Castration-resistant prostate cancer (CRPC) is the state wherein the disease progresses despite androgen depletion therapy. The disease may present itself as either a continuous rise in serum prostate-specific antigen (PSA) levels, progression of an already existing disease, and/or appearance of new metastases. The prevalence of metastatic CRPC (mCRPC) was estimated as 62 cases per 100,000 men in France in 2014. Less than one mCRPC case per 100,000 was observed in men within the age group of 40-49 years. Maximum mCRPC incidence was observed in men aged 80-89 years (175 per 100,000).1

Current treatment options in the first-line setting of mCRPC mainly comprise next-generation hormonal agents (e.g., abiraterone and enzalutamide) or cytotoxic chemotherapy agents, AR blocking agents, immunotherapies, and radiopharmaceuticals. However, taxane chemotherapy using docetaxel and cabazitaxel is routinely implemented as the treatment option for mCRPC.2 The main challenge of these treatments is the shorter overall survival of these patients.

Ever since the results of the PROfound trial made headlines with significant progression-free survival and overall survival in olaparib-treated patients who were diagnosed with mCRPC and had BRCA1/2 and ATM mutations, several olaparib combination studies have been initiated in the mCRPC setting. One such combination is abiraterone+olaparib, which is suggested to have a combined antitumor effect. It is suggested that the next-generation hormonal agents like abiraterone induces homologous recombination repair (HRR) deficiency and increases sensitivity to PARP inhibitors like olaparib, which then positively regulates the androgen receptor (AR) signaling and enhances the AR target gene suppression. 

In line with this, a randomized double-blind, placebo-controlled Phase 3 trial of abiraterone (1000 mg once daily) and olaparib (300 mg twice daily) was conducted in South Korean patients with mCRPC in the first-line setting.3 All patients had histologically or cytologically confirmed prostate adenocarcinoma and had at least one metastatic lesion detected either on a bone scan, MRI, or CT scan. All patients were administered prednisone or prednisolone (5 mg twice daily). Determination of HRRm status was conducted using tumor tissue test (FoundationOne CDX) and ctDNA samples (FoundationOne Liquid CDx test) post randomization and before the primary analysis. HRRm testing assessed the following genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L. Based on HRRm status, 28.4% of patients were assigned to the HRRm subgroup and 69.3% were assigned to non-HRRm subgroup; 2.3% of patients had unknown HRRm status.

Overall, median PFS (imaging based) was significantly longer in patients treated with abiraterone plus olaparib than those treated with abiraterone alone (24.8 versus 16.6 months; p=0.001). Amongst the patients treated with abiraterone plus olaparib, the median PFS was improved in patients with HRRm than in those without HRRm (p=0.034). Consistent with these findings, TFST and PFS2 also were found to be improved in patients treated with abiraterone plus olaparib combination. There was a clear separation seen in the KM curves of both treatment groups suggesting a delay of 5.1 months to the next subsequent therapy with the combination treatment.

There were approximately 40% of patients with measurable disease at baseline; of these, 58.4% of patients in the abiraterone plus olaparib group had ORR versus 48.1% of patients treated with abiraterone alone (odds ratio, 1.60). More patients in the abiraterone plus olaparib group (than abiraterone alone group) demonstrated a confirmed PSA response (79.3% versus 69.2%). The median time to PSA progression was not reached in patients treated with abiraterone plus olaparib and was 12 months for patients treated with abiraterone alone. Overall survival was not reached in any of the treatment groups. 

Patients in the abiraterone plus olaparib group experienced more adverse events, particularly anemia, than those treated with abiraterone alone. However, the safety profile of abiraterone and olaparib was consistent with the known toxicity of both drugs. There were no new safety concerns were reported. 

Thus, the study demonstrates the clinical benefits of olaparib in combination with abiraterone as the first-line treatment for patients with mCRPC. 

References:

1. Thurin H et al., Epidemiology of metastatic castration-resistant prostate cancer: A first estimate of incidence and prevalence using the French nationwide healthcare database. cancer epide [Internet]. 2020;69:101833. 

2. He L et al., Metastatic castration-resistant prostate cancer: Academic insights and perspectives through bibliometric analysis. Medicine. 2020;99:e19760. 

3. Clarke W et al., Abiraterone and olaparib for metastatic castration-resistant prostate cancer. NEJM Evid. 2022;1(9).