Statistically significant improvement in radiographic progression-free survival (rPFS) was achieved with olaparib treatment compared with enzalutamide or abiraterone plus prednisone in men with metastatic castration-resistant prostate cancer (mCRPC) and alterations in genes with direct or indirect roles in DNA homologous recombination repair (HRR), researchers reported at the ESMO Congress 2019 in Barcelona, Spain.
During the Presidential Symposium, Maha Hussain, deputy director of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University in Chicago, United States of America presented findings on behalf of colleagues based on results from the randomised, multinational, open-label phase III PROfound trial (NCT02987543) investigating olaparib versus enzalutamide or abiraterone plus prednisone in patients with previously treated mCRPC and alterations in any of 15 prespecified genes with a direct or indirect role in HRR activity that have been associated with response to PARP inhibitors such as olaparib.
Patients experiencing disease progression on a previously administered new hormonal agent therapy (e.g. enzalutamide and/or abiraterone plus prednisone) were eligible for the trial. The patients were assigned to two cohorts according to their HRR mutation status. Qualifying HRR alterations in tumour tissue were centrally and prospectively identified using an investigational clinical trial assay, based on the FoundationOne CDx next-generation sequencing (NGS) test, developed in partnership with Foundation Medicine, Inc (FMI; Cambridge, MA, USA). Cohort A comprised patients with alterations in BRCA1, BRCA2 or ATM; this cohort was used for the primary endpoint as at the time these were the most well characterised and prevalent alterations. Cohort B was similarly designed but exploratory in nature, patients had alterations in any of 12 other HRR genes, including BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L.
Of the 4425 men who were screened for HRR gene alterations based on prospective tissue testing, 245 were included in cohort A, and 142 in cohort B; of note, 65.6% of all patients had received prior taxane therapy. In each cohort patients were randomised 2:1 to olaparib at 300 mg twice daily and to enzalutamide at 160 mg once daily or abiraterone acetate at 1000 mg once daily in combination with prednisone 5 mg twice daily per physician’s choice hormonal therapy.
PROfound study design.
© Maha Hussain.
The primary endpoint in PROfound was rPFS in cohort A patients, as assessed by blinded independent central review (BICR) and analysed via stratified log-rank test. Of the patients assigned physician’s choice hormonal therapy and whose disease progressed by BICR in cohorts A and B, 80.6% and 84.6% crossed over to olaparib treatment, respectively.
Patients in the cohort with alterations in BRCA1, BRCA2 or ATM derived superior benefit from olaparib over physician’s choice hormonal therapy
The primary endpoint assessed in cohort A was met, wherein patients demonstrated a median rPFS of 7.39 months with olaparib compared with 3.55 months with physician’s choice of either enzalutamide or abiraterone plus prednisone (hazard ratio [HR] 0.34; 95% confidence interval [CI] 0.25-0.47; p < 0.0001).
The confirmed objective response rate (ORR) by BICR in evaluable patients was 33.3% versus 2.3%, respectively (odds ratio [OR] 20.86; 95% CI 4.18-379.18; p < 0.0001). There was a statistically significant and clinically meaningful delay in time to pain progression (based on the Brief Pain Inventory-Short Form worst pain [Item 3] and opioid use) in the olaparib arm compared with physician’s choice hormonal therapy in cohort A (HR 0.44, 95% CI 0.22-0.91; p = 0.0192; median not reached vs 9.92 months, respectively).
Median OS in cohort A at the interim analysis was 18.50 months with olaparib compared with 15.11 months with physician’s choice hormonal therapy (HR 0.64; 95% CI 0.43-0.97; p = 0.0173).
Patients in the overall population also derived benefit from olaparib over physician’s choice hormonal therapy
In the overall population (cohorts A and B), 256 men received olaparib and 131 received physician’s choice of enzalutamide or abiraterone plus prednisone. Median rPFS was 5.82 months with olaparib compared with 3.52 months with physician’s choice hormonal therapy, HR 0.49 (95% CI 0.38-0.63; p < 0.0001). The 12-month PFS rates were 22.13% versus 13.47% with olaparib versus physician’s choice hormonal therapy, respectively.
The confirmed ORRs in the respective cohorts were 21.7% versus 4.5% (OR 5.93; 95% CI 2.01-25.40; p = 0.0006, nominal).
The median time to pain progression was not reached (NR) in either arm in the overall population. Median OS at interim analysis in the overall population was 17.51 versus 14.26 months with olaparib versus physicians’ choice hormonal therapy, respectively (HR 0.67; 95% CI 0.49-0.93; p = 0.0063, nominal).
The safety profile for all agents was consistent with previous reports
Adverse events (AEs) occurred more frequently with olaparib than with physician’s choice hormonal therapy; the most commonly reported AEs were anaemia (46.1% vs 15.4%), nausea (41.4% vs 19.2%), fatigue and asthenia (41.0% vs 32.3%) and decreased appetite (30.1% vs 17.7%). With olaparib, 16.4% of patients discontinued treatment due to an AE compared with 8.5% of patients receiving enzalutamide or abiraterone plus prednisone. Of note, patients on the olaparib arm had longer duration of therapy, at a median of 7.4 months compared with 3.9 months in the physician’s choice hormonal therapy arm.
