Courtney Marabella

First-line maintenance treatment with the PARP inhibitor niraparib (Zejula) yielded a clinically meaningful and statistically significant improvement in progression-free survival (PFS) vs placebo in Chinese patients with platinum-responsive advanced ovarian cancer, regardless of biomarker status, according to topline data from the phase 3 PRIME trial (NCT03705156) released by Zai Lab Limited.

Results showed that the study met its primary end point of PFS and demonstrated a tolerable safety profile in those with newly diagnosed advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer, following a response to platinum-based chemotherapy.

“I believe the data of the PRIME study will have a significant impact on the clinical practice in the first-line treatment of ovarian cancer in China and beyond, as the individualized starting dose regimen has demonstrated an improved safety profile,” Lingying Wu, PhD, director of the Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, said in a press release. “In addition, the PRIME study is the only study conducted in China that has demonstrated that a PARP inhibitor significantly improved PFS when given as monotherapy maintenance therapy in all Chinese patients with newly diagnosed ovarian cancer, regardless of biomarker status.”

The PRIME study enrolled 384 patients with advanced ovarian cancer who achieved a complete response (CR) or partial response (PR) to first-line platinum-based chemotherapy. Patients were randomized 2:1 to receive niraparib or placebo until disease progression. The starting dose of niraparib was individualized at 200 mg except for in patients with a baseline body weight 77 kg or more and a platelet count of 150K/μL or more, in which case the starting dose increased to 300 mg.

The primary end point of the study was PFS as assessed by blinded independent central review. Secondary end points included chemotherapy-free interval, time to first subsequent anti-cancer treatment, and overall survival.

Niraparib is an oral, once-daily PARP inhibitor that has shown promising activity in prior studies in patients with ovarian cancer. In September 2020, the China National Medical Products Administration (NMPA) 

approved a supplemental new drug application for the agent

 as a frontline maintenance treatment for adult patients with advanced ovarian cancer who achieved a CR or PR to first-line platinum-based chemotherapy.

Niraparib was also approved as a maintenance treatment for adult patients with high-grade serous epithelial ovarian cancer who achieved a CR or PR to first-line platinum-based chemotherapy by the Hong Kong Department of Health.

Currently, Zai Lab Limited is seeking National Reimbursement Drug List (NRDL) inclusion for niraparib for a first-line ovarian cancer indication. Additionally, the agent is being examined in China in a phase 1b/2 trial (NCT04178460) in combination with tebotelimab for the treatment of patients with advanced gastric cancer, triple-negative breast cancer, biliary tract cancer, and endometrial cancer.

“The PRIME clinical data in Chinese patients confirmed the clinical profile of niraparib and were consistent with the results seen in the global PRIMA study [NCT02655016],” Alan Sandler, MD, president and head of Global Development, Oncology, Zai Lab, said in a press release. “Importantly, the PRIME study further underscores the status of niraparib as the first and only PARP inhibitor approved globally, including in China, as monotherapy for all-comer patients in the first-line maintenance treatment settings.”

This article was initially published by our sister publication Onc Live.

Zai Lab announces positive topline results from phase 3 PRIME study of ZEJULA (niraparib) as first-line monotherapy maintenance treatment in Chinese women with platinum-responsive advanced ovarian cancer. News release. Zai Lab Limited. November 30, 2021. Accessed November 30, 2021. 

Clinical trial evaluating the efficacy and safety of ZL-2306 (niraparib) in ovarian cancer patient. clinicaltrials.gov. Updated October 15, 2021. Accessed November 30, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03705156

A study of niraparib combined with MGD013 in patients with advanced or metastatic solid tumor who failed prior treatment. clinicaltrials.gov. Updated April 1, 2021. Accessed November 30, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04178460

Articles

First-line maintenance treatment with the PARP inhibitor niraparib yielded a clinically meaningful and statistically significant improvement in progression-free survival vs placebo in Chinese patients with platinum-responsive advanced ovarian cancer, regardless of biomarker status, according to data from the phase 3 PRIME trial.

