Selection of maintenance therapy and the importance of HRD testing in the management of ovarian cancer | Latest news for doctors, nurses and pharmacists

Poly(ADP-ribose) polymerase (PARP) inhibitors, such as niraparib (Zejula®Zai Lab), play an important role in the current treatment algorithm for advanced ovarian cancer (OC), with proven benefitsIfts, including delayed progression or death, when used as maintenance therapy. During a recent industry-sponsored webinar, Dr. Domenica Lorusso of the Fondazione Istituto di Ricovero e Cura a Carattere ScientiIfco, National Cancer Institute of Milan, Italy, discussed the maintenance use of niraparib in different patient groups, while Dr. Ka-Yu Tse from the Department of Obstetrics and Gynecology, University of Hong Kong focused on the latest clinical evidence from the PRIME study and offered practical information on the use of niraparib at the individualized starting dose (ISD).

CO as a chronic disease

The treatment of CO remains difficult, as more than 80 percent of patients
relapse after primary cytoreduction surgery and standard first line
chemotherapy and without progression the intervals become shorter and shorter according to
each subsequent processing line. [Gynecol Oncol 2018;150:239-246;
N Engl J Med 2019;381:2391-2402] “When we recognize CO as a chronic disease, the need to prolong the time between recurrences as much as possible becomes clear,” Lorusso said. “All patients with OC should receive first-line maintenance therapy, as it has been shown to improve progression-free survival [PFS].”

Current first-line maintenance options for CO include bevacizumab, an anti-angiogenic agent, and PARP inhibitors. [Cancer Treat Rev 2020;91:102111] Although several studies have shown PFS benefits associated with first-line maintenance therapy, none have directly compared treatment options to date. [Ann Oncol 2021;32:1300-1303]

HRD: A predictive biomarker of PARP inhibitor efficacy

Up to 50 percent high quality serous OC patients have counterparts
recombination deficiency (HRD), presenting faults in counterpart
recombinant DNA repair pathway. [Ann Oncol 2020;31:1606-1622]

HRD is an important CO biomarker that predicts the magnitude of the benefits of PARP inhibition in the first line maintenance setting. [Ann Oncol 2020;31:1606-1622]HRD patients, even when they are
BRCA wild type [BRCAwt]have a better prognosis vs homologous recombinationcompetent [HRP] the patients,Lorusso said. [N Engl J Med 2019;381:2391-2402]

With recent data demonstrating the HRDs predictive and prognostic value, the European Society of Medical Oncology recommends the HRD test to identify HRD
BRCAwt patients likely to benefit from maintenance therapy with PARP inhibitors. [ESMO Open 2021;6:100144; Ann Oncol 2021;32:1300-1303]
HRD test should be performed after diagnosis of CO,recommended Lorusso.

Although two branded HRD genomic scar tests are available, the results they give are inconclusive in up to 18% of cases. [ESMO Open 2021;6:100144;
Ann Oncol 2020;31:1148-1159] We need a simple technique to perform HRD testing in every oncology lab. Ideally, any HRD test would be validated against the established Myriad myChoice test, commented Lorusso. [Ann Oncol 2020;31:1148-1159]

Benefits of using PARP inhibitors early

According to the current treatment algorithm, BRCA mutated (BRCAm) patients with first line complete answer platinum-based chemotherapy
should receive a PARP inhibitor alone or in combination with bevacizumab.
[Ann Oncol 2021;32:1300-1303]

For BRCAwt patients with HRD, both a PARP inhibitor monotherapy or a PARP inhibitor in combination with bevacizumab are possible first-line options. [ESMO Open 2020;5:e001110] Additionally, bevacizumab and niraparib may be considered as maintenance treatment options in patients with HRP tumors. (Figure 1) However, toxicity should be considered as a higher discontinuation rate was observed in patients receiving the combination.
[N Engl J Med 2019;381:2391-2402; N Engl J Med 2018;379:2495-2505;
N Engl J Med 2019;381:2416-2428] The addition of bevacizumab may be reserved for patients in whom immediate tumor shrinkage is required, Lorusso added.

CO management is a continuous strategy, where the choice of IfFirst line maintenance impacts the options available at the time of the recurrence.

