Abstract

Objective: This review aimed to systematically synthesize and report the clinical outcomes of poly-ADP ribose polymerase inhibitors (PARPis) for maintenance therapy among ovarian cancer (OC) patients.

Methods: This review was based on the updated PRISMA statement 2020. Eligible studies were identified from PubMed and the Cochrane Library from the database inception to October 7, 2021. Randomized controlled trials reporting the clinical outcomes of PARPis as maintenance therapy for OC were included in this review. The Risk of Bias 2 tool was used for the quality assessment of studies.

Results: Out of 26 studies, 10 were eligible. For patients with newly diagnosed disease, compared with placebo, either olaparib or niraparib considerably prolonged progression-free survival (PFS), with hazard ratios (HRs) of 0.59 (95% confidence interval [CI]: 0.49–0.72) and 0.62 (95% CI: 0.50–0.76), respectively. Among recurrent patients, olaparib, niraparib, and rucaparib also achieved higher PFS than placebo, with HRs of 0.39 (95% CI: 0.27–0.55), 0.32 (95% CI: 0.23–0.45), and 0.35 (95% CI: 0.28–0.45), respectively. Regarding adverse events, patients taking PARPis experienced a higher risk of hematologic events than the placebo group.

Conclusions: PARPis as maintenance therapy were beneficial in PFS improvement for OC patients. However, the considerable risk of hematologic events must be considered when using this treatment class.

Introduction

In 2020, ovarian cancer (OC) was the eighth most common malignancy in women, with an incidence of 314,0001. Given its lack of specific symptoms, OC is often detected at later stages, making it the most lethal gynecological cancer, with a 49% five-year survival rate (2011–2017)2, 3, 4. The currently recommended treatment for advanced OC is neo-adjuvant therapy followed by cytoreductive surgery and subsequent adjuvant chemotherapy with platinum compounds (a combination of carboplatin and paclitaxel or docetaxel)5. Although platinum-based chemotherapy has a good response rate, approximately 80% of patients have advanced-stage OC within 18 months6. Therefore, new therapies are needed to improve responsiveness and prolong survival in advanced OC patients.

Poly-ADP ribose polymerase inhibitors (PARPis) are among the most promising therapeutic maintenance treatments for OC7. PARP is a protein family required to repair single-strand breaks by base excision repair. PARP includes PARP1—the best-known—and PARP2. All PARPis currently being developed are believed to block both PARP1 and PARP28. PARPis block SSB repair and lead to the formation of DNA double-strand breaks that cannot be correctly repaired in homologous recombination-deficient (HRD) tumors, such as those with deleterious mutations in breast cancer genes BRCA1 and BRCA2. These are the genes most at risk of HRD expression, which causes the accumulation of DNA aberrations and leads to the synthetically lethal phenotype in cancer cells9.

The Food and Drug Administration and European Medicine Agency have licensed the use of olaparib, olaparib, and rucaparib for advanced OC10. Few systematic reviews have examined PARPis regarding their efficacy and safety in OC treatment11, 12, 13, 14, 15, 16, 17. Given the latest published study on the efficacy of niraparib, conducted at 30 centers in China by Wu et al.18, this systematic review aimed to update the current evidence on the efficacy and safety of PARPis in OC maintenance treatment.

Methods

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement (see Appendix 3 for the PRISMA checklist) 19.

Study selection

For inclusion in this review, studies needed to meet the following criteria: (i) targeted advanced OC; (ii) the intervention arm was PARPi monotherapy or PARPi in combination with chemotherapy; (iii) the comparison arm was either placebo or chemotherapy or chemotherapy plus placebo; (iv) reported survival outcomes, with or without adverse events (AEs) or health-related quality of life (HRQoL); (v) designed as phase II or III randomized control trials (RCTs).

Search method

RCTs were searched in PubMed and the Cochrane Library up to October 7, 2021. Additionally, the website https://clinicaltrials.gov/ was considered for unpublished relevant trials that presented outcomes of interest. Data were searched using key terms including “ovarian neoplasms,” “PARP inhibitors,” “olaparib,” “niraparib,” “rucaparib,” “randomized controlled trial”, and “controlled clinical trial”. The full search strategies are presented in Appendix 1.

