Olaparib outperforms enzalutamide or abiraterone acetate in men with metastatic castration resistant prostate cancer with HRR alterations

At ESMO 2019, the results of the phase III PROfound trial were presented. These results demonstrated that a statistically significant improvement in radiographic progression-free survival could be obtained with olaparib treatment as compared to enzalutamide or abiraterone plus prednisone in men with metastatic castration-resistant prostate cancer and alterations in genes with direct or indirect roles in DNA homologous recombination repair.

Introduction

Despite a significant progress in systemic therapy, metastatic castration-resistant prostate cancer (mCRPC) continues to be lethal. mCRPC is a molecularly heterogeneous disease with up to 30% of cancers that harbour deleterious alterations in DNA damage repairs genes, including those with a direct or indirect role in homologous recombination repair (HRR). These gene alterations can confer sensitivity to poly (adenosine diphosphate-ribose) polymerase (PARP) inhibition, of which BRCA1, BRCA2 and ATM are the most well characterized. The PARP inhibitor olaparib has previously demonstrated an anti-tumour activity in patients with prostate cancer that harbour HRR alterations.

Methods

Key eligibility criteria for inclusion in the PROfound trial were mCRPC with disease progression on prior NHA, for example abiraterone or enzalutamide. All patients had alterations in at least 1 gene with a direct or indirect role in HRR. Stratification factors were the previous administration of a taxane and a measurable disease. In cohort A, 245 patients with alterations in BRCA1, BRCA2 or ATM were included. Cohort B included 142 patients with other alterations. In both cohorts, patients were randomized (2:1) to receive olaparib 300 mg twice daily or physician’s choice of treatment (abiraterone/enzalumatide). Upon BICR progression, patients in the physician’s choice of treatment were allowed to cross-over to olaparib. The primary endpoint was radiographic progression-free survival (rPFS) in cohort A.

Results

In cohort A, 54.3% of the patients had a single BRCA1 or BRCA2 alteration and 37.0% of the patients had ATM alterations, 8.6% of the patients had co-occurring alterations. Median age of the patients in cohort A was 68 years, but even patients in their late 80’s or early 90’s were included in the study. More than 90% of the patients had an ECOG performance status of 0 or 1 and more than 60% of the patients had received previous taxane treatment. Median time on treatment was 7.4 months for the olaparib arm and 3.9 months for patients treated with physician’s choice. The most common adverse events were anaemia (46.5%), nausea (41.4%), and fatigue and asthenia (41.0%). In the olaparib group, 4.3% of the patients had a pulmonary embolism (versus 0.8% in the control group), none of these events were fatal. The primary endpoint assessed in cohort A was met and patients demonstrated a median rPFS of 7.39 months with olaparib, as compared to 3.55 months with physician’s choice of treatment (HR 0.34 [95% CI: 0.25-0.47]; p<0.0001). At six months, 59.76% of the patients in the olaparib arm were progression-free, as compared to 22.63% of the patients treated with physician’s choice. At 12 months, these rates were 28.11% and 9.40% respectively. The results were consistent among all subgroups. The confirmed objective response rate (ORR) by BICR in evaluable patients was 33.3% versus 2.3% respectively. Time to pain progression (based on the Brief Pain Inventory-Short Form worst pain [Item 3] and opioid use) in cohort A was not reached in the olaparib arm and was 9.92 months in the physician’s choice arm (HR 0.44 [95% CI: 0.22-0.91]; p<0.0192). In the overall population (cohort A+B) the rPFS by BICR was 5.82 months in the olaparib arm (versus 3.52 months in the physician’s choice arm, HR 0.49 [95% CI: 0.38-0.63]; p<0.0001). An interim overall survival analysis (38% maturity in cohort A, 41% maturity in cohort B) demonstrated a median OS of 18.50 months in the olaparib arm and a median OS of 15.11 months in the physician’s choice arm for cohort A. In the overall population (cohort A+B) the median OS was 17.51 months and 14.26 months respectively.

Conclusions

In patients with mCRPC with disease progression on prior NHA, olaparib provided a statistically significant and clinically meaningful improvement in BICR rPFS as compared to enzalutamide or abiraterone plus prednisone in patients with alterations in BRCA1, BRCA2 and/or ATM as well as in the overall population with alterations in any qualifying gene with a direct or indirect role in homologous recombination repair. Olaparib improved rPFS, ORR and time to pain progression. Despite a cross-over of more than 80%, the at interim analysis showed a favourable trend in OS. Olaparib was well tolerated, with a safety profile generally consistent with that seen in other cancers. In conclusion, PROfound is the first positive biomarker-selected phase III study evaluating a molecularly-targeted therapy in men with mCRPC and highlights the importance of genomic testing in this population.

Reference

Hussain M, Mateo J, Fizazi K, et al. PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Presented at ESMO 2019; Abstract LBA12.