5-year follow-up from SOLO-1 Trial
AstraZeneca presented the 5 years follow-up trial—1st ever long-term trial—that reported the efficacy of a maintenance PARP inhibitor in patients with newly diagnosed advanced ovarian cancer.
Two hundred and sixty patients were randomized to olaparib; 131 to placebo (median treatment duration 24.6 vs. 13.9 months, respectively). After a median of 4.8 and 5.0 years of follow-up, the median PFS was 56 vs. 14 months. Among patients in CR at baseline, the risk of disease recurrence or death was reduced by 63%.
The benefit derived from maintenance olaparib was sustained substantially beyond the end of treatment. Median PFS was 56 months, whereas the median treatment duration was only 25 months.
More than half of the women in complete response at baseline who received maintenance olaparib for 2 years remained free from relapse 5 years later. These results provide further evidence to support the use of maintenance olaparib as the standard of care for women with newly diagnosed advanced ovarian cancer and a BRCA mutation, and suggest the possibility of long-term remission or even cure for some patients.
According to one of the experts’ opinions, “These results represent a significant step forward in the treatment of newly diagnosed advanced ovarian cancer and give us real hope for more long term survivors. Previous research in PARP inhibitors in ovarian cancer has only been in patients with relapsed disease, so SOLO-1 has given us the evidence to show that as a first-line therapy, it can have substantial benefits for patients earlier in the cancer pathway”.
PAOLA-1/ENGOT-ov25 Trial
PAOLA-1/ENGOT-ov25 is a phase III trial in patients with newly diagnosed, FIGO stage III‒IV HGOC. Adding olaparib to maintenance bevacizumab (bev) after first-line platinum-based chemotherapy + bev led to a statistically significant progression-free survival (PFS) benefit in patients with advanced HGOC (hazard ratio 0.59; 95% confidence interval 0.49–0.72; p).
The addition of olaparib maintenance to bevacizumab improved RECIST ORR and CR in the ITT population.
The trial depicted that Olaparib combined with bevacizumab maintenance treatment, reduced the risk of disease progression or death by 67%. The addition of Olaparib improved the progression-free survival (PFS) to a median of 37.2 months versus 17.7 months with bevacizumab alone in patients with HRD-positive advanced ovarian cancer.
Together with the previously reported significant PFS improvement, these data further support the addition of maintenance olaparib to bevacizumab for women with newly diagnosed advanced ovarian cancer.
For patients with advanced ovarian cancer, the primary aim of first-line treatment is to delay disease progression for as long as possible with the intent to achieve long-term remission.
On 21st Sept 2020, based on this trial, Lynparza (olaparib) received the recommendation for marketing authorization in the European Union (EU) for the first-line maintenance treatment with bevacizumab of patients with homologous recombination deficient (HRD)-positive advanced ovarian cancer.
The SOLO2/ENGOT Ov-21 trial
SOLO2 trial is the first Phase 3 trial of maintenance therapy with a PARP inhibitor (Olaparib) showing a clinically meaningful prolongation of PFS1 by 13.6 months over placebo, and of OS by 12.9 months.
SOLO2/ENGOT Ov-21 is a post-hoc analysis of patients in the SOLO2 trial who had a RECIST progression.
As per the analysis of the results, the efficacy of subsequent chemotherapy (particularly platinum-based chemotherapy) assessed by time to the second progression appears to be less in patients having received maintenance olaparib than placebo; the exact reason remains to be explored in detail.
Olaparib maintenance versus placebo increased overall survival in the SOLO2/ENGOT Ov-21 population, and remained the best option for these patients.
NORA Trial
NORA study was designed to evaluate the efficacy and safety profile of niraparib in Chinese patients with an individualized starting dose (ISD) regimen.
NORA is the first fully powered phase III randomized clinical trial (RCT) evaluating a PARP inhibitor in Chinese patients with ovarian cancer. In September 2020, the drug recently received approval in China based on this trial’s results.
NORA met its primary endpoint demonstrating that niraparib administered with an ISD regimen significantly improves the outcome in the patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. [PFS in gBRCA mutation subgroup: HR 0.22; PFS in non-gBRCA mutation subgroup – HR 0.40].
Prospective evaluation of ISD in NORA validated the NOVA retrospective analysis. ISD of niraparib demonstrated consistent PFS benefit compared to NOVA with an improved safety profile, especially the hematological toxicities.
ISD of niraparib is effective and safe and should be considered the standard clinical practice for the maintenance therapy of patients with ovarian cancer.
