Olaparib shows survival benefits in mCRPC and OC
Olaparib has demonstrated survival benefits in BRCA1/2-positive metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2-positive ovarian cancer (OC), according to results of the PROfound trial and 5-year results of the SOLO1 trial presented at the European Society for Medical Oncology Virtual Congress 2020 (ESMO 2020).
PROfound: Significant OS benefit in BRCA1/2-positive mCRPC
The phase III PROfound study included 245 mCRPC patients harbouring BRCA1, BRCA2 or ATM mutations (cohort A), and 142 mCRPC patients harbouring at least one of 12 other genetic alterations (cohort B). Patients in both cohorts were randomized in a 2:1 ratio to receive olaparib 300 mg BID or control therapy (either enzalutamide 160 mg QD, or abiraterone 1,000 mg QD plus prednisone 5 mg BID). The study met its primary endpoint of prolonged radiographic progression-free survival (PFS), as reported previously. [N Engl J Med 2020;382:2091-2102]
Results of the final overall survival (OS) analysis, presented at ESMO 2020, showed a significant 31 percent improvement in OS with olaparib vs control in cohort A (median, 19.1 months vs 14.7 months; hazard ratio [HR], 0.69; 95 percent confidence interval [CI], 0.50 to 0.97; p=0.0175). [de Bono J, et al, ESMO 2020, abstract 610O; N Engl J Med 2020, doi: 10.1056/NEJMoa2022485]
“The OS benefit was observed despite having 67 percent of crossover from the control arm to the olaparib arm,” said investigator Dr Joaquin Mateo of Vall d’Hebron Institute of Oncology, Barcelona, Spain. “The benefit became more prominent after adjusting for the impact of crossover [HR, 0.42; 95 percent CI, 0.19 to 0.91]. This suggests that the actual treatment effect of olaparib is likely to be greater than what has been observed in the PROfound study.”
Meanwhile, no significant OS benefit was observed in cohort B (median, 14.1 months with olaparib vs 11.5 months with control; HR, 0.96; 95 percent CI, 0.63 to 1.49), as well as in cohorts A and B combined (median, 17.3 months vs 14.0 months; HR, 0.79; 95 percent CI, 0.61 to 1.03).
“In an exploratory gene-level analysis, patients with tumours harbouring BRCA1/2 mutations appeared to derive the greatest OS benefit from olaparib, but the OS improvement was not significant in those with ATM mutations,” said Mateo.
The safety profile of olaparib was consistent with the primary analysis. Grade ≥3 adverse events (AEs) were reported by 52 percent of patients in the olaparib arm and 40 percent in the control arm. Treatment discontinue due to AEs was required in 20 percent and 8 percent of patients, respectively.
“The PROfound study demonstrated OS improvement in a molecularly-defined subset of mCRPC patients, supporting the implementation of genomic testing in clinical practice,” concluded Mateo.
SOLO1: Olaparib’s benefit in OC sustained at 5 years
The SOLO1 study included 391 patients with newly-diagnosed BRCA1/2-positive OC who were in complete or partial response to platinum-based chemotherapy. The patients were randomized to receive olaparib 300 mg BID or placebo for up to 2 years.
The primary analysis, conducted after a median follow-up of 40.7–41.2 months, showed a significant PFS improvement with olaparib vs placebo (median, not reached vs 13.8 months; HR, 0.30; 95 percent CI, 0.23 to 0.41; p<0.001). [N Engl J Med 2018;379:2496-2505]
“The PFS benefit of olaparib was sustained beyond the end of treatment after 5 years of follow-up [median, 56.0 months vs 13.8 months; HR, 0.33; 95 percent CI, 0.25 to 0.43],” reported investigator Dr Susana Banerjee of the Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK. “The 5-year PFS rate was 48 percent vs 21 percent.” [Banerjee S, et al, ESMO 2020, abstract 811MO]
“Notably, median recurrence-free survival was not reached with olaparib vs 15.3 months with placebo in patients who achieved complete response to chemotherapy [HR, 0.37; 95 percent CI, 0.27 to 0.52],” she added. “This means that more than half of the patients in complete response at baseline who received maintenance olaparib for 2 years remained relapse-free at 5 years.”
No new safety signals were observed with olaparib at long-term follow-up. No additional cases of myelodysplastic syndrome or acute myeloid leukaemia were reported.
“The 5-year results of SOLO1 suggest the possibility of long-term remission or even cure in patients with BRCA1/2-positive OC,” concluded Banerjee.