Niraparib Demonstrates PFS Benefit in Chinese Population With Advanced Ovarian Cancer

Sacituzumab govitecan-hziy (Trodelvy) resulted in a statistically significant and clinically meaningful improvement in health-related quality of life (HRQoL) compared with single-agent chemotherapy of physician’s choice (TPC) in patients with metastatic triple-negative breast cancer (mTNBC), according to data from an analysis of the phase 3 ASCENT trial (NCT02574455) presented during the 

Results indicated that although the sacituzumab govitecan arm experienced greater symptomatology than the TPC arm with respect to nausea/vomiting and diarrhea, this did not appear to translate to an adverse impact on functioning or global health status/QoL domains at the cohort level.

Moreover, the antibody-drug conjugate (ADC) resulted in a significant prolongation of time to first deterioration in all HRQoL domains except for global health status/QoL; the agent also significantly reduced the time to improvement in physical functioning and pain.

“In patients with refractory or relapsed mTNBC cancer after [at least 2] prior lines of therapy [at least 1 in the metastatic setting], sacituzumab govitecan not only significantly extended progression-free survival [PFS] and overall survival [OS] compared [with] TPC, but also maintained or improved HRQoL,” Sibylle Loibl, MD, PhD, of the Department of Medicine and Research at Hämatologisch-Onkologische Gemeinschaftspraxis am Bethanien-Krankenhaus, and colleagues wrote in the poster on the data.

Sacituzumab govitecan is an ADC composed of an anti–Trop-2 antibody coupled with SN-38 through a proprietary hydrolysable linker. The agent was compared with TPC in the phase 3 ASCENT trial, which enrolled patients with refractory or relapsed mTNBC who had received at least 2 prior lines of therapy, including 1 in the metastatic setting. To be eligible for participation, patients had to have an ECOG performance status of 0 or 1.

Study participants were randomized 1:1 to receive either sacituzumab govitecan on days 1 and 8 of every 21-day cycle (n = 267) or TPC in the form of either capecitabine, eribulin, vinorelbine, or gemcitabine (n = 262). The schedules for TPC varied between the agents used. Treatment in both arms was continued until either disease progression or unacceptable toxicity.

Earlier results from the intent-to-treat (ITT) analysis showed that sacituzumab govitecan significantly improved PFS vs TPC, at 4.8 months and 1.7 months, respectively (HR, 0.41; 95% CI, 0.32-0.52; P < .0001); the ADC also significantly prolonged OS, at 11.8 months and 6.9 months, respectively (HR, 0.51; 95% CI, 0.41-0.62; 

For the analysis presented during the 2021 ESMO Congress, investigators sought to assess the impact of sacituzumab govitecan on HRQoL in the patients enrolled to ASCENT. The key objective of the analysis was to identify whether HRQoL was comparable between the arms over the course of treatment.

HRQoL was assessed at baseline, within 28 days of cycle 1 day 1, as well as on day 1 of each cycle, and at the final study visit, which was 4 weeks after a patient’s last study dose, or at premature study termination. The European Organization for Research and Treatment of Cancer Quality of Life Core 30 Questionnaire (EORTC QLQ-C30) was utilized to evaluate HRQoL.

Global health status/QoL, physical functioning, role functioning, pain, and fatigue were selected as the primary HRQoL domains because of their clinical relevance to the target population, and the rest of the EORTC QLQ-C30 domains were examined as secondary domains. An increased score for global health status/QoL and functioning domains were indicative of improvement, as an increased score for the symptom domains was indicative of worsening.

The analyses were based on the HRQoL-evaluable population, or all patients in the ITT population who had an evaluable assessment of the EORTC QLQ-C30 at baseline and at least 1 post-baseline assessment. Linear mixed-effect models for repeated measures were utilized to examine between-group differences in data collected up to cycle 6, adjusting for baseline scores, treatment, visit, and stratification factors.

Least-square mean changes from baseline in HRQoL scores were estimated for sacituzumab govitecan and TPC and were compared between the arms. Moreover, to examine the noninferiority and superiority of the ADC vs TPC, minimal important difference values based on previously published thresholds were applied.