However, there is one critical point which was highlighted in the ESMO-2020 Q&A session that only 14 patients were on 300 mg dose, out of 249 patients; the dose was decided based on the bodyweight estimation. The majority of patient (94%) had reduced dose, and moving further into the study period, the dose was also reduced to 100 mg for more than half of the patients. Now, although it is believed that the outcome and median PFS were consistent for all the patients, the dose reduction effect is something that needs to be further analyzed.
PRIMA/ENGOT-OV26/GOG-3012 Trial
Niraparib is a poly (ADP-ribose) polymerase (PARP) inhibitor that is approved for use in heavily pretreated patients and as maintenance treatment of patients with newly diagnosed or recurrent ovarian cancer following response to platinum-based chemotherapy (CT).
The primary endpoint was progression-free survival (PFS), and the secondary endpoint was Patient-reported outcomes (PROs) which, were collected every 8 weeks for 56 weeks, then every 12 weeks thereafter while treatment was ongoing. Once a patient discontinued treatment, PRO evaluations were performed at the time of treatment discontinuation and then at 4, 8, 12, and 24 weeks (±1 week for each time point) after the end of treatment, regardless of the status of subsequent treatment.
As per the results, the compliance rates were high for all of the PRO instruments used in the study. PRO analysis of the EORTC-QLQ-C30 and EORTCQLQ-OV28 did not indicate a difference in health-related quality of life scores of patients treated with niraparib vs. placebo. Consistent with PRO results in the NOVA study, patients receiving niraparib in the PRIMA trial did not experience a decrease in quality of life than those receiving placebo.
SELECTIVE STORIES OF SETBACKS
NINJA TRIAL
A phase II trial has supported the efficacy of nivolumab in platinum-resistant ovarian cancer, but a randomized trial is required to confirm its efficacy.
This multicenter, open-label, randomized, phase III study investigated the efficacy and safety of nivolumab vs. gemcitabine or pegylated liposomal doxorubicin (GEM/PLD) in platinum-resistant ovarian cancer. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS) and safety.
The results demonstrated that the median OS was 10.12 (95% confidence interval [CI], 8.34–14.09) months with nivolumab (n = 157) and 12.09 (95% CI, 9.26–15.34) months with GEM/PLD (n = 159), with no statistically significant difference between the groups (hazard ratio [HR] 1.03, 95% CI, 0.80–1.32; p = 0.808). Median PFS was 2.04 (95% CI, 1.91–2.20) months with nivolumab and 3.84 (95% CI, 3.58–4.17) months with GEM/PLD (HR 1.46; 95% CI, 1.15–1.85; p = 0.002). There was no difference in the toxicity profile of nivolumab.
Nivolumab did not improve OS compared to GEM/PLD in patients with platinum-resistant ovarian cancer. Further subgroup analysis needs to be conducted to see if Nivolumab could show prolonged response with GEM/PLD in those who were responsive.
INOVATYON Trial
The INternational OVArian cancer patients Trial with YONdelis (INOVATYON), is a randomized phase III international study performed for comparing trabectedin/PePLD followed by platinum at progression vs. Carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6–12 months after last platinum line.
The primary endpoint was overall survival, while the secondary endpoint was progression-free survival.
This study did not meet its primary endpoint, i.e., improving OS with the sequential use of Trabectedin/PLD followed, at progression, by platinum over Carboplatin/PLD. PFS was longer with Carboplatin/PLD (HR: 1.26, 95% CI: [1.07–1.49], while PFS after the subsequent line (PFS-ST) was in favor of Trabectedin/PLD, mainly when platinum was administered (HR: 0.80; 95% CI [0.65–0.98]).
Platinum-based regimens remain standard of care in patients with recurrent ovarian cancer progressing 6–12 months after the last platinum line.
As per the expert comments, only 6% patients in this trial received PARP inhibitors; however, it can be speculated that resistance to PARP inhibitors translates to resistance to platinum, i.e., PARP inhibitor tends to induce platinum resistance whereas there is no data available regarding Trebectidin’s impact.
IMagyn050/GOG 3015/ENGOT-OV39 Trial
Roche presented the data from the pivotal trial of bevacizumab and atezolizumab in the ESMO 2020.
The study discussed the primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo (pbo)-controlled randomized phase III trial of bevacizumab (bev)-containing therapy ± atezolizumab (atezo) for newly diagnosed stage III/IV ovarian cancer (OC).
The addition of atezolizumb to a chemotherapy + bevacizumab backbone did not significantly improve PFS vs. chemotherapy + bevacizumab alone in the ITT or PD-L1+ populations.
Moreover, the first interim OS analysis did not show a significant OS benefit with the addition of atezolizumab to chemotherapy + bevacizumab.
Final OS results are expected by 2023.
