FPI-2265 (225Ac-PSMA-I&T) and Olaparib for Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC)

This study is an open-label, multicenter study designed to investigate the efficacy, safety and tolerability of FPI-2265 (225Ac-PSMA-I&T) in combination with Olaparib in participants with mCRPC. The study will be conducted in two parts, with Part A enrolling participants who have been previously treated with lutetium-177 (177Lu) vipivotide tetraxetan or other 177Lu-PSMA radioligand therapy (RLT) and Part B enrolling participants who have not been previously treated with lutetium-177 (177Lu) vipivotide tetraxetan or other 177Lu-PSMA radioligand therapy. For each part of the study, a Simon 2-stage design will be used to evaluate two dosing regimens. The purpose of this investigation is to determine the recommended FPI-2265 dose and regimen. Conclusions from this Phase 2 study will be based on safety, tolerability, and anti-tumor activity data. Participants with PSMA-positive mCRPC will be allocated to Arm 1 and Arm 2 in a singular, alternating fashion, until all Stage 1 participants are enrolled into each of the two regimens:

Arm 1: Will consist of up to six doses of FPI-2265 every six weeks at Dose A and olaparib twice a day on days 1 to 14 of each cycle.

Arm 2: Will consist of up to nine doses of FPI-2265 every four weeks at Dose B and olaparib twice a day on days 1 to 14 of each cycle Participants will be monitored and assessed for efficacy response, disease progression, and adverse events.

Inclusion criteria

• Adult male participants with mCRPC that is progressing at the time of study entry
• ECOG performance status 0-1 and life expectancy of at least three months
• Must have received at least one novel anti-androgen deprivation therapy
• Participants with known BRCA mutations should have received approved therapies such as PARP inhibitors, per Investigator discretion.
• All prior treatment-related AEs must have resolved to CTCAE Grade ≤1 (except alopecia).
• Participants must have had prior orchiectomy and/or ongoing androgen deprivation therapy and a castrate level of serum testosterone (<50 ng/dL or <1.7 nmol/L)
• Positive PSMA PET/CT scans .
• Participants must have adequate organ and bone marrow function:

• Hgb >/= 9g/dL
• Platelets >/= 100 x 10^9/L
• ANC </= 1.5 x 10^9/L
• CrCL >/= 50 mL/min

Exclusion criteria

• Previous treatment with any of the following within 6 months of first dose: Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation.
• Participants who received more than two (2) prior lines of cytotoxic chemotherapy for CRPC.
• Participants with known unresolved urinary tract obstruction.
• Transfusion- or growth factor-dependent participants.
• Participants with a history of CNS metastases are excluded, except those who have received therapy (and are neurologically stable, asymptomatic, and not receiving corticosteroids for the purposes of maintaining neurologic integrity.
• Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression.
• Participants with any liver metastases.
• Participants with skeletal metastases presenting as a superscan .
• Previous history of interstitial lung disease or non-infectious pneumonitis.
• Participants with a history or clinical and/or laboratory features suggestive of MDS/AML.
• Major surgery ≤28 days prior to the first dose of study treatment.
• Planning to conceive a pregnancy during the treatment and up to six months after the last treatment.
• Participants unable to swallow orally administered medications or with malabsorptive gastrointestinal disorders.
• Concomitant use of known strong or moderate CYP3A inhibitors or inducers