Phase Ib/II Platform Study of Multiple Anti-Cancer Agents in Participants With Metastatic Prostate Cancer

This is a multicentre, open-label and platform study to evaluate multiple anti-cancer agents in participants with metastatic prostate cancer. This platform study will comprise a series of substudies. Each substudy will follow a 2-part structure (unless otherwise stated in the individual substudy):

* Part A: A dose escalation (DE) phase to identify dose limiting toxicities (DLTs), characterise safety, PK, pharmacodynamics, preliminary efficacy, and determine biologically and clinically suitable dose levels to proceed into the dose optimisation/expansion.
* Part B: A dose optimisation/expansion phase to inform recommended Phase 3 dose (RP3D), explore efficacy with Prostate-specific antigen (PSA) decrease ≥ 50% (PSA50) rate as primary endpoints, alongside continued safety monitoring.

Sub-study 1 focuses on a specific combination regimen and it will assess the safety, tolerability, PK, pharmacodynamics, and preliminary anti-tumour activity of AZD2265 (FPI-2265) actinium (225Ac) zadavotide guraxetan \[hereafter referred to as AZD2265 (FPI-2265)\] in combination with palacaparib (AZD9574) compared with AZD2265 (FPI-2265) monotherapy and with standard-of-care (SoC) docetaxel chemotherapy in participants with metastatic castration resistant prostate cancer (mCRPC).

• AZD2265 (FPI-2265) (Drug), also known as FPI-2265, 225Ac-PSMA-I&T: AZD2265 (FPI-2265) will be administered as an intravenous (IV) injection.
• Palacaparib (AZD9574) (Drug): Palacaparib (AZD9574) will be administered orally.
• Docetaxel (Drug): Docetaxel will be administered as an IV infusion.
• AZD2287 (Imaging agent) (Drug): AZD2287 will be administered as an IV injection.

Primary outcomes

• Part A: Number of participants with treatment-emergent adverse events (TEAEs)including serious adverse events (SAEs), treatment-related AEs (TRAEs) and adverse events of special interests (AESIs) [Up to approximately 1 year after last dose]: To assess the safety and tolerability of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A: Number of participants with dose limiting toxicities (DLTs) [From date of first dose up to approximately 2 cycles (up to 3 months)]: To assess the safety and tolerability, and characterise the DLTs of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part B: Number of participants with TEAEs [Up to approximately 1 year after last dose]: To further assess the safety and tolerability, and determine the recommended Phase 3 dose (RP3D) of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part B: Prostate Specific Antigen 50 (PSA50) response rate [Up to 3 years 4 months]: PSA50 response rate is defined as proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later, and occurring prior to confirmed PSA progression. PSA50 will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).

