EAU 2019: PROpel: Olaparib Combined with Abiraterone as First-Line Therapy In mCRPC

Barcelona, Spain (UroToday.com) PARP inhibitors have been increasingly recognized for their potential therapeutic role in patients with advanced prostate cancer, particularly in the setting of DNA repair defects. Prior work by Dr. Clarke and colleagues demonstrated, in a phase II clinical trial (NCT01972217), that olaparib (given as tablets, 300 mg bid) in combination with abiraterone (1000 mg od plus prednisone/prednisolone 5 mg bid) significantly prolonged radiologic progression-free survival (rPFS) compared with abiraterone alone (median 13.8 vs 8.2 months; HR 0.65, 95% CI 0.44–0.97, P=0.034) in patients with mCRPC in the second-line metastatic setting who received prior docetaxel1. Building on this, the authors are now taking this to a randomized phase III multi-institution international clinical trial – but as a first-line therapy for patients with mCRPC.

Importantly, in the first phase II trial, the treatment benefits of the combination therapy were achieved irrespective of homologous recombination repair (HRR) mutation status, which suggests a potential synergy between the two treatments. This may mean that patients without known DNA repair defects may still benefit from combination therapy.

PROpel (NCT03732820) is the title of the first Phase III trial to assess a PARP inhibitor in combination with abiraterone as first-line treatment in a genetically unselected mCRPC patient population. Enrollment began October 2018.

Study Design: PROpel is a double-blind, placebo-controlled, international, multicenter study of patients. Patients are randomized 1:1 to abiraterone (1000 mg daily plus prednisone/prednisolone 5 mg bid) plus either olaparib (tablets, 300 mg bid) or placebo.

The full protocol is below:
EAU 2019 propel


Imaging assessment will include CT and MRI scans of the Chest/Abdomen/Pelvis and a bone scan – performed at baseline, every 8 weeks until week 24, then every 12 weeks.

Cross-over is not allowed in this trial.

Inclusion/Exclusion Criteria:
Inclusion:
  • Men aged 18+
  • Histologically or cytologically confirmed prostate cancer
  • Metastatic status defined by at least 1 metastatic site
  • First-line treatment at the mCRPC stage
  • ECOG 0-1
  • Availability of FFPE tissue or new tumor biopsy tissue for HHR status evaluation
  • Candidate for abiraterone therapy
  • Patients must not have received prior chemotherapy, new hormonal agents or other systemic treatment at mCRPC stage – but they may have received prior docetaxel at metastatic hormone-sensitive prostate cancer stage [mHSPC]) per CHAARTED data.
  • Patients will be excluded if: other malignancy is present, clinically significant cardiovascular risk, uncontrolled hypertension, planned cardiac intervention.
Randomization is stratified according to site of metastases (bone only vs visceral vs other) and docetaxel treatment at mHSPC stage (yes, no).

Outcomes: Primary endpoint is investigator-assessed radiographic progression-free survival (rPFS) per RECIST v1.1 [soft tissue] and Prostate Working Cancer Group 3 [PCWG3 criteria; bone].

Secondary objectives include:
  • Time to first subsequent therapy or death
  • Time to pain progression
  • Time to second progression (PFS2)
  • Overall survival
  • Health-related quality of life (using BPI, FACT-P, and EQ-5D-5L)
Safety and tolerability will also be described, though were tolerable in prior Phase II trials. Exploratory endpoints include HRR subgroup analyses to confirm that efficacy is independent of HRR status.

Population Expected:
Screening across ~200 sites in 20 countries is being conducted to identify a target sample of ~720 patients.
Enrollment began in October 2018

Preliminary Enrollment data: None provided

Presented by: Noel W Clarke, Professor of Urologic Oncology, Director of the Genitourinary Research Group, Manchester University, Consultant Urologist at Salford Royal Hospital and The Christie, Manchester

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona, Spain, March 15-19, 2019.

Reference:
1. Clarke N et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):975-986. doi: 10.1016/S1470-2045(18)30365-6. Epub 2018 Jun 4. 
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