In the SOLO2 study of olaparib, dose reductions and interruptions were used to manage adverse events. However, patients who underwent protocol recommended dose alterations related to adverse events did not have inferior survival outcomes compared to those who received at or very close to the recommended dose. This was the case both for patients with a reduced relative dose intensity (RDI) in the first 12 weeks of treatment and extended to those with a reduced RDI in the first 6 months of treatment. Most dose alterations were due to adverse events, and these were most commonly due to anaemia. Reduced performance status (PS) at baseline was the strongest predictor of reduced RDI. The findings from this ancillary study are published by Dr. Katherine E. Francis of the National Health and Medical Research Council Clinical Trial Centre, Australia and colleagues on 24 February 2022 in the Annals of Oncology.
The authors wrote in the background that a PARP inhibitor, olaparib improved in the SOLO2 study median progression-free survival (PFS) and overall survival (OS) over placebo in germline BRCA-mutated platinum sensitive recurrent ovarian cancer. In newly diagnosed setting, olaparib as a maintenance treatment also reduced the risk of disease progression or death over placebo for germline BRCA-mutated high-grade ovarian cancer. Olaparib maintenance therapy is now the standard of care in patients with BRCA-mutated ovarian cancer in both treatment indications.
Maintenance treatment is often administered for prolonged periods of time and tolerability is important to minimise the impact on quality of life. With any long-term therapy, it is expected that treatment interruptions and dose reductions will be necessary to manage cumulative toxicities, and these are included and allowed for in the treatment protocol.
In the SOLO2 study, olaparib interruption, dose reduction, and discontinuation occurred in 50%, 28%, and 17% of patients as related to adverse events. The most common adverse event leading to dose alteration was anaemia in 45%, 50% and 24% of patients respectively.
The authors used data from the SOLO2 study to evaluate the impact of dose alterations on survival outcomes and identify baseline characteristics associated with dose alteration. They calculated RDI and examined the types of adverse events that led to reduced RDI. They sought to identify factors that could potentially be associated with the need for dose modifications with maintenance olaparib, as well as to determine whether dose reductions for adverse events impacted on PFS and OS.
RDI was defined as received dose as a percentage of the standard dose (olaparib 300 mg twice a day) during the first 12 weeks on treatment. Patients were categorised into RDI >98%, RDI 90-98% and RDI <90%. The association between RDI categories with PFS and OS were examined using a 12-week landmark Cox regression analysis. Logistic regression analysis was used to correlate baseline factors with RDI at 12-weeks.
In patients on olaparib included in the landmark analysis comprised of 185 patients, the mean 12-week RDI was 91.4%. There was no significant difference across 12-week RDI >98% (n = 110), 90-98% (n = 29), and <90% (n = 45) categories for PFS (median 14.2 versus 19.3 versus 34.4 months; p = 0.37) and OS (median 49.7 versus 49.5 versus 54.1 months; p = 0.84).
Risk of RDI ≤90% increased with baseline PS 1 (odds ratio [OR] 2.54; 95% confidence interval [CI] 1.11-5.82), any nausea (OR 3.17; 95% CI 0.9-11.23) and with body weight ≤70kg (OR 1.86; 95% CI 0.92-3.76).
The authors concluded that in the SOLO2 study, adherence to treatment was high with the majority of patients having a 12-week RDI ≥90%. There was no difference in PFS and OS across the different levels of adherence. Lower baseline PS was the strongest predictor of a first 12-week RDI ≤90%. The results will help to assure patients that their outcomes will not be adversely affected by adverse events related dose alterations.
Reference
Francis KE, Kim SI, Friedlander M, et al. The impact of olaparib dose reduction and treatment interruption on treatment outcome in the SOLO2/ENGOT-ov21 platinum-sensitive recurrent ovarian cancer. Annals of Oncology; Published online 24 February 2022. DOI: https://doi.org/10.1016/j.annonc.2022.02.222.