Furthermore, time to first clinically meaningful improvement or deterioration of HRQoL was analyzed via the Kaplan-Meier product limit method. Cox proportional hazards regression models were used to estimate hazard ratios for first clinically meaningful improvement or deterioration of HRQoL for both arms. The models were adjusted for baseline score and were stratified by number of prior treatments for advanced disease (2 or 3 vs more than 3), geographic region (North America vs rest of the world), and known brain metastases at study entry (yes vs no).

Among those included in the HRQoL population, 236 had received sacituzumab govitecan and 183 patients received TPC. In the HRQoL-evaluable population, the 2 arms were noted to be well balanced with respect to demographics and baseline clinical characteristics.

Across the arms, the median age of patients was 54.7 years in both treatment arms. Additionally, the majority of patients in the investigative and control arms were White (82.6% vs 76.0%, respectively), had received 2 or 3 lines of prior therapy (71.2% and 72.1%), did not have brain metastases (88.6% and 90.2%), were based in North America (64.8% and 65.0%), were 

The completion rate, or number of valid HRQoL assessments divided by number of ITT patients expected to provide a HRQoL assessment, was 90% or higher up to cycle 6 and was found to be comparable between the treatment arms. However, the available data rate, or number of valid HRQoL assessments divided by the ITT patients randomized at the start of the study, was noted to decline in both arms; however, this rate proved to be consistently higher in the sacituzumab govitecan arm vs the TPC arm.

Mean baseline scores for the primary HRQoL domains were generally comparable between the arms. The mean global health status/QoL score in patients treated with the ADC was 63.2 vs 58.1 in the TPC arm, and the physical functioning and role functioning scores were 74.9 vs 73.0, respectively, and 69.6 vs 67.9, respectively. The score for pain in the sacituzumab govitecan arm was 36.4 vs 40.3 in the TPC arm, and the scores for fatigue were 38.3 and 40.1, respectively.

In terms of secondary HRQoL domains, sacituzumab govitecan induced more instances of nausea/vomiting and diarrhea but was noninferior in all other domains. Additionally, sacituzumab govitecan was also superior to TPC in terms of emotional functioning, dyspnea, and insomnia.

Notably, sacituzumab govitecan had a statistically significantly better overall mean change, as well as changes at 1 or more assessments, for each of the primary HRQoL domains. The overall mean change from baseline for the primary HRQoL domains for sacituzumab govitecan vs TPC were as follows:

: 0.66 (-2.21 to 3.53) vs -3.42 (-6.77 to -0.08)

: 1.31 (-1.38 to 3.99) vs -4.39 (-7.52 to -1.26)

: -2.24 (-6.13 to 1.65) vs -7.83 (-12.41 to -3.25)

: 1.97 (-1.20 to 5.13) vs 7.13 (3.40 to 10.87)

: -8.93 (-12.57 to -5.30) vs -1.89 (-6.18 to 2.40)

Time to first clinically meaningful deterioration was significantly longer for sacituzumab govitecan compared with TPC with respect to physical functioning (22.1 weeks vs 12.1 weeks, respectively), role functioning (11.4 weeks vs 7.1 weeks), fatigue (7.7 weeks vs 6.0 weeks), and pain (21.6 weeks vs 9.9 weeks).

The only primary HRQoL domain where sacituzumab govitecan was not superior to TPC in terms of time to first clinically meaningful deterioration was global health status/QoL, at 14.1 weeks vs 15.1 weeks, respectively. Moreover, the time to first clinically meaningful improvement in physical functioning and pain was shorter with sacituzumab govitecan.

Loibl S, Loirat D, Tolaney SM, et al. Health-related quality of life (HRQoL) in the ASCENT study of sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC). 

; 2021;32(5) S457-S515. doi:10.1016/annonc/annonc689

Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. 

. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

This article was originally posted on Onc Live®. 

Sacituzumab govitecan-hziy resulted in a statistically significant and clinically meaningful improvement in health-related quality of life compared with single-agent chemotherapy of physician’s choice in patients with metastatic triple-negative breast cancer.

Courtney Marabella

Articles

Niraparib Demonstrates PFS Benefit in Chinese Population With Advanced Ovarian Cancer

Sacituzumab govitecan-hziy improves quality of life in patients with metastatic triple-negative breast cancer