For many patients, first-line therapy may represent the only option to receive PARP inhibitor therapy, as up to 40% of patients will be classifiedIfed as platinum resistant after primary chemotherapy [ie, platinum-free interval 6 months] and a similar proportion will be platinum resistant after the second line, Lorusso said.Accordingly, earlier introduction of PARP inhibitors may provide the opportunity [for efficacious treatment] to a greater number of patients. [Gynecol Oncol 2018;150:239-246]

In addition to maximizing the number of eligible patients, the use of PARP inhibitors in the first line appears to avoid certain safety risks. Long-term follow-up in the SOLO-2 trial of patients receiving maintenance olaparib or placebo for recurrent CO reported increased rates of combined myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML; 8 % versus 4%) with olaparib versus placebo. [Lancet
Oncol 2021;22:620-631] Reassuringly, to date, longer-term follow-up of first-line patients in the PAOLA-1 and SOLO-1 trials of olaparib (+/- bevacizumab, respectively) has shown no new cases. SMD or LAM. [Lancet Oncol 2021;22:1721-1731; J Gynecol Oncol 2021;doi:10.3802/ jgo.2021.32.e82]

PRIME: Consistent PFS benefits with niraparib across all subgroups

In the double-blind, placebo-controlled Phase III PRIME trial, 384 Chinese patients with postoperative residual disease after cytoreductive surgery for advanced CO in complete/partial response to platinum-based chemotherapy were randomized 2 :1 to receive niraparib at ISD (n=225; median age, 53.0 years) or placebo (n=129; median age, 54.0 years) for 36 months or until disease progression or unacceptable toxicity. [Li N, et al, SGO 2022, abstract LBA5]

In a subgroup analysis of PRIME, niraparib reduced the risk of disease progression or death by 60% in patients with
BRCA mutation (gBRCAm: median PFS, not reached vs 10.8 months; Dangerousness rate [HR], 0.40; 95% confidence interval [CI]0.230.68, pBRCAm patients (median PFS, 19.3 months versus 8.3 months; HR, 0.48; 95% CI, 0.340.67; p
HK-ZAI-054mo_02

In non-gBRCAm patients, niraparibs PFS benefit was also consistently observed regardless of HRD status (HRD: median PFS, 24.8 months versus 11.1 months; RR, 0.58; 95% CI, 0.360.93; p=0.022) (HRP: median PFS, 14.0 months versus 5.5 months; RR, 0.41; 95% CI, 0.250.65; p
HK-ZAI-054mo_03

PRIME has demonstrated a benefit on PFS with niraparib, regardless of the biomarker and postoperative residual disease status, whether there were germline or somatic mutations, and in the case of DRH or HRP, summary Tse. [Li N, et al, SGO 2022, abstract LBA5]

ISD Benefits of Niraparib

ISD (initial dose of 200 mg QD orally, or 300 mg QD for patients
with body weight 77 kg and pads count
150,000/µL) was adopted in all PRIME patients, on the other hand
to the previous PRIMA study where the majority of patients received
fixed dose niraparib. [Li N, et al, SGO 2022, abstract LBA5;
N Engl J Med 2019;381:2391-2402]

The PRIME study demonstrated a significant benefit on PFS with niraparib ISD maintenance compared to placebo in patients with newly diagnosed OC, regardless of biomarker status. While overall survival (OS) data were still immature at the data cutoff date, there was a trend suggesting a survival benefit with niraparib ISD maintenance treatment compared to placebo. [Li N, et al, SGO 2022, abstract LBA5]

The treatment-related adverse events (TEAEs) reported in the PRIME study were manageable and consistent with the class of PARP inhibitors. Similar discontinuation rates were observed between niraparib and placebo (6.7% versus 5.4%). With the implementation of DSI, the incidence of dose reduction was numerically lower in PRIME than in previous niraparib trials. [Li N, et al, SGO 2022, abstract LBA5]

Compared to the initial fixed dose, application of the ISD regimen of niraparib reduced the incidence of haematological TEAEs. [Li N, et al, SGO 2022, abstract LBA5]
In clinical practice, there appears to be a lower incidence of serious adverse events when using niraparib DSI,
confirmed Tse.

Summary

Quick access to HRD tests helps inform treatment decisions
and predicts the magnitude of the benefits PARP inhibitor treatment
in OC patients. Front line maintenance with niraparib monotherapy
offers a significant improvement in PFS in advanced OC. Latest PRIME data
support the use of niraparib ISD in Chinese patients on the front line
platinum-based chemotherapy regardless of biomarker and postoperative
residual disease status.

Martin E. Berry