A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Dosimetry of [177Lu]Lu-PSMA-617 in Chinese Adult Male Patients With Progressive PSMA-Positive mCRPC

This was a 2-part study:

• Main part: Thirty participants with at least 1 measurable lesion by PCWG3-modified RECIST v1.1 criteria were enrolled in the main part. The primary endpoint of confirmed overall response rate (ORR) was analyzed with participants in this part and was assessed via independent centralized review of radiographic images provided by the Investigator and as outlined in PCWG3-modified RECIST v1.1 criteria.
• Extension part: The extension part enrolled additional 30 participants with or without measurable lesions following the main part. The secondary endpoints were analyzed with all participants in both main part and extension part.

Screening and enrollment period:

Written informed consent form (ICF) was obtained prior to any screening procedures. All screening procedures described in the Assessment Schedule were completed within 28 days prior to enrollment, except for radiographic imaging assessment, which was done within 21 days prior to enrollment.

The participants were assessed for eligibility and underwent a mandatory [68Ga]Ga-PSMA-11 Positron Emission Tomography (PET)/Computed Tomography (CT) scan to evaluate Prostate-specific Membrane Antigen (PSMA) positivity for eligibility as assessed by central readers. Only participants with PSMA positive cancer and confirmed eligibility criteria were enrolled.

Following completion of all required screening procedures and verifying participant eligibility, the participant was enrolled. [177Lu]Lu-PSMA-617 was ordered in parallel with interactive response technology (IRT) enrollment registration to allow at least 2 weeks to order and deliver [177Lu]Lu-PSMA-617.

Treatment period:

In principle, all participants should begin [177Lu]Lu-PSMA-617 dosing within 14 days after enrollment registration. However, Cycle 1 Day 1 (C1D1) could be delayed by up to an additional 3 days only for unexpected scheduling delays. Participants received 7.4 Gigabecquerel (GBq) (200 Millicuries (mCi)) +/- 10% [177Lu]Lu-PSMA-617 once every 6 weeks for a planned 6 cycles. BSC/BSoC coud be used, including available care for the eligible participants according to best institutional practice. ARPIs (e.,g., abiraterone, etc.) were allowed. BSC/BSoC for each participant was selected at the discretion of the Investigator prior to [177Lu]Lu-PSMA-617 administration, and could be modified over time as needed. BSC/BSoC was administered per the physician's orders according to clinical best practice.

Radiographic imaging (CT with contrast/Magnetic Resonance Imaging (MRI) and bone scan) was done at every 8 weeks (± 4 days) after first dose of [177Lu]Lu-PSMA-617 for the first 24 weeks (independent of dose delays), then every 12 weeks (± 4 days) thereafter and at End of Treatment (EOT) Visit (if not done within 28 days of EOT) until radiographic disease progression confirmed by central reader, death, withdrawal of consent, loss to follow-up, or subject/guardian's decision.

After the last day of study treatment period of [177Lu]Lu-PSMA-617 (i.e. after completion of 6 cycles of treatment OR treatment discontinuation for any reason) [e.g. upon radiographic progression as confirmed by blinded independent centralized review]), the participants have to have an EOT visit performed ≤ 7 days and enter into the Post-treatment Follow-up period.

If a participant withdrew consent for the treatment period of the study, an EOT is supposed to be done and the participant would enter into the Post-treatment Follow-up unless he specifically withdrew consent for post-treatment follow-up.

Post-treatment Follow-up period:

• 30-day Safety Follow-up. All treated participants are to have a safety follow-up conducted approximately 30 days after EOT visit.
• Long term Follow-up. The long-term follow-up would start after the 30-day Safety follow-up and would last until study completion. If a participant in the long-term follow-up period discontinued treatment for reasons other than BICR-determined radiographic progression, his tumor assessments were required to be performed every 8 weeks after first dose of study treatment for the first 24 weeks (week 9, 17, 25) and then every 12 weeks (week 37, 49, etc) until confirmation of radiographic progression by BICR. The long-term follow-up period also includes the collection of survival and treatment updates, patient reported outcomes (PROs), serious adverse events (suspected to be related to study treatment), as well as blood sampling for hematology, chemistry testing, coagulation, and PSA. The visits are supposed to be carried out every 12 weeks (± 4 weeks) until death, lost to follow-up, withdrawal of consent, opposition to use data/biological samples or study completion, whichever occurs first. This follow-up allows the data collection on medically significant long-term toxicities, such as long-term radiotoxicity.

