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GYNECOLOGIC CANCER: Edited by Gottfried E. Konecny

Latest clinical evidence of maintenance therapy in ovarian cancer

Walsh, Christine S.

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Current Opinion in Obstetrics and Gynecology: February 2020 - Volume 32 - Issue 1 - p 15-21
doi: 10.1097/GCO.0000000000000592
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Abstract

INTRODUCTION

In a rapidly evolving treatment landscape, data now support the use of maintenance therapy in epithelial ovarian cancer. The purpose of this review is to summarize the clinical trial evidence that has led to this changing treatment paradigm. The term ‘ovarian cancer’ in this review refers to the spectrum of epithelial cancers arising from the ovaries, fallopian tubes and peritoneum.

Administration of maintenance therapy is currently appropriate at two time-points in the ovarian cancer disease course, after up-front treatment for initial diagnosis of stage III or IV disease and after treatment for platinum-sensitive recurrence (defined as less than recurrence greater than 6 months from prior platinum-based chemotherapy).

There are two classes of medications that are currently approved for maintenance therapy administration in the United States. Bevacizumab is an antiangiogenic therapy that targets vascular endothelial growth factor. Olaparib, niraparib, rucaparib and veliparib belong to a class of medications that target poly (adenosine diphosphate-ribose) and are known as PARP inhibitors. Data suggest that PARP inhibitors have enhanced efficacy in ovarian cancer subpopulations with BRCA mutations or other mechanisms that lead to homologous recombination deficiency (HRD).

Box 1
Box 1:
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Current Food and Drug Administration approvals and new data supporting maintenance therapy in ovarian cancer

Since December 2016, the United States Food and Drug Administration (FDA) has approved six different treatments for use in maintenance therapy of ovarian cancer. Four approvals are for use in the platinum-sensitive recurrence setting and two approvals are for use in the upfront treatment setting (Table 1).

Table 1
Table 1:
Timeline of Food and Drug Administration approvals for maintenance therapies in ovarian cancer

In patients with platinum-sensitive recurrent ovarian cancer, the FDA has approved the use of bevacizumab, niraparib, olaparib and rucaparib as options for maintenance therapy. Bevacizumab was approved on 12/6/2016 to be given either in combination with carboplatin and paclitaxel (based on data from GOG-0213 [1▪]) or with carboplatin and gemcitabine (based on data from OCEANS [2]) chemotherapy, followed by bevacizumab maintenance treatment. Niraparib was approved on 3/27/2017 (based on data from NOVA [3]), olaparib was approved on 8/17/2017 (based on data from Study 19 [4,5] and SOLO2 [6▪]) and rucaparib was approved on 4/6/2018 (based on data from ARIEL3 [7▪]). All three PARP inhibitors are approved for maintenance treatment of recurrent epithelial ovarian cancer who are in complete or partial response to platinum-based chemotherapy. There is no biomarker restriction for these approvals.

In patients with newly diagnosed ovarian cancer, the FDA has approved the use of bevacizumab and olaparib for maintenance therapy. Bevacizumab was approved on 6/13/2018 for use in combination with carboplatin and paclitaxel chemotherapy followed by single-agent bevacizumab maintenance for stage III and IV ovarian cancer after initial surgical resection (based on data from GOG-0218 [8]). Olaparib was approved on 12/19/2018 for maintenance treatment of patients with germline or somatic BRCA mutations and advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy (based on data from SOLO1 [9▪▪]).

At the time of this writing (October 2019), three new trials supporting maintenance treatment in the initial ovarian cancer diagnosis setting were presented at the European Society for Medical Oncology (ESMO) meeting, which took place from 9/27/2019 to 10/1/2019 in Barcelona, Spain. The PRIMA study evaluated the use of niraparib maintenance after platinum-based chemotherapy, regardless of BRCA mutation status [10▪▪]. The VELIA/GOG-3005 study evaluated the addition of veliparib to front-line chemotherapy followed by veliparib maintenance therapy, also regardless of BRCA mutation status [11▪▪]. The PAOLA-1 trial evaluated patients who received chemotherapy and bevacizumab upfront therapy and compared the efficacy of maintenance therapy with bevacizumab with or without the addition of olaparib [12▪▪]. All three trials reported positive results and are likely to change the current landscape of FDA drug approvals.

The remaining review will summarize these seminal clinical trials. Efficacy results are summarized in Tables 2 and 3 and include median progression-free survival (PFS), hazard ratios and 95% confidence interval (CI) for each analysis.

