Clinical Study to Assess the Efficacy and Safety of Olaparib in Chinese Patients With Metastatic Castration-Resistant Prostate Cancer Who Have Failed Prior Treatment With a New Hormonal Agent and Have BRCA1/2 Mutations

This is a Phase IV, randomized, open-label, 2-arm, multicenter study evaluating the efficacy and safety of olaparib in Chinese men with metastatic castration-resistant prostate cancer (mCRPC) who have failed prior treatment with a new hormonal agent (NHA) and have BRCA1/2 mutations. Approximately 42 subjects will be randomized in a 2:1 ratio to olaparib or to investigator's choice of NHA (enzalutamide or abiraterone acetate).

• olaparib (Drug), also known as Lynparza: 300 mg (2x 150 mg tablets) twice daily
• enzalutamide (Drug), also known as XTANDI: 160 mg (4 x 40 mg capsules) once daily
• abiraterone acetate (Drug), also known as ZYTIGA: 1,000 mg (4 x 250 mg tablets) once daily
• Prednisone (Drug): 5mg(5mg x 1 tablet) twice daily

Primary outcomes

• Radiological Progression-free Survival - Based on Blinded Independent Central Review (BICR) [Tumor assessments every 8 weeks (± 1 week) relative to the date of randomization until radiological progression as assessed by BICR or death (median duration of treatment of 9 and 6 months for Olaparib and Investigators Choice of NHA respectively).]: rPFS is defined as the time from randomization until the date of objective disease progression (soft tissue or bone) or death (by any cause in the absence of progression) regardless of whether the patient withdraws from randomized therapy or receives another anti-cancer therapy prior to progression.

Secondary outcomes

• Confirmed Objective Response Rate (ORR), Based on Blinded Independent Review (BICR) [Tumor assessments every 8 weeks (± 1 week) from randomisation until radiographic progression assessed by BICR (median duration of treatment of 9 and 6 months for Olaparib and Investigators Choice of NHA respectively).]: Confirmed ORR is the percentage of patients with a Complete response (CR) or Partial response (PR), in their soft tissue disease per (RECIST v1.1), in the absence of progression on bone scan per Prostate Cancer Working Group 3 (PCWG3), confirmed >=4 weeks later. Per RECIST v1.1, CR=Disappearance of all target lesions; PR = >=30% decrease in the sum of diameters of target lesions. For each treatment group, confirmed ORR is the number of patients with a confirmed CR or PR divided by the number of patients in the treatment group.
• Overall Survival [From the time from the date of randomization until death due to any cause. Assessments continue up to 27 months after the first patient was randomized.]: OS is the time from the date of randomization until death due to any cause.
• Time to First Symptomatic Skeletal-related Event [Time from randomization to the first SSRE-radiation for skeletal symptoms, confirmed pathological fracture, confirmed spinal cord compression, or orthopaedic surgery for bone metastases. Assessments continue up to 27 months post first patient enrolled.]: Time from first dose to the first symptomatic skeletal-related event
• Time to Opiate Use for Cancer-related Pain [Opioid use will be recorded at baseline and at every study visit, including the safety follow-up visit. Assessments continue up to 27 months post first patient enrolled.]: Time from randomization to opiate use for cancer-related pain
• Prostate-specific Antigen Response [Blood samples for PSA assessment will be collected at baseline and every 4 weeks throughout the treatment phase, including at the study treatment discontinuation visit. Assessments continue up to 27 months post first patient enrolled.]: 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 (PSA50 response)
• Prostate-specific Antigen Response [Blood samples for PSA assessment will be collected at baseline and every 4 weeks throughout the treatment phase, including at the study treatment discontinuation visit. Assessments continue up to 27 months post first patient enrolled.]: Best percentage change from baseline in PSA is defined as the biggest reduction in PSA level compared with baseline (or the smallest increase in the absence of a reduction) taking account of all PSA values collected for each patient.
• Time From Randomization to Second Progression or Death [Tumor assessments will be performed every 8 weeks (±7 days) after randomization until radiologic progression or death, unless the participant withdraws consent. Assessments continue up to 27 months post first patient enrolled.]: Time from randomization to second progression by investigator assessment of radiological or clinical progression or death (PFS2)
• Subsequent Anticancer Therapy [Recorded from post discontinuation of study treatment up to primary data cut off date. Assessments continue up to 27 months post first patient enrolled.]