Article screening process

Articles identified from the databases were initially imported into EndNote to remove duplicates. Two independent reviewers (PNNQ, HTN) conducted title and abstract screening using Rayyan20. The two reviewers then retrieved and reviewed potential full-text papers to determine the articles eligible for the review. The third reviewer (KD) was consulted to address any conflicts.

Data synthesis

Data from all eligible articles were extracted. In trials with more than one publication, data from the most updated publication were extracted. The extracted information covered the study design, the characteristics of the intervention or comparison, and the overall treatment outcomes and associated factors. This process was carried out by two independent reviewers (PNNQ, HTN), and any conflicts were addressed via discussions or reassessed by the third reviewer (KD).

Methodological quality assessment

The Cochrane Risk of Bias tool version 2 (RoB 2) was employed21. The tool consists of five aspects: (i) the randomization process; (ii) any deviations from the intended interventions; (iii) missing outcome data; (iv) the measurement of the outcome; (v) the selection of the reported result. The assessment result was assigned as “low risk”, “high risk”, or “some concerns.” Two reviewers (PNNQ, HTN) performed the assessment independently, and any discrepancies were resolved by consensus.

× Figure 1 . PRISMA flow diagram of trials selection. Figure 1 . PRISMA flow diagram of trials selection. Results Study selection

The search located 788 records. Of these, 119 were removed due to duplication, and 669 were screened based on their titles and abstracts. The full texts of 26 articles were retrieved and screened. Finally, 22 articles from 10 RCTs were included in the analysis (Figure 1).

Trial characteristics

Two of the 10 RCTs were phase II trials22, 23, 24, 25, and the others were phase III18, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. One trial had an open-label design22, whereas the others were double-blind studies18, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40. The SOLO126, 27 and SOLO231, 32, 33 studies included only OC patients with a BRCA mutation, whereas the other eight included all OC patients regardless of their BRCA status18, 22, 23, 24, 25, 28, 29, 30, 34, 35, 36, 37, 38, 39, 40. In those eight studies, 25.3% to 51.3% of patients had the BRCA mutation. Four studies evaluated PARPis in newly diagnosed OC patients, of which two used olaparib26, 28, one used niraparib29, and one used veliparib30. The SOLO126, 27 and PRIMA29 studies compared PARPi monotherapy to placebo, and the PAOLA128 and VELIA30 studies compared a PARPi in combination with bevacizumab or platinum-based chemotherapy. Six studies evaluated PARPis in recurrent OC patients. Of these, Oza et al.22 compared olaparib plus chemotherapy followed by maintenance with olaparib versus chemotherapy alone, whereas the remaining studies, comprising STUDY1923, 24, 25, SOLO231, 32, 33, NOVA34, 35, 36, 37, NORA18, and ARIEL338, 39, 40, compared PARPi monotherapy versus placebo. NORA18 was a dose-adjustment study of niraparib in each patient population based on the weight index and platelet count per all. Table 1 presents the specific characteristics of the selected trials.

Table 1.

Main characteristic of included studies

Study, Year of Publication Setting Study design Intervention arm (no. patient) Control arm (no. patient) No. patient mBRCA (%) HR of PFS (95% CI, p value) HR of OS (95% CI, p value) First-line maintenance treatment SOLO1, 2018 31 , 33 International Phase III, double-blind olaparib 300 mg twice daily (tablets) (260) placebo (131) 391 (100) 0.30 (0.23 – 0.41, p 0.95 (0.6 – 1.53) PAOLA1, 2019 28 International Phase III, double-blind olaparib 300 mg twice daily (tablets) plus bevacizumab (537) bevacizumab (269) 241 (29,9) 0.59 (0.49 – 0.72, p - PRIMA, 2019 29 International Phase III, double-blind niraparib 300 mg once daily (487) placebo (246) 223 (30,4) 0.62 (0.50 – 0.76, p 0.70 (0.44 – 1.11) VELIA, 2019 30 International Phase III, double-blind veliparib 150 mg twice daily plus pc and carboplatin followed by veliparib 300/400 mg twice daily maintenance (the veliparib-throughout group) (382); placebo plus pc followed by placebo maintenance (375) 298 (26,1)