Table 2
Table 2:
Efficacy data for maintenance therapy options after platinum-sensitive recurrence
Table 3
Table 3:
Efficacy data for maintenance therapy options after initial ovarian cancer diagnosis

OCEANS and GOG-0213: bevacizumab in recurrent ovarian cancer

OCEANS (NCT00434642) [2] demonstrated the addition of bevacizumab to a carboplatin and gemcitabine backbone improved PFS (12.4 versus 8.4 months, hazard ratio 0.48, 95% CI 0.39–0.61). There was no difference in overall survival (OS) [13]. The most common grade 3 and 4 adverse events included hypertension (17.4%) and proteinuria (8.5%). Twenty percent of patients discontinued bevacizumab because of toxicities.

GOG-0213 (NCT00565851) [1▪] demonstrated the addition of bevacizumab to a carboplatin and paclitaxel backbone improved PFS (13.8 versus 10.4 months, hazard ratio 0.63, 95% CI 0.53–0.74) and OS (42.2 versus 37.3 months, adjusted hazard ratio 0.82, 95% CI 0.68–0.996). The most common grade 3 and 4 adverse events included blood/bone marrow toxicity (86%), metabolic/laboratory abnormalities (20%) and cardiac adverse events (14%). Twenty-five percent of patients discontinued bevacizumab because of an adverse event.

NOVA: niraparib in recurrent ovarian cancer

In the NOVA/ENGOT-OV16 trial (NCT01847274) [3], patients with recurrent ovarian cancer were randomized in a 2 : 1 ratio to receive either niraparib maintenance therapy at a dose of 300 mg daily or placebo in 28-day cycles. Among 553 patients enrolled, 203 carried a germline BRCA mutation (gBRCA) and 350 did not (nongBRCA) determined by BRACAnalysis testing (Myriad Genetics). Tumor tissue was tested with myChoice HRD (Myriad Genetics) to determine HRD-positivity among the nongBRCA cohort [14].

Among all subgroups analyzed, PFS was longer with niraparib maintenance therapy. The magnitude of benefit was greatest in the gBRCA cohort (PFS 21.0 versus 5.5 months, hazard ratio 0.27, 95% CI 0.17–0.41). Benefit was also seen in the nongBRCA, HRD+ cohort (PFS 12.9 versus 3.8 months, hazard ratio 0.38, 95% CI 0.24–0.59) and in the overall nongBRCA cohort (PFS 9.3 versus 3.9 months, hazard ratio 0.45, 95% CI 0.34–0.61). Modest activity was seen in the HRD-negative cohort (PFS 6.9 versus 3.8 months, hazard ratio 0.58, 95% CI 0.36–0.92).

Niraparib was associated with moderate bone marrow toxicity. The most common grade 3+ adverse events included thrombocytopenia (33.8%), anemia (25.3%), neutropenia (19.3%), fatigue (8.2%) and hypertension (8.2%). Adverse events occurring in more than 20% included nausea, thrombocytopenia, fatigue, anemia, constipation, vomiting, neutropenia, headache, decreased appetite, insomnia and abdominal pain. Most of the hematologic adverse events occurred within the first three treatment cycles and could be managed with dose adjustments. Myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML) occurred in 1.4% of patients receiving niraparib and in 1.1% receiving placebo. 14.7% of patients discontinued niraparib because of adverse events.

Study 19 and SOLO2: olaparib in recurrent ovarian cancer

Study 19 (NCT00753545) [4] was a randomized, double-blind, placebo-controlled phase 2 trial. In total, 265 patients were randomized in a 1 : 1 ratio to receive either olaparib capsules at a dose of 400 mg twice daily or placebo. Approximately 22% of the participants carried a germline BRCA mutation. Patients receiving olaparib maintenance had longer median PFS of 8.4 versus 4.8 months (hazard ratio 0.35, 95% CI 0.25–0.49).

In a subsequent preplanned retrospective analysis [5], the subgroup of patients with a BRCA mutation were found to have the greatest PFS benefit with olaparib maintenance (PFS 11.2 versus 4.3 months, hazard ratio 0.18, 95% CI 0.10–0.31). Among the non-BRCA cohort, the PFS difference was 7.4 versus 5.5 months (hazard ratio 0.54, 95% CI 0.34–0.85). OS was significantly improved with olaparib in the BRCA+ cohort (34.9 versus 30.2 months, hazard ratio 0.62, 95% CI 0.41–0.94) but was not different in the non-BRCA cohort (24.5 versus 26.6 months, hazard ratio 0.83, 95% CI 0.55–1.24). The authors note the original study was not powered to assess OS and that this analysis should be considered descriptive [15].

