PROfound paves the way for precision medicine in mCRPC
medwireNews: Treatment with the PARP inhibitor olaparib improves the outcomes of men with metastatic castration-resistant prostate cancer (mCRPC) harboring deleterious mutations in homologous recombination repair (HRR) genes, show trial results.
“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,” presenter Maha Hussain (Northwestern University, Chicago, Illinois, USA) told delegates at the ESMO Congress 2019 in Barcelona, Spain.
The trial included men who had experienced disease progression with a prior novel hormonal agent, such as abiraterone or enzalutamide; participants were required to have at least one alteration in one of 15 HRR genes, as assessed by the FoundationOne® CDx assay (Foundation Medicine, Cambridge, Massachusetts, USA).
Eleni Efstathiou explains why the PROfound tral is the first step towards treating metastatic castration-resistant prostate cancer in a more precise way (3:09):
The primary endpoint was radiographic progression-free survival (PFS) in the cohort of participants with alterations in BRCA1, BRCA2, or ATM, and this was a median of 7.39 months for the 162 men who were randomly assigned to receive olaparib 300 mg twice daily.
This was statistically and clinically significantly longer than the median of 3.55 months achieved by the 83 men who were instead given physician’s choice of either enzalutamide 160 mg/day or abiraterone 1000 mg/day plus prednisone 5 mg twice daily, and translated into a 66% reduced risk for progression or death, said Hussain.
Olaparib treatment also improved key secondary endpoints, she added. For instance, the objective response rate in this cohort was significantly higher with olaparib than with enzalutamide or abiraterone, at 33.3% versus 2.3% (hazard ratio [HR]=20.86), and the median time to pain progression was significantly longer, at unreached versus 9.92 months (HR=0.44).
The study also included a second cohort of 142 men carrying alterations in the other 12 HRR genes assayed and olaparib continued to offer a significant radiographic PFS benefit when both cohorts were considered together, at a median of 5.82 and 3.52 months with olaparib and the control treatment, respectively, equating to a reduction in the risk for progression or death of 51%.
The overall survival data were immature at the time of analysis, but show a promising trend in favor of olaparib in the primary analysis and overall cohorts, said the presenter.
Hussain drew attention to the efficacy of olaparib in the cohort of men with alterations in the other genes, highlighting that although outcomes tended to be better with the PARP inhibitor than with enzalutamide or abiraterone, “the magnitude of benefit is not as deep” as that observed in the primary analysis cohort.
With regard to toxicity, “olaparib was well tolerated, with a safety profile generally consistent with that seen in other cancers,” she commented.
Adverse events (AEs) of grade 3 or worse were seen in 50.8% of olaparib-treated patients and 37.7% of those given the control treatment, with a respective 16.4% and 8.5% of participants discontinuing treatment as a result.
The most common high-grade AE in the olaparib and control groups was anemia, occurring at a rate of 21.5% and 5.4%, respectively, but other AEs tended to be of low grade, noted Hussain.
She highlighted the “unexpectedly” high incidence of pulmonary embolism among men given olaparib, at 4.3% compared with 0.8% among those who received enzalutamide or abiraterone, but none of the cases were fatal or led to discontinuation of the study drug.
And there were no cases of myelodysplastic syndromes or acute myeloid leukemia.
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