Sex: Male, ages: 18 Years to any

Inclusion criteria：

1. Histologically confirmed diagnosis of prostate cancer.
2. Documented evidence of metastatic castration resistant prostate cancer (mCRPC).
3. Subjects must have progressed on prior new hormonal agent (e.g. abiraterone acetate and/or enzalutamide) for the treatment of metastatic prostate cancer and/or CRPC .
4. Ongoing therapy with LHRH analog or bilateral orchiectomy.
5. Radiological progression at study entry while on androgen deprivation therapy (or after bilateral orchiectomy).
6. Deleterious or suspected deleterious BRCA1/2 mutation in tumor tissue.
7. Normal organ and bone marrow function measured within 28 days prior to administration of study treatment.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.

Exclusion criteria：

1. Any previous treatment with a poly (adenosine diphosphate \[ADP\] ribose) polymerase (PARP) inhibitor, including olaparib.
2. Subjects who had any previous treatment with DNA-damaging cytotoxic chemotherapy, except if for non-prostate cancer indication and last dose > 5 years prior to randomization.
3. History of another primary malignancy except for malignancy treated with curative intent with no known active disease for ≥5 years before the first dose of study intervention and of low potential risk for recurrence.
4. Spinal cord compression or brain metastases unless asymptomatic, stable, and not requiring steroids for at least 4 weeks prior to start of study intervention.

Participant flow

Outcome results

• Radiological Progression-free Survival - Based on Blinded Independent Central Review (BICR) (Primary), Median, Months: Olaparib 300 mg bd 9.331 (5.65 to 11.20); Investigators Choice of NHA 8.838 (1.77 to NA) (p 0.726)
• Confirmed Objective Response Rate (ORR), Based on Blinded Independent Review (BICR) (Secondary), Count of participants, Participants: Olaparib 300 mg bd 5; Investigators Choice of NHA 1 (p 0.498)
• Overall Survival (Secondary), Median, Months: Olaparib 300 mg bd 17.314 (13.90 to NA); Investigators Choice of NHA NA (10.32 to NA) (p 0.440)
• Time to First Symptomatic Skeletal-related Event (Secondary), Median, Months: Olaparib 300 mg bd NA (NA to NA); Investigators Choice of NHA NA (NA to NA)
• Time to Opiate Use for Cancer-related Pain (Secondary), Median, Months: Olaparib 300 mg bd NA (11.20 to NA); Investigators Choice of NHA 17.281 (1.31 to NA) (p 0.604)
• Prostate-specific Antigen Response (Secondary), Number, Percentage of participants: Olaparib 300 mg bd 48 (29 to 67); Investigators Choice of NHA 36 (13 to 65)
• Prostate-specific Antigen Response (Secondary), Mean, Percentage change from baseline: Olaparib 300 mg bd 37.2 +/- 252.62; Investigators Choice of NHA -15.0 +/- 53.84
• Time From Randomization to Second Progression or Death (Secondary), Median, Months: Olaparib 300 mg bd NA (15.41 to NA); Investigators Choice of NHA NA (5.91 to NA) (p 0.889)
• Subsequent Anticancer Therapy (Secondary), Count of participants, Participants: Olaparib 300 mg bd 14; Investigators Choice of NHA 3

Adverse events

Time frame: From the time of signature of the ICF, throughout the treatment period and until the 30-day follow-up period is completed or 27 months post first patient enrolled, whichever occurs earlier

Serious adverse events by term

Other adverse events by term

7 more terms not shown.

• Study Protocol (PDF, 2023-04-13)
• Statistical Analysis Plan (PDF, 2024-09-23)

• Fangjian Zhou, M.D., Principal investigator, Sun Yat-Sen University Cancer Center