SOLO2 evaluated olaparib maintenance therapy using a tablet formulation, which reduced the pill burden from 16 capsules to 4 tablets per day. In total, 295 BRCAm patients were randomized 2 : 1 to receive olaparib tablets at a dose of 300 mg twice daily or placebo. Olaparib resulted in longer PFS (19.1 versus 5.5 months, hazard ratio 0.30, 95% CI 0.22–0.41).

The most common grade 3 and 4 adverse events with olaparib tablets were anemia (19%) and neutropenia (5%). Adverse events occurring in more than 20% of patients included nausea, fatigue/asthenia, anemia, vomiting, diarrhea, dysgeusia, headache, abdominal pain, decreased appetite and constipation. Eleven percent of patients discontinued olaparib because of adverse events. There was one case of treatment-related AML that led to death in the olaparib arm. During long-term follow-up, AML/MDS/chronic myeloid leukemia events were diagnosed in 2% who received olaparib and 4% who received placebo.

ARIEL3: rucaparib in recurrent ovarian cancer

In ARIEL3 (NCT01968213) [7▪], germline BRCA mutation status was assessed with the BRCAnalysis CDx test (Myriad Genetics) and tumor tissue samples were assayed with the T5 next-generation sequencing assay (Foundation Medicine) to detect mutations in homologous recombination pathway genes and to assess genomic loss of heterozygosity (LOH). A cutoff of 16% or greater was classified as LOH+ based on data from ARIEL2 part 1 [16]. In total, 540 patients were randomized in a 2 : 1 ratio to oral rucaparib 600 mg twice daily in 28-day cycles or placebo. Patients were treated until disease progression or unacceptable toxicity.

Rucaparib maintenance improved PFS across all analysis subgroups analyzed with the largest benefit seen in patients with germline or somatic BRCA mutations (PFS 16.6 versus 5.4 months, hazard ratio 0.23, 95% CI 0.16–0.34). In the HRD+ cohort (BRCAm or non-BRCA with high LOH), rucaparib improved PFS (13.6 versus 5.4 months, hazard ratio 0.32, 95% CI 0.24–0.42). In the intention-to-treat population, PFS was 10.8 versus 5.4 months (hazard ratio 0.36, 95% CI 0.30–0.45).

The most common grade 3 and 4 adverse events with rucaparib were anemia (19%), increased liver enzymes (10%), neutropenia (7%) and thrombocytopenia (5%). Adverse events occurring in at least 20% of patients included nausea, fatigue, dysgeusia, anemia, vomiting, constipation, increased liver enzymes, diarrhea, abdominal pain, thrombocytopenia and decreased appetite. MDS/AML were reported in 1% receiving rucaparib and 0% in the placebo group. Thirteen percent discontinued rucaparib because of adverse events.

GOG-0218: bevacizumab in newly diagnosed ovarian cancer

GOG-0218 evaluated the efficacy of adding bevacizumab dosed at 15 mg/kg to front-line chemotherapy and as maintenance in newly diagnosed advanced ovarian cancer [8]. In total, 1873 women were randomized to chemotherapy only (arm 1, control), chemotherapy combined with bevacizumab and no maintenance (arm 2, bevacizumab initiation) and chemotherapy combined with bevacizumab followed by bevacizumab maintenance for 16 additional cycles (arm 3, bevacizumab throughout). Median PFS in the three arms was 10.3 versus 11.2 versus 14.1 months (hazard ratio for arm 3 compared to arm 1 was 0.72, 95% CI 0.63–0.82). There was no difference in OS [17].

The most frequent adverse events with bevacizumab throughout included grade 4+ neutropenia (63.3%), grade 2+ pain (47.0%) and grade 2+ hypertension (22.9%). Other selected adverse events of interest included venous thromboembolism (6.7%), wound disruption (3.0%), grade 2+ gastrointestinal wall disruption events (2.6%), grade 3+ proteinuria (1.6%), arterial thromboembolism (0.7%) and reversible posterior leukoencephalopathy syndrome (0.2%). Hypertension was the only adverse event seen more commonly in the bevacizumab throughout arm and led to drug discontinuation in 2.4%. Adverse events reported more commonly with bevacizumab maintenance included hypertension, proteinuria and pain.

