Background

Newly diagnosed advanced OC pts are at high risk of relapse and 5-y survival is 30–50%. Delay of recurrence, prolonged survival and, for some patients, increased chance of cure are goals of treatment in this setting. In SOLO1 (NCT01844986; GOG-3004) pts with OC and a BRCAm who were in response after first-line platinum-based chemotherapy derived significant progression-free survival (PFS) benefit from maintenance olaparib vs placebo (pbo; median 41 months [m] f/u; median not reached vs 13.8 m; HR 0.30; P<0.001; Moore et al. NEJM 2018). We report data from 5-y f/u (data cut-off 5 March 2020).

Methods

Pts received maintenance olaparib (tablets; 300 mg bid) or pbo for up to 2 y or until progression. PFS and recurrence-free survival (RFS) were investigator-assessed by modified RECIST v1.1. For pts in complete response (CR) at baseline, RFS was defined post hoc as time from randomization to disease recurrence (new lesions by imaging) or death.

Results

260 pts were randomized to olaparib; 131 to pbo (median treatment duration 24.6 vs 13.9 m, respectively). After a median of 4.8 and 5.0 y of f/u, median PFS was 56 vs 14 m (Table). Among pts in CR at baseline, risk of disease recurrence or death was reduced by 63%. Additional secondary endpoints will be reported.

The safety profile of olaparib was consistent with previous observations. No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported and incidence of new primary malignancies remained balanced between arms (olaparib, 7/260 [3%]; pbo, 5/130 [4%]).

Conclusions

For pts with a BRCAm and newly diagnosed advanced OC the benefit derived from 2 y of maintenance olaparib was sustained beyond the end of treatment and after 5 y almost half of pts were progression-free vs 20% with pbo. Over 50% of pts in CR after first-line platinum-based chemotherapy remained free from relapse 5 y later. 5-y f/u is the longest for any PARP inhibitor in this setting and no new safety signals were observed.

Clinical trial identification

NCT01844986

Editorial acknowledgement

Medical writing assistance was provided by Elin Pyke, MChem, Mudskipper Business Limited, funded by AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Background

Niraparib, a potent inhibitor of PARP 1/2, maintenance therapy significantly improved the outcome of platinum-sensitive recurrent ovarian cancer (PSROC) in Caucasian and Chinese patients in NOVA and NORA studies. An individualized starting dose according to the baseline body weight and platelet count was utilized in the majority of patients in NORA trial aiming to decrease incidence of AE while maintaining efficacy.

Methods

NORA was conducted in 32 hospitals in China. Eligible patients were women aged ≥ 18 years with PSROC who had either germline BRCA mutation or high-grade serous histologic features, and a complete or partial response after completion of the last round of platinum therapy. Patients were randomly allocated (2:1) to receive oral niraparib or placebo at 300mg once daily. After a protocol amendment in December 2017, the starting dose was subsequently changed to an individualized dosing regimen of 200 mg except for those with a baseline body weight >77kg and a platelet count >150K/μL in which case the starting dose is 300 mg. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review.

Results

In total, 265 patients were randomized and included in the intent-to-treat (ITT) efficacy population. Of these, 249 patients (median body weight 61kg) received the individualized dosing of niraparib/placebo. Patients in the niraparib group had a significantly longer median PFS than did those in the placebo group, 18.3 vs. 5.4 months (HR=0.30; 95% CI, 0.21–0.43). The incidences of grade ≥3 treatment emergent AEs and ≥ 3 grade hematological AEs of neutrophil count decreased, platelet count decreased and anemia were 48.8% vs 20.5%, 19.9% vs 8.4%, 8.4% vs 1.2%, 13.9% vs 2.4% in niraparib group and placebo arm, respectively.

Conclusions

This is the first study to demonstrate the efficacy and safety of niraparib in Chinese patients with PSROC. Individualized starting dosing of niraparib is effective and safe and should be considered standard clinical practice in this patient population, especially in Asian patients with low body weight.

Clinical trial identification

NCT03705156

Editorial acknowledgement

This study was funded by Zai Lab. The study was also partially supported by the National Major Scientific and Technological Special Project for “Significant New Drugs Development” in 2018 (No. 2018ZX09736019), China, and Shanghai Municipal Commission of Economy and Infomatization (No. 18XI-24).

Background

International Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644) found that pts with newly diagnosed advanced OC who received mx ola in addition to standard first-line platinum-based chemotherapy (PBC) plus bev had a statistically significant progression-free survival (PFS) benefit (HR 0.59; 95% CI 0.49–0.72; Ray-Coquard et al. NEJM 2019). Here we present results of the Japan subset.

Methods

Pts had newly diagnosed, FIGO stage III–IV, high-grade OC, fallopian tube or primary peritoneal cancer and were in clinical complete or partial response following PBC + bev. Pts were randomised (2:1) to ola tablets (300 mg bid for up to 24 months [m]) + bev (15 mg/kg d1, q3w for up to 15 m in total) or placebo (pbo) + bev, stratified by treatment outcome and tumour BRCA mutation (tBRCAm) status. Primary endpoint was investigator-assessed PFS (modified RECIST v1.1).