Secondary outcomes

• Part A and Part B: PSA50 response rate [Up to 3 years 4 months]: PSA50 response rate is defined as proportion of participants achieving a ≥ 50% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later, and occurring prior to confirmed PSA progression. PSA50 will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265) (Part A) and to demonstrate effectiveness of AZD2265 (FPI-2265) + palacaparib (AZD9574) relative to AZD2265 (FPI-2265) alone and relative to docetaxel (Part B).
• Part A and Part B: Prostate Specific Antigen 90 (PSA90) response rate [Up to 3 years 4 months]: PSA90 response rate is defined as proportion of participants achieving a ≥ 90% decrease in PSA from baseline to the lowest post-baseline PSA result, confirmed by a second consecutive PSA assessment at least 3 weeks later, and occurring prior to confirmed PSA progression. PSA90 will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265) (Part A and Part B) and to demonstrate effectiveness of AZD2265 (FPI-2265) + palacaparib (AZD9574) relative to AZD2265 (FPI-2265) alone and relative to docetaxel (Part B only).
• Part A and Part B: Time to PSA50 (TTPSA50) response [Up to 3 years 4 months]: TTPSA50 response is defined as the time from date of randomisation/first dose of study intervention until the date of first documented PSA50 response (≥ 50% decrease in PSA from baseline), confirmed by a second consecutive PSA assessment at least 3 weeks later. TTPSA50 response will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Time to PSA90 (TTPSA90) response [Up to 3 years 4 months]: TTPSA90 response is defined as the time from date of randomisation/first dose of study intervention until the date of first documented PSA90 response (≥ 90% decrease in PSA from baseline, respectively), confirmed by a second consecutive PSA assessment at least 3 weeks later. TTPSA90 response will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Duration of PSA50 (DoPSA50) response [Up to 3 years 4 months]: DoPSA50 response is defined as the time from the date of first documented PSA50 response, that is subsequently confirmed by a second consecutive PSA assessment at least 3 weeks later, until the date of documented PSA progression. DoPSA50 response will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Duration of PSA90 (DoPSA90) response [Up to 3 years 4 months]: DoPSA90 response is defined as the time from the date of first documented PSA90 response, that is subsequently confirmed by a second consecutive PSA assessment at least 3 weeks later, until the date of documented PSA progression. DoPSA90 response will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Time to PSA progression [Up to 3 years 4 months]: TTPSA progression is defined as time from the date of randomisation/first dose of study intervention until the date of documented PSA progression or the last PSA result in the absence of progression. PSA progression is defined as an increase in PSA of ≥ 25% from the nadir and an absolute increase of at least 2 ng/mL above nadir beyond 12 weeks. PSA progression must be confirmed by a second value taken at least 3 weeks later. TTPSA progression will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: PSA over time [Up to 3 years 4 months]: PSA over time is defined as the longitudinal change in serum PSA from baseline across all on-study timepoints. PSA over time will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Radiographic Progression-free survival (rPFS) [From Day 1 to 3 years 4 months]: rPFS is defined as the time from date of randomisation/first dose of study intervention until the date of objective disease progression according to response evaluation criteria in solid tumors (RECIST) 1.1 (for soft tissue disease) and prostate cancer working group 3 (PCWG3) criteria (for bone disease) as assessed by the investigator at the local site, or death (by any cause in the absence of progression), regardless of whether the participant withdraws from therapy or receives another anti-cancer therapy prior to progression. rPFS will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265) (Part A and Part B) and to demonstrate effectiveness of AZD2265 (FPI-2265) + palacaparib (AZD9574) relative to AZD2265 (FPI-2265) alone and relative to docetaxel (Part B only).
• Part A and Part B: Overall Response Rate (ORR) [From Day 1 to 3 years 4 months]: The ORR is defined as the percentage of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as the time from the date of first documented objective response (which is subsequently confirmed) until the date of radiographic disease progression or censored according to rules for rPFS. The ORR will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265) (Part A and Part B) and to demonstrate effectiveness of AZD2265 (FPI-2265) + palacaparib (AZD9574) relative to AZD2265 (FPI-2265) alone and relative to docetaxel (Part B only).
• Part A and Part B: Best Overall Response (BOR) [From Day 1 to 3 years 4 months]: The BOR is defined as the best overall visit response the participant achieves as determined by the investigator at the local site. The BOR will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265) (Part A and Part B) and to demonstrate effectiveness of AZD2265 (FPI-2265) + palacaparib (AZD9574) relative to AZD2265 (FPI-2265) alone and relative to docetaxel (Part B only).
• Part A and Part B: Duration of response (DoR) [From Day 1 to 3 years 4 months]: The DoR is defined based on RECIST 1.1 (for soft tissue disease) and PCWG3 criteria (for bone disease) as the time from the date of first documented objective response (which is subsequently confirmed) until date of radiographic disease progression or censored according to rules for rPFS. The DoR will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265) (Part A and Part B) and to demonstrate effectiveness of AZD2265 (FPI-2265) + palacaparib (AZD9574) relative to AZD2265 (FPI-2265) alone and relative to docetaxel (Part B only).
• Part A and Part B: Time to Response (TTR) [From Day 1 to 3 years 4 months]: The TTR is defined as the time from the date of randomisation/first dose of study intervention until the date of first documented objective response, which is subsequently confirmed. The TTR will be assessed to check the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265) (Part A and Part B) and to demonstrate effectiveness of AZD2265 (FPI-2265) + palacaparib (AZD9574) relative to AZD2265 (FPI-2265) alone and relative to docetaxel (Part B only).
• Part A: Disease control rate (DCR) [From Day 1 to 3 years 4 months]: To assess the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265)
• Part A and Part B: Percentage change in tumour size [From Day 1 to 3 years 4 months]: To assess the anti-tumour activity of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Plasma concentration of palacaparib (AZD9574) [From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days)]: To determine the PK of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Plasma concentration of AZD2265 (FPI-2265) [From Cycle 1 Day 1 to Cycle 2 Day 1 (each cycle will be 42 days)]: To determine the PK of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Area under the concentration time curve (AUC) [From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days)]: To determine the PK (AUC) of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Maximum observed drug concentration (Cmax) [From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days)]: To determine the PK (Cmax) of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Time to reach Cmax (tmax) [From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days)]: To determine the PK (tmax) of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Terminal elimination half-life (t½λz) [From Cycle 1 Day 1 to Cycle 2 Day 15 (each cycle will be 42 days)]: To determine the PK (t½λz) of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265).
• Part A and Part B: Change from baseline in study-specific biomarker ABC in response to treatment [Up to 3 years 4 months]: To investigate pharmacodynamics of palacaparib (AZD9574) in combination with AZD2265 (FPI-2265) (for Part A and Part B) and of AZD2265 (FPI-2265) monotherapy (for Part B only).
• Part A and Part B: Change from baseline in study-specific biomarker XYZ in response to treatment [Up to 3 years 4 months]: To investigate study-specific XYZ expression and relationship to response to the treatment.

