFY PET-positive lesion generally increased with higher serum PSA level.

16.1 How Supplied

PYLARIFY injection is supplied in a 50 mL multiple-dose glass vial (NDC# 71258-022-01) containing a clear, colorless solution at a strength of 37 MBq/mL to 2,960 MBq/mL (1 mCi/mL to 80 mCi/mL) piflufolastat F 18 at calibration time and date.

16.2 Storage and Handling

Adequate Hydration

Instruct patients to drink a sufficient amount of water to ensure adequate hydration before their PET study and urge them to drink and urinate as often as possible during the first hours following the administration of PYLARIFY, in order to reduce radiation exposure [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)].