SOLO1: olaparib in newly diagnosed ovarian cancer

SOLO1 (NCT01844986) [9▪▪] was a randomized, double-blind, placebo-controlled, multicenter trial evaluating the efficacy of olaparib maintenance in patients with a BRCA mutation. In total, 391 patients were randomized in a 2 : 1 ratio to receive olaparib tablets at a dose of 300 mg twice daily or placebo. Treatment was continued until disease progression or to 2 years if patients were without evidence of disease. Those with partial response at 2 years were permitted to continue to receive therapy.

With 40 months follow-up, median PFS had not been reached among those receiving olaparib compared to 13.8 months in those receiving placebo (hazard ratio 0.30, 95% CI 0.23–0.41). PFS rate was higher in the olaparib group than placebo at 1 year (88 versus 51%), 2 years (74 versus 35%), 3 years (60 versus 27%) and 4 years (53 versus 11%). There was no difference in OS at 3 years at 21% data maturity (84 versus 80%). Crossover was not specified in the protocol.

The most common grade 3+ adverse events were anemia (22%) and neutropenia (9%). Toxicities occurring in at least 20% of patients included nausea, fatigue/asthenia, vomiting, anemia, diarrhea, constipation, dsygeusia, arthralgia, abdominal pain, neutropenia, headache, dizziness and decreased appetite. Twelve percent of patients discontinued olaparib because of adverse events. One percent developed AML with all cases occurring more than 30 days after discontinuation of olaparib. Two percent of patients on both arms developed subsequent new primary cancers.

PRIMA: niraparib in newly diagnosed ovarian cancer

The PRIMA/ENGOT-OV26/GOG-3012 trial (NCT02655016) [10▪▪] evaluated the efficacy of niraparib maintenance in newly diagnosed ovarian cancer. In total, 733 patients were enrolled, regardless of BRCA mutation status, and were randomized 2 : 1 to receive niraparib or placebo after achieving complete or partial response to six to nine cycles of first-line chemotherapy. Niraparib was initially dosed at 300 mg once daily, but the trial was later amended to allow patients to start at a dose of 200 mg once daily based on weight less than 77 kg or platelet count less than 150 000 per cubic millimeter [18▪]. Tumors were tested by myChoice (Myriad Genetics) for LOH, telomeric allelic imbalance and large-scale transitions. Scores of at least 42 (scale of 1–100) were considered HRD+.

PFS was longer with niraparib maintenance therapy in all subgroups analyzed. The benefit was greatest for BRCAm patients (PFS 22.1 versus 10.9 months, hazard ratio 0.40, 95% CI 0.27–0.62) and HRD+ patients (21.9 versus 10.4 months, hazard ratio 0.43, 95% CI 0.31–0.59). Benefit was seen even in the HRD-negative subset (8.1 versus 5.4 months, hazard ratio 0.68, 95% CI 0.49–0.94).

The most common grade 3+ adverse events were anemia (31%), thrombocytopenia (28.7%) and neutropenia (12.8%). Adverse events occurring in more than 20% of patients included anemia, nausea, thrombocytopenia, constipation, fatigue, neutropenia, headache, insomnia, vomiting and abdominal pain. There was one case of MDS in the group receiving niraparib. Twelve percent of patients discontinued niraparib because of toxicity.

VELIA/GOG-3005: veliparib in newly diagnosed ovarian cancer

The VELIA/GOG-3005 trial (NCT02470585) [11▪▪] evaluated the efficacy of veliparib in combination with front-line chemotherapy (six cycles) and as maintenance monotherapy (30 cycles) in newly diagnosed ovarian cancer. In total, 1140 patients were randomized 1 : 1:1 to chemotherapy/placebo + placebo (arm 1), chemotherapy/veliparib + placebo (arm 2) or chemotherapy/veliparib + veliparib (arm 3). Patients were assessed with the BRACAnalysis CDx or myChoice HRD CDx assay (Myriad Genetics). Tumors with HRD score of at least 33 were considered HRD+, revised from original threshold score of 42 based on retrospective analyses [19,20]. Veliparib was dosed at 150 mg daily during chemotherapy, 300 mg twice daily during a 2-week transition period and 400 mg twice daily during the maintenance phase.

Arm 3 demonstrated improved PFS compared to arm 1 across all subgroup analyses. In the BRCAm population, PFS was 34.7 versus 22.0 months (hazard ratio 0.44, 95% CI 0.28–0.68). In the HRD+ subgroup, PFS was 31.9 versus 20.5 months (hazard ratio 0.57, 95% CI 0.43–0.76). In the overall population, PFS was 23.5 versus 17.3 months (hazard ratio 0.68, 95% CI 0.56–0.83). PFS was measured from start of chemotherapy in this trial, which contrasts with the other PARP inhibitor maintenance trials where PFS is measured from end of chemotherapy. Arm 2 did not demonstrate improved efficacy compared to arm 1.

