PARP Inhibitors as Frontline Treatment in Patients With Ovarian Cancer

March 19, 2020

PARP inhibitors take center stage at the Society of Gynecologic Oncology’s 25th Annual Winter Meeting

The time has come for maintenance treatment with poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors to become the standard of care in the frontline setting for patients with ovarian cancer. This message, backed by recent data from clinical trials, was at the forefront of the Society of Gynecologic Oncology’s 25th Annual Winter Meeting held February 6-8 in Aspen, CO.

“The rationale is that we may be curing more patients,” said Kathleen M. Moore, MD, the Jim and Christy Everest Endowed Chair in Cancer Research at the Stephenson Cancer Center in Oklahoma City during a presentation. “If patients are going to benefit from [a] PARP, they're going to benefit most early on. We just need to identify those patients a little bit more accurately.”1 Moore’s assertion is supported by results from 3 clinical trials-PAOLA-1, PRIMA, and VELIA-that were first released at the European Society for Medical Oncology Congress 2019.

The phase III PAOLA-1 trial, which tested the combination of bevacizumab (Avastin) plus olaparib (Lynparza) as maintenance therapy, showed an increase in median progression-free survival (PFS) of nearly 6 months with bevacizumab plus olaparib compared with bevacizumab plus placebo (22.1 months vs 16.6 months, hazard ratio (HR) for disease progression or death, 0.59; 95% CI, 0.49-0.72; P <.001).2 In this trial, patients with homologous recombination deficiency (HRD) tumors and BRCA mutations derived the greatest benefit in median PFS with olaparib compared with placebo (HRD: 37.2 months vs 17.7 months, HR, 0.33; 95% CI, 0.25-0.45; BRCA: 37.2 months vs 21.7 months, HR, 0.31; 95% CI, 0.20-0.47).

In the phase III PRIMA trial, frontline maintenance therapy with niraparib (Zejula) also improved median PFS compared with placebo (13.8 months vs 8.2 months, (HR  for disease progression or death, 0.62; 95% CI, 0.50 to 0.76; P <.001).3 Similar to the PAOLA-1 trial, patients with HRD tumors derived the greatest benefit, with an increase in median PFS of almost 12 months (21.9 months vs 10.4 months; HR, 0.43; 95% CI, 0.31 to 0.59; P <.001).

Positive findings for a third PARP inhibitor, veliparib, were demonstrated in the phase III VELIA trial, which measured the effectiveness of veliparib as a first-line treatment and maintenance therapy. The combination of veliparib, carboplatin, and paclitaxel followed by maintenance veliparib monotherapy extended median PFS by nearly 7 months compared with chemotherapy plus placebo followed by placebo maintenance (23.5 months vs 17.3 months; HR for disease progression or death, 0.68; 95% CI, 0.56 to 0.83; P <.001) in the overall population, while patients with BRCA mutations saw median PFS increase by more than a full year (34.7 months vs 22.0 months; HR, 0.44; 95% CI, 0.28 to 0.68; P <.001).4

“What was really neat about the presentation of [data from] all 3 trials was the differences between them in terms of the patient populations [examined], the drug combinations evaluated, and the different drugs used,” said Angeles Alvarez Secord, MD, a gynecologic oncologist at the Duke Cancer Center. “We are able to synthesize this information to determine what the best option is for our patients.”5

Secord, who moderated a case-based symposium entitled “Feed Your Brain-Digesting PAOLA, PRIMA, VELIA,” noted that when it comes to choosing the right PARP inhibitor, there is not necessarily 1 right answer. Instead, it is important to consider the different patient populations evaluated in each trial and the benefits of the agents in each subgroup, to aid in the decision-making process.5

The use of PARP inhibitors does come with an increased risk of bone marrow and gastrointestinal toxicity, along with the risk of severe hematologic toxicity. Twelve percent of patients in the PRIMA trial and 20% of those enrolled in the olaparib arm of the PAOLA-1 trial discontinued therapy due to adverse events, with 70.9% of patients from PRIMA and 41% of patients from PAOLA-1 requiring a dose reduction.2,3

The benefits far outweigh the risks, however, according to Moore. “What we know…at least when you consider fatigue, nausea, and vomiting…is that time spent without toxicity far exceeds time spent with toxicity. The patients are telling us, at least from what we ask them, that [PARP inhibitors] are well tolerated.”

Disclosures:

References

1.     Moore KM. Paradigm changes in front line ovarian cancer. Presented at: Society of Gynecologic Oncology’s 25th Annual Winter Meeting; February 7, 2020; Aspen, CO.

2.     Ray-Coquard I, Pautier P, Pignata S, et al; PAOLA-1 Investigators. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi: 10.1056/NEJMoa1911361.

3.     González-Martin A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019;381(25):2391