If the participant withdrew consent for the collection of blood samples, PROs, and imaging assessments during the long-term follow-up, the information on survival, serious adverse events (SAEs) related to study treatment and post-treatment antineoplastic therapy are to be collected.

PK/dosimetry assessments:

Both PK and dosimetry of [68Ga]Ga-PSMA-11 was to be evaluated in at least 10 and up to 12 participants (at least 6 participants in main part). PK and dosimetry of [68Ga]Ga-PSMA-11 could be evaluated in any participant regardless of his PSMA status.

Both PK and dosimetry of [177Lu]Lu-PSMA-617 are to be evaluated in at least 10 and up to 12 participants (at least 6 participants in main part).

Participants who took part in PK and dosimetry evaluation of [177Lu]Lu-PSMA-617 were to take part in the efficacy and safety evaluation together with the other participants. The treatment and assessment procedure followed the same as above.

Inclusion criteria

• Written informed consent must be obtained before any assessment is performed.
• Participants must be Chinese male adults >= 18 years of age.
• Participants must have histological, pathological, and/or cytological confirmation of prostate cancer.
• Participants must be [68Ga]Ga-PSMA-11 PET/CT scan positive, and eligible as determined by the sponsor's central reader according to the VISION read rules.
• Participants must have a castrate level of serum/plasma testosterone (< 50 ng/dl, or < 1.7 nmol/L).
• Participants must have received at least one ARPI (such as enzalutamide and/orabiraterone).
• Participants must have been previously treated with at least 1, but no more than 2 previous taxane regimens.

• A taxane regimen is defined as a minimum exposure of 2 cycles of a taxane. If a participant has received only 1 taxane regimen, the participant is eligible if: the participants' physician deems him unsuitable to receive a second taxane regimen (e.g., frailty assessed by geriatric or health status evaluation or intolerance, etc.)
• Documented progressive mCRPC, based on at least 1 of the following criteria:

• Serum/plasma PSA progression defined as 2 consecutive increases in PSA measured at least 1 week apart, the minimal start value is 2.0 ng/ml
• Soft-tissue progression defined based on PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016)
• Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016)
• Participants must have >= 1 metastatic lesion that is present on baseline CT, MRI or bone scan imaging obtained =< 21 days prior to enrollment via central reading.

• In main part: participant must have at least one measurable lesion by PCWG3-modified RECIST v1.1 via central reading
• Participants must have adequate organ function:

• Bone marrow reserve:
• White blood cell (WBC) count >= 2.5 × 109/L OR absolute neutrophil count (ANC) >= 1.5 × 109/L
• Platelets >=100 × 109/L
• Hemoglobin >= 9 g/dL
• Hepatic:
• Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome =< 3 × ULN is permitted
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =< 3.0 × ULN OR =< 5.0 × ULN for participants with liver metastases
• Renal:
• eGFR >= 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
• Albumin >3.0 g/dL.

Exclusion criteria

• Previous treatment with Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223 or hemi-body irradiation.
• Previous PSMA-targeted radioligand therapy.
• Any systemic anti-cancer therapy (e.g. chemotherapy, immunotherapy or biological therapy [including monoclonal antibodies], APRI is not included) within 28 days prior to day of enrollment.
• Any investigational agents (e.g. poly adenosine diphosphate-ribosyl polymerase inhibitors [PARPi]) within 28 days prior to day of enrollment.
• History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes.
• Other concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, or investigational therapy.
• Transfusion for the sole purpose of making a subject eligible for study inclusion.
• Participants with a history of central nervous system (CNS) metastases who are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity.

• Participants with CNS metastases are eligible if received therapy (surgery, radiotherapy, gamma knife), asymptomatic and neurologically stable without corticosteroids.
• Participants with epidural disease, canal disease and prior cord involvement are eligible if those areas have been treated, are stable, and not neurologically impaired.
• Symptomatic spinal cord compression, or clinical or radiologic findings indicative of impending cord compression.