Olaparib May Have PROfound Effect On mCRPC

medwireNews: Second-line or later olaparib therapy improves the outcomes of men with metastatic castration-resistant prostate cancer (mCRPC) and a homologous recombination deficiency (HRD) gene mutation, suggests research reported at the ESMO 2019 Congress in Barcelona, Spain. 

“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”, said presenting author Maha Hussain, from Northwestern University in Chicago, Illinois, USA. 

The primary endpoint of radiographic progression-free survival (rPFS) was determined for a group of 245 men with a BRCA1, BRCA2, or ATM mutation, all of whom had progressed while taking the new hormonal agents (NHAs) apalutamide or enzalutamide for mCRPC. 

rPFS was a median of 7.39 months for the 162 men who were randomly assigned to receive the PARP inhibitor olaparib 300 mg twice daily versus 3.55 months for the 83 men who were instead given their physician’s choice of a NHA. This achieved a significant hazard ratio (HR) for death or progression of 0.34 in favour of olaparib. 

rPFS at 6 months was achieved by 59.76% of olaparib-treated patients and 22.63% of controls, with 12-month rates of 28.11% and 9.40%, respectively, Hussain said. 

Patients given olaparib were also significantly more likely than the NHA-treated patients to achieve a confirmed objective response (33.3 vs 2.3%, odds ratio=20.86), as well as having a significantly longer time to pain progression (median unreached vs 9.92 months, HR=0.44). 

At the time of interim overall survival (OS) analysis over 80% of the patients in the NHA arm had crossed over to olaparib therapy, Maha Hussain explained. Nevertheless, median OS showed a “favorable trend” for olaparib treatment, at a median of 18.50 versus 15.11 months, albeit the HR of 0.64 did not reach significance. 

A second cohort of 142 patients with one or more other known HRD alterations – such as BARD1, BRIP1, CDK12, CHEK1 or 2 and PALB2 – were also randomly assigned to receive olaparib or a physician’s choice of NHA. 

And rPFS remained significantly in favour of olaparib use over NHA when data for both the patient cohorts were pooled, with median durations of 5.82 versus 3.52 months and a HR of 0.49, the presenter said. 

Maha Hussain described the olaparib safety profile as “well tolerated” and “generally consistent with that seen in other cancers”.  

Analysis of the combined cohorts showed that olaparib-treated patients continued treatment for a median of 7.4 months versus 3.9 months for those given a NHA. Grade 3–4 adverse events occurred in a comparable 50.8% and 37.7% of the arms, respectively, with anaemia (21.5%) the most prevalent event at this severity for the olaparib group. 

Maha Hussain told medwireNews that ongoing studies are exploring the potential for PARP inhibitors as a first-line therapy for men with mCRPC and HRD mutations, including a phase III trial assessing the use of an androgen receptor agent in combination with a PARP inhibitor. 

“When you talk about front-line castration resistance versus second-line, we know that in second-line olaparib worked better”, she cautioned. 

“I don’t know that in front line it will. And I think that is where […] a trial ought to be done head to head”, the presenter concluded. 

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. ESMO 2019 Congress; Barcelona, Spain: 27 September–1 October. LBA12_PR