Results

24 pts were randomised, 15 to ola + bev and 9 to pbo + bev. Pt characteristics, including tBRCAm and homologous recombination deficiency (HRD) status were generally well balanced; 20% vs 22% of pts had a tBRCAm in the ola + bev vs pbo + bev arms and 67% had an HRD positive test result in each arm. Median follow up was 27.7 m in the ola + bev arm vs 24.0 m in the pbo + bev arm. Median PFS was 27.4 m (11.1–not reached) in the ola + bev arm vs 19.4 m (3.1–24.0) in the pbo + bev arm (Table).

Grade ≥3 adverse events (AEs) were reported by 73% vs 33% of pts in the ola + bev and the pbo + bev arms, respectively; the most common were anaemia (n=5 vs n=0) and leukopenia (n=4 vs n=0). AEs led pts to dose interruptions (73% vs 44%), reductions (60% vs 0%) and discontinuations (27% vs 11%) in the ola + bev vs the pbo + bev arms, respectively.

Conclusions

In the Japan subset of PAOLA-1, the efficacy results were generally consistent with the overall efficacy results, and the proportion of pts who had a grade ≥3 AE was generally higher than in the overall population. A limitation of this subgroup analysis is the small number of pts.

Clinical trial identification

NCT02477644

Editorial acknowledgement

Medical writing assistance was provided by Laura Smart, MChem, of Mudskipper Business Limited

Background

For ovarian cancer patients with unresectable disease, neoadjuvant chemotherapy (NACT) plus interval debulking surgery (IDS) is an important treatment option. Previously, we reported that hyperthermic intraperitoneal chemotherapy (HIPEC) could be used in the neoadjuvant setting. In this retrospective cohort study, we sought to investigate whether the use of NHIPEC could improve patient outcomes compared with traditional intravenous NACT for patients with high-grade serous ovarian cancer (HGSOC).

Methods

HGSOC patients who received NACT-IDS between 2012 to 2019 were identified. Tumor response to NACT was evaluated with the chemotherapy response score (CRS) system. The effects of NACT modality on survival outcomes were assessed using the Kaplan-Meier method and multivariable regression analysis.

Results

Of the 106 included patients, 38 (35.8%) received NHIPEC (one cycle) + intravenous NACT (two cycles), while 68 (64.2%) received intravenous NACT (three cycles). The use of NHIPEC was independently associated with an increased likelihood of CRS3 [odd ratio = 6.99; 95% confidence interval (CI), 1.95 to 25.01, P = 0.003]. The median progression-free survival (PFS) was 21 months for patients treated with NHIPEC + intravenous NACT versus 16 months for patients treated with intravenous NACT [hazard ratio (HR) 0.57; 95% CI, 0.33 to 0.99, P = 0.048). Median overall survival (OS) was not reached, and no association was found between NACT types and OS (HR 1.41; 95% CI, 0.49 to 4.06, P = 0.526). NHIPEC was not associated with an increased risk of adverse events.

Conclusions

The application of the NHIPEC was associated with an improved tumor response and PFS. It could be considered as a treatment option for HGSOC patients who are not suitable for upfront cytoreduction.

Background

Platinum-sensitive is an important basis for the treatment of recurrent epithelial ovarian cancer (EOC) without effective methods to predict. We aimed to develop and validate the EOC deep learning system to predict the platinum-sensitive of EOC patients through analysis of enhanced magnetic resonance imaging (MRI) images before initial treatment.

Methods

Ninety-three EOC patients received platinum-based chemotherapy (>= 4 cycles) and debulking surgery from Sun Yat-sen Memorial Hospital in China from January 2011 to January 2020 were enrolled. We defined platinum-resistant and platinum-refractory patients as platinum-resistant group, and patients who relapsed 6 months or more after initial platinum-base chemotherapy as platinum-sensitive group. Patients were collected and randomly assigned (2:1) to the training and validation cohorts. A deep learning model-Med3D (Resnet 10 version) was first applied to two MRI sequences (T1+C, T2WI) to automatically extract 1024 features of each patient, then established signatures to predict platinum-resistance.

Results

The area under curve (AUC) of the whole MRI volume signature yielded was 0.97, 0.98 for the training and validation cohorts, respectively, which was better than that with the primary tumor signature (AUC 0.78 and 0.85 in training and validation cohorts, respectively). The whole MRI volume signature sensitivity was 0.96 in identifying platinum-sensitive in training cohort, and validated in 0.96(95%CI 0.88-1.0) in the validation cohort. The whole MRI volume signature was superior sensitivity than with MRI primary tumor signature (0.86 and 0.84 [95%CI 0.70-0.98] in training and validation cohort, respectively). The whole MRI volume signature’s specificity was 0.92 and 1 (95%CI 1.0-1.0) in the training and validation cohorts. The primary tumor MRI signature’s specificity was 0.77 and 0.66 (95%CI 0.28-1.0) in the training and validation cohorts.

Conclusions

This deep-learning EOC signature achieved a high predictive power for platinum-sensitive, and the signature based on MRI whole volume is better than that on primary tumor area only.