Ovarian cancer doesn’t hold back

Recurrence is an ever-present threat to women with ovarian cancer1

Advanced ovarian cancer is characterized by treatment-resistant recurrence and decreasing periods of remission.2

Approximately 7 in 10 women with advanced ovarian cancer experience disease recurrence within ~3 years of first-line treatment without maintenance therapy.3,4

Recurrence is associated with2:

  • Worsening prognosis
  • Decreasing intervals of PFS
  • Increased cumulative toxicity over multiple lines of chemotherapy

A key objective of designing a treatment strategy at diagnosis is planning to intervene with maintenance therapy as early as possible to delay recurrence.1

The goal of maintenance therapy is to…


Prognosis worsens and resistance to chemotherapy increases with each line of treatment5

In women with newly diagnosed advanced ovarian cancer, the efficacy of platinum-based chemotherapy may be greatest in first line.5

BRCAm status is a strong predictor of response to platinum-based chemotherapy6-9

Clinical studies have shown that women with non-BRCAm ovarian cancer do not respond as well to platinum-based chemotherapy as women with BRCAm ovarian cancer.6-9

Compared with women with BRCAm ovarian cancer, women with non-BRCAm ovarian cancer who have been treated with platinum-based chemotherapy:

Develop resistance more frequently7

Experience even shorter periods of PFS9,10

Experience decreased overall survival8,9*

Research demonstrates that 2-year recurrence following first-line platinum-based chemotherapy is ~23% greater in women with non-BRCAm ovarian cancer compared with women with BRCAm ovarian cancer.6†

*A meta-analysis of OS assessed the role of BRCA dysfunction in patients with EOC and included a subgroup analysis of 22 studies categorized by BRCA1/2 mutation status. This subgroup suggests a potentially better prognosis indicator for OS (HR=0.67, 95% CI: 0.57–0.78) vs women with non-BRCAm EOC.

In a retrospective chart review, a total of 128 patients from a single institution met the following criteria:

  • Diagnosed with The International Federation of Gynecology and Obstetrics (FIGO) stage III-IV high-grade serous ovarian cancer (HGSOC) between 2008 and 2017
  • Underwent BRCA1/2 gene testing at or within 2 years of diagnosis

Investigators compared patients’ clinicopathological characteristics and survival outcomes after primary treatment according to germline BRCAm status. Treatment-related factors that might affect patients’ survival outcome were also investigated.

Considering their comparatively poor response to platinum-based chemotherapy with each subsequent line…


BRCA=BReast CAncer susceptibility gene; BRCAm=BReast CAncer susceptibility gene mutation; EOC=epithelial ovarian cancer; OS=overall survival; PFS=progression-free survival.


More opportunities to delay recurrence

The goal of maintenance therapy is to prolong the time to recurrence1

Introducing maintenance therapy at the earliest opportunity may offer women with advanced ovarian cancer their best chance of defying recurrence.1

Maintenance strategies may2:

  • Involve optimization of the induction-treatment phase
  • Vary based on patient and tumor characteristics, including biomarkers of DNA damage–repair dysfunction
  • Target residual or slow-dying cancer cells

Even in women with no visible disease after primary surgical cytoreduction and chemotherapy, as many as 2 out of 3 have residual cancer cells.2

Active surveillance—sometimes referred to as "watch and wait"—was once common clinical practice.11

Today, approximately 56% of women receive maintenance therapy after first-line treatment.12

For the best chance to delay recurrence for your patients with advanced ovarian cancer…


Established and novel pathway targets in ovarian cancer

Cancer cells rely on their ability to exploit many pathways to survive13

Changes in these pathways enable cancers to13:

Multiple pathways are being investigated for maintenance in ovarian cancer, including1,14-17:

  • DNA-damage repair
  • Angiogenesis
  • Immune checkpoints

PARP inhibition leverages the DNA damage–repair pathway18

PARP enzymes, and homologous recombination repair (HRR) proteins such as BRCA, are involved in DNA-damage repair.18

In tumor cells with a compromised DNA damage–repair pathway (for example, mutations in HRR genes), PARP inhibition causes an excessive accumulation of DNA damage and, thus, tumor-cell death.19,20

Angiogenesis is driven through increased production of VEGF20,21

VEGF ligands and their receptors (VEGFRs) have been shown to play major roles in tumor-cell angiogenesis.22

Inhibition of VEGF or VEGFR activity interferes with neovascularization, leading to cancer-cell death.22

Avoidance of immune destruction, which may be modulated by the PD-1 and PD-L1 pathways23

Binding of the PD-L1 protein to the PD-1 receptor protein found on T cells inhibits immune-mediated anti-tumor activity. Inhibition of this interaction results in the restoration of anti-tumor immune responses.24

Combination strategies may regulate multiple mechanisms that lead to cancer by targeting non-overlapping pathways14-17

Simultaneous inhibition of various pathways involved in cancer-cell survival may13,25,26:

  • Impede tumor-cell survival
  • Prevent resistance to pathway inhibition
  • Maximize the effects of targeting different pathways

Combination strategies include inhibition of the DNA damage–repair pathway through PARP.
These combinations target14-17:

  • DNA-damage repair + angiogenesis
  • DNA-damage repair + immune checkpoints
  • DNA-damage repair + angiogenesis + immune checkpoints

For women with advanced ovarian cancer...


BRCA=BReast CAncer susceptibility gene; MHCI=major histocompatibility complex 1; PARP=poly (ADP-ribose) polymerase; PD-1=programmed cell death-1; PD-L1=programmed death-ligand 1; TCR=T-cell receptor; VEGF=vascular endothelial growth factor.


Hallmarks of her tumor

When any mechanism regulating DNA-damage repair is impaired or deficient, tumorigenesis may occur13,27

BRCAm is the most well-known cause of impaired DNA damage-repair in ovarian cancer.28 However, other genetic mutations in homologous recombination repair (HRR) genes, promoter methylation, and unidentified causes can cause DNA damage–repair dysfunction, resulting in a homologous recombination deficiency (HRD) phenotype. This inability to repair DNA damage leads to genomic instability.29,30

Because multiple mechanisms of DNA damage–repair deficiency can result in genomic instability,* a biomarker of HRD, even women without a BRCA mutation may still harbor tumors with an HRD phenotype.31

*Genomic instability assays are also commonly referred to as “genomic scar” assays.

Identification of the biomarkers of
HRD can reveal tumor reliance on the DNA damage–repair pathway

Key genotypic biomarkers of HRD in tumor cells include13,28:

  • BRCA mutations
  • Mutations in other specific homologous recombination repair (HRR) genes
  • Other causes of altered gene expression (eg, epigenetic alterations)

The HRD phenotype may be detected by measuring genomic instability through the following:

  • Loss of heterozygosity
  • Telomeric allelic imbalance
  • Large-scale state transitions

In advanced ovarian cancer…


BRCAm=BReast CAncer susceptibility gene mutation; HRD=homologous recombination deficiency; HRR=homologous recombination repair.

Put it all on the line for her.

Defying recurrence depends on it.

Recurrence is an ever-present threat to women undergoing treatment for advanced ovarian cancer. Treatment strategies that include maintenance therapy at the earliest possible opportunity are critical for delaying recurrence.

The baseline knowledge that cancer cells rely on their ability to modulate many pathways to survive has led to research in combination pathway inhibition. Consider biomarkers of HRD, including BRCAm, at diagnosis to know the hallmarks of her tumor.

BRCAm=BReast CAncer susceptibility gene mutation; HRD=homologous recombination deficiency.

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