Sex: Male, ages: 18 Years to 99 Years

Inclusion Criteria:

1. Participants with a diagnosis of histologically confirmed adenocarcinoma of the prostate (no small cell, neuroendocrine, sarcomatoid, spindle or signet cell).
2. Minimum life expectancy of 3 months or more.
3. Eastern Cooperative Oncology Group (ECOG) performance status of O or 1 at screening, with no deterioration.
4. PCWG3 (Prostate Cancer Working Group 3) modified RECIST Version 1.1 evaluable disease.
5. Must have received at least one novel androgen receptor pathway inhibitor (ARPI), such as enzalutamide or darolutamide or apalutamide or abiraterone acetate.
6. Must have one or more unresectable metastatic lesions.
7. Must have had prior orchiectomy and/or ongoing androgen deprivation therapy, and a castrate level of serum testosterone (<50ng/dL or <l.7nmol/L).
8. Progressive metastatic castration-resistant prostate cancer (mCRPC) following the most recent treatment at time of study entry.
9. Adequate organ and marrow function.
10. Non sterilised participants who are sexually active with a partner of childbearing potential must use a condom (plus spermicide, if available), must refrain from fathering a child, freezing or donating sperm, and it is recommended for the partner to also use a highly effective contraceptive method.

Inclusion Criteria for Sub study 1:

1. Must have received a single line of ARPI, such as enzalutamide, darolutamide, apalutamide or abiraterone acetate. Participants who were exposed to more than one ARPI due to toxicity or intolerance (not due to disease progression) are eligible.
2. PSMA positive mCRPC by computed tomography positron emission tomography, obtained with PSMA ligand defined as at least 1 PSMA positive metastatic lesion with tracer uptake greater than liver, and no PSMA negative lesions. All measurable or intraprostatic lesions must be PSMA positive.
3. Capable of self-administering oral formulations.

Exclusion Criteria:

1. Any evidence of non adenocarcinomatous forms of prostate cancer (including small cell, spindle cell, signet cell, neuroendocrine, sarcomatous).
2. Known, unresolved urinary tract obstruction.
3. Participants with a history of central nervous system metastases.
4. Symptomatic malignant spinal cord compression or findings indicative of impending cord compression.
5. Participants with a history of leptomeningeal carcinomatosis.
6. Previous or concurrent cancer distinct from the cancer under investigation in primary site or histology .
7. Concurrent serious medical conditions.
8. Previous history of interstitial lung disease or non-infectious pneumonitis.
9. Participants with a history or clinical/laboratory features suggestive of myelodysplastic syndrome or acute myeloid leukaemia.
10. Persistent toxicities caused by previous therapy.
11. Participants unable to swallow orally administered medications or with gastrointestinal disorders likely to interfere with absorption.
12. Active infection, including tuberculosis, hepatitis C virus, and hepatitis B virus infection.
13. Known hypersensitivity to study intervention or any of their excipients.

Exclusion Criteria for Sub study 1:

1. History of uncontrolled seizures or requirement for >2 antiepileptic drugs.
2. History of severe brain injury or stroke.
3. Skeletal metastases demonstrating a superscan appearance on bone scan.
4. Participants have received prior therapy with palacaparib (AZD9574) or more than 1 prior line of any other Poly-ADP-ribose polymerase inhibitor (PARPi)-based regimen (either as a treatment or as maintenance).

NIH grants: 2025