BackgroundUse of first-line PARP inhibitor maintenance therapy is increasing in advanced ovarian cancer. Understanding the efficacy of first subsequent therapy (FST) in patients experiencing disease progression in the first-line setting is important to optimize post-progression treatments. We evaluated the efficacy of FST in patients from PAOLA-1/ENGOT-ov25 (NCT02477644) who received first-line olaparib maintenance. Patients and methodsThis post hoc analysis evaluated the efficacy of subsequent chemotherapy following disease progression by assessing time from FST to second subsequent therapy (SST) according to whether progression occurred during versus after first-line olaparib maintenance and FST type. A multivariate Cox model was used in the olaparib plus bevacizumab arm to identify prognostic factors influencing the efficacy of subsequent chemotherapy. ResultsOf 806 randomized patients, 544 (67.5%) progressed and received subsequent chemotherapy. The median time from FST to SST was shorter in patients in the olaparib plus bevacizumab arm who progressed during first-line olaparib maintenance (6.1 months) than in those who progressed after first-line olaparib maintenance (11.4 months). Multivariate analysis indicated that progression after (versus during) first-line olaparib maintenance influenced time from FST to SST (hazard ratio 0.65, 95% CI 0.50-0.84; P=0.0011) independently of platinum-free interval or clinical risk. Among patients who progressed and received platinum-based chemotherapy with a PARP inhibitor as FST, the efficacy of subsequent therapies was also dependent upon whether progression occurred during versus after first-line olaparib maintenance. ConclusionsThese results suggest that the timing of disease progression relative to first-line olaparib maintenance may impact the efficacy of subsequent platinum-based chemotherapy. Although results should be interpreted with caution, across all subgroups, including patients who received platinum-based chemotherapy with PARP inhibitor rechallenge as FST, the median time from FST to SST was longer if progression occurred after versus during first-line olaparib maintenance.

The OPERA trial has shown that a contact X Ray Brachytherapy 50kV (CXB) boost with neoadjuvant chemoradiotherapy (NCRT) can increase organ preservation (OP) rate for early rectal adenocarcinoma (ADK) of low-mid rectum. We report the results after 5 years of follow-up. OPERA was a multicenter, phase III trial that included operable patients (pts), with cT2-cT3b low-mid rectal ADK, tumors <5 cm, cN0 or cN1 <8 mm. All pts received external beam radiotherapy (EBRT): 45Gy in 25 fractions with concurrent capecitabine. Pts were randomly assigned (1:1) to receive a boost of EBRT in group A (9Gy/5 fractions) or a boost with CXB (90Gy/3 fractions) in group B. The primary end point was OP rate. Out of 148 patients randomized, 141 were eligible. Between week 14-24, a clinical complete (or near) response was observed in 44 pts in group A (64%) vs 66 in group B (92%); p<0.001. The 3-year OP rate was 59% in group A vs 81% in group B (p=0.003). After update the median follow-up was 61.1 months [56.8-64.5]. The 5-year local regrowth was 39% in group A and 17% in group B (p=0.1). The difference in OP was still highly significant between both groups: A 56% vs B 79% (p=0.004). The difference was more significant if tumors < 3cm, with an OP rate of 93% in group B compared to 54% in group A. Of the 28 local regrowths, 3 occurred after 3 years of follow-up. Rectal bleeding (grade 1-2), which was the most prevalent toxicity during follow-up, disapeared most of the time after three years. Bowel function was not worsened by the CXB boost. The OPERA trial was the first trial to demonstrate that CXB dose escalation was increasing the OP rate with good bowel function at 3 years. At 5 years, these results are sustained, specially in small early-stage tumors. The occurrence of some local regrowth after 3 years necessitates close surveillance of these pts during the 5-year period.