Olaparib Leads PARP Inhibitor Charge in the Treatment of BRCA-Mutated, HRD Ovarian Cancer

Optimal decision-making between available PARP inhibitors for the treatment of patients with ovarian cancer relies on individual patient characteristics, such as the presence of homologous recombination deficiency (HRD) and BRCA mutations, according to Whitney Goldsberry, MD. 

“Overall, PARP inhibitors have changed the way we think about [managing] ovarian cancer,” Goldsberry said in an interview with OncLive®.

In the interview, Goldsberry discussed individual characteristics and disease factors that influence her decision between available PARP inhibitors in the frontline maintenance and second-line maintenance settings; the importance of building on individual patient experiences when refining clinical practice; and how updates to the National Comprehensive Cancer Network (NCCN) guidelines are shifting standards of care for patients with HER2-positive ovarian cancer.

In particular, she highlighted data that support the use of olaparib (Lynparza) in the first-line maintenance setting. In the phase 3 SOLO-1 trial (NCT01844986), the median overall survival (OS) was not reached (NR; 95% CI, NR-NR) in the olaparib arm (n = 260) vs 75.2 months (95% CI, 65.4-NR) in the placebo arm (n = 130; HR, 0.55; 95% CI, 0.40-0.76; P = .0004) in patients with newly diagnosed, BRCA1/2-mutated ovarian cancer.¹ The median follow-up for these groups were 88.9 months (interquartile range [IQR], 85.7-93.6) and 87.4 months (IQR, 84.3-91.7), respectively.

Goldsberry also noted that the phase 3 PRIMA trial (NCT02655016) data have prompted her to reach for niraparib (Zejula), mainly in patients with BRCA mutations or HRD disease. Notably the PRIMA trial investigated niraparib vs placebo as first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer.² In the HRD population, at a median follow-up of 6.2 years, the median OS was 71.9 months with niraparib (n = 247) vs 69.8 months with placebo (n = 126).

Goldsberry, who is an assistant professor of gynecology and women’s health in the Department of Obstetrics at the University of Louisville School of Medicine in Kentucky, sat down with OncLive to share more insights into these data.

OncLive: How do you select between the 3 available PARP inhibitors for patients with ovarian cancer in the second-line maintenance setting?

Goldsberry: Niraparib, rucaparib [Rubraca], and olaparib are all approved for second-line maintenance for [patients with] HRD disease or BRCA mutations. [I make this decision] based on my anecdotal use of [these agents] and how my patients tolerate them. Overall, there are not a lot of huge differences between them.

What notable safety concerns are associated with PARP inhibitors?

With these drugs, the risk of developing secondary malignancies needs to be talked about [with] patients. All [these agents are associated with] hematologic adverse effects [AEs], such as thrombocytopenia and neutropenia, as well as nonhematologic AEs, like gastrointestinal issues. However, the secondary malignancies need to be brought up when considering putting a patient on a PARP inhibitor. Most of the trials [investigating PARP inhibitors] showed that approximately 2% of patients [who received these agents] developed secondary malignancies, such as myelodysplastic syndromes or acute myeloid leukemia, which can be deadly.

How do you determine which PARP inhibitor to use for patients with BRCA mutations?

With the [publication of the] OS data with niraparib [in the PRIMA trial], olaparib is probably the best treatment option we have [for patients with BRCA mutations]. I like the idea that we can combine olaparib with bevacizumab [Avastin] if we think that’s appropriate to be used in the maintenance setting.

What are your key considerations when sequencing PARP inhibitors in the frontline maintenance setting?

Although niraparib [currently has a] biomarker-agnostic indication [in the frontline maintenance setting] for patients with homologous repair proficient disease [in the pivotal PRIMA trial], there was only a 3-month improvement in progression-free survival [with niraparib vs placebo]. Therefore, I’m hesitant to put patients on any type of PARP inhibitor unless they are HRD or have a BRCA mutation. If they [have these disease characteristics], then right now, olaparib is probably the best choice, given the OS data from SOLO-1 compared with the PRIMA data.

What factors do you consider when sequencing PARP inhibitors in later-line settings?

In later lines, anecdotally, my patients seem to tolerate olaparib well, so that’s typically the agent I choose first. With niraparib, I almost always have to [decrease] dosing and [patients often need] dose interruptions. That’s all anecdotal but definitely [important] to consider when trying to put a patient who might be sicker on maintenance therapy. We need to [consider] how the patient might react to that drug.

What is your main message for colleagues regarding the use of PARP inhibitors in ovarian cancer?

Previously, ovarian cancer wasn’t a disease that patients often lived with for many years because it is deadly, and the risk of recurrence is high. However, now, with these new introductions of agents like PARP inhibitors, we can cure patients of this disease and give them longer life expectancies. [PARP inhibitors are] changing the overall [ovarian cancer management] approach and the overall effects of having ovarian cancer.

What 2024/2025 updates to the NCCN guidelines for the management of ovarian cancer are important to highlight?

The new tumor-agnostic data coming out with some of the antibody-drug conjugates that are being applied to solid tumors, including ovarian cancer, are important because [those agents are] new in our realm. We haven’t used a lot of those treatments in gynecologic cancers. As we get more of those data and more of those [datasets] start to read out, [they will] help us determine what we need to be doing up front, like testing tumors, even ovarian cancer, for HER2 and other tumor markers.

References

1. DiSilvestro P, Banerjee S, Colombo N, et al. Overall survival with maintenance olaparib at a 7-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation: the SOLO1/GOG 3004 Trial. J Clin Oncol. 2023;41(3):609-617. doi:10.1200/JCO.22.01549
2. Monk BJ, Barretina-Ginesta MP, Pothuri B, et al. Niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer: final overall survival results from the PRIMA/ENGOT-OV26/GOG-3012 trial. Ann Oncol. 2024;35(11):981-992. doi:10.1016/j.annonc.2024.08.2241