In arm 3, the most common grade 3+ adverse events included neutropenia (58%), anemia (38%), thrombocytopenia (28%) and leukopenia (18%). Adverse events occurring in more than 20% of patients included nausea, neutropenia, fatigue, peripheral sensory neuropathy, anemia, thrombocytopenia, alopecia, vomiting, diarrhea, constipation, abdominal pain, leukopenia, decreased appetite, insomnia, arthralgia, dizziness, headache, hypomagnesemia and dyspnea. There was one case of MDS in arm 2 and one case of AML in arm 3. In the maintenance phase, 19% of patients discontinued veliparib because of toxicities.

PAOLA-1: olaparib and bevacizumab in newly diagnosed ovarian cancer

Results from the PAOLA-1/ENGOT-OV25 trial (NCT02477644) [12▪▪] were reported at the 2019 ESMO Congress. In total, 806 patients with newly diagnosed advanced ovarian cancer were treated with upfront chemotherapy + bevacizumab and then randomized 2 : 1 to receive maintenance olaparib 300 mg twice daily + bevacizumab 15 mg/kg IV every 3 weeks for 15 months versus bevacizumab maintenance alone. In the overall population, the median PFS for olaparib/bevacizumab was 22.1 versus 16.6 months (hazard ratio 0.59, 95% CI 0.49–0.72). The benefit was greatest for the BRCAm subgroup with median PFS of 37.2 versus 21.7 months (hazard ratio 0.31, 95% CI 0.20–0.47). Benefit was also seen in HRD+ patients (excluding BRCA+) with PFS 28.1 versus 16.6 months (hazard ratio 0.43, 95% CI 0.28–0.66) but not in HRD-negative patients (PFS 16.9 versus 16.0 months, hazard ratio 0.92, 95% CI 0.72–1.17).

The most common adverse events reported were hypertension (19%) and anemia (17%). The rate of treatment discontinuation because of adverse events was 20%.

CONCLUSION

The landscape of maintenance therapy for ovarian cancer is rapidly changing. Currently, bevcacizumab, olaparib, niraparib and rucaparib are all FDA approved and new data are emerging that will lead to ever more increasing treatment options in the future.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

C.W. has received honoraria from AstraZeneca and research funding from Merck.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest

REFERENCES

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Data from the GOG-0213 trial led to the approval of bevacizumab use in combination with paclitaxel and carboplatin in platinum-sensitive recurrent ovarian cancer.

2. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol 2012; 30:2039–2045.
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Data from the ARIEL3 trial led to the approval of rucaparib for maintenance therapy in platinum-sensitive recurrent ovarian cancer.

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Data from the SOLO1 trial led to the approval of olaparib for maintenance therapy in patients with BRCA mutations and newly diagnosed ovarian cancer.

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Data from the PRIMA trial provide evidence for niraparib use for maintenance therapy in patients with newly diagnosed ovarian cancer, irrespective of BRCA or HRD status.

11▪▪. Coleman RL, Fleming GF, Brady MF, et al. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. N Engl J Med 2019; doi: 10.1056/NEJMoa1909707. [Epub ahead of print].

Data from the VELIA trial demonstrate the efficacy of combining veliparib with chemotherapy and then treating with veliparib maintenance monotherapy in patients with newly diagnosed ovarian cancer.

12▪▪. Ray-Coquard I, Pautier P, Pignata S. Phase III PAOLA-1/ENGOT-OV25 trial: olaparib plus bevacizumab (BEV) as maintenance therapy in patients (pts) with newly diagnosed, advanced ovarian cancer (OC) treated with platinum-based chemotherapy (PCH) plus BEV.

Data from the PAOLA-1 trial demonstrate the efficacy of combining olaparib with bevacizumab for maintenance therapy following upfront treatment with carboplatin, paclitaxel and bevacizumab in patients with newly diagnosed ovarian cancer.

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20. Hodgson DR, Dougherty BA, Lai Z, et al. Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Br J Cancer 2018; 119:1401–1409.
Keywords:

antiangiogenic therapy; bevacizumab; homologous recombination deficiency; maintenance therapy; niraparib; olaparib; ovarian cancer; PARP inhibitors; rucaparib; veliparib

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