Over 4000 tissue samples were prospectively tested to detect qualifying HRR alterations
NGS findings from the population screened for the PROfound study is the largest dataset performed within central, prospective detection of HRR gene mutations in tumour tissue of men with pre-treated mCRPC who might be candidates for the treatment with PARP inhibitors. Johann S. de Bono of The Institute of Cancer Research and Royal Marsden, London, UK and colleagues conducted a biomarker analysis of tumour tissues tested in the PROfound study, which was presented during the poster discussion session at ESMO 2019 Congress.
In the PROfound trial, patients were screened for qualifying HRR mutations in a tissue specimen to determine the prevalence in patients with mCRPC and to prospectively select patients for study treatment. Screening was performed using an investigational clinical trial assay, based on the FoundationOne CDx NGS test developed by the investigators in partnership with Foundation Medicine Inc. to identify deleterious or suspected deleterious alterations (‘qualifying mutations’) in 15 prespecified HRR genes. These 15 qualifying genes were selected based on mechanistic role in HRR, clinical efficacy data, involvement in hereditary cancer risk, preclinical evidence of sensitivity to PARP inhibition, prevalence across solid tumour types, and genetic reversion events that restore gene function in tumours from patients who have developed clinical resistance to PARP inhibitors. The tissue samples were clinically heterogeneous; archival or fresh biopsy tissue from primary or metastatic tumour tissue was allowed. Patients meeting the eligibility requirements and with a qualifying mutation were randomised to one of the two trial cohorts.
Among the men who underwent screening, 4047 had samples that were tested, among which 2792 (69%) were successfully sequenced and yielded biomarker status. In screened patients, samples were mainly derived from archived tissue (89.9%); most archived samples (79.7%) were from the primary tumour and 10.1% were derived from metastatic tissue. A higher prevalence of HRR gene mutations was found in metastatic tumour tissue from both archived (33.2% in metastatic vs 27.1% in primary sample) and newly collected tissue (29.5% vs 28.9%, respectively), with a similar trend observed in the randomised population.
A qualifying HRR mutation was detected in 778 patients (27.9%), consistent with other studies, and established a prevalence of HRR mutations among the genes included in cohort A of 17.1%. Mutations in BRCA2 were the most prevalent and were detected in 8.7% of screened patients, followed by CDK12 (6.3%) and ATM (5.9%). A co-occurring qualifying HRR alteration in ≥1 gene was detected in 59 patients (7.6%), most frequently BRCA2 in 30 patients, CDK12 in 24 patients, and ATM in 13 patients.
Discussant points
Eleni Efstathiou of the MD Anderson Cancer Center, Houston, TX, US who discussed the study findings said that it is a truly practice changing study that meets the requirements for study outcomes to be defined as truly “practice changing” in terms of addressing unmet need(s), having study design that compares experimental arm to a ‘standard’ practice, positive outcomes that are clinically meaningful, reproducible results, and practices accessible to the community. Study report signifies the targeted therapy era initiation in prostate cancer. Community educationwill ease of and therefore, access to education is needed to secure practice uptake of novel therapeutic strategies.
Conclusions
Patients with mCRPC and HRR alterations whose disease had progressed on prior new hormonal agent treatment (e.g. abiraterone plus prednisone and/ or enzalutamide) demonstrated significantly improved rPFS and ORR compared with physician’s choice of either enzalutamide or abiraterone plus prednisone. Furthermore, a favorable trend for OS was observed despite crossover by a large proportion of patients initially treated with physician’s choice hormonal therapy in both cohort A and the overall population. Olaparib demonstrated a familiar and generally manageable side effect profile. According to the investigators, PROfound is the first positive phase III biomarker-selected study to evaluate a molecularly targeted treatment in patients with mCRPC.
The biomarker analysis from the PROfound trial represents the largest study to date of prospectively performed central HRR mutation tissue testing in patients with prostate cancer. Targetable HRR mutations most commonly occurred in BRCA2, followed by ATM and CDK12. Further analyses are warranted to determine the association between HRR mutations and patients’ clinical and/or demographic characteristics.
This study confirms that there is a significant proportion of mCRPC patients with alterations in HRR genes that can be identified through tissue testing. Results from the PROfound trial support the implementation of tumour testing for HRR gene alterations in routine clinical practice.
Disclosure
This study was funded by AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ, USA (MSD).
References
LBA12_PR – Hussain M, Mateo J, Fizazi K, et al. PROfound: Phase 3 study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations.
847PD – De Bono JS, Fizazi K, Saad F, et al. Central, prospective detection of homologous recombination repair gene mutations (HRRm) in tumour tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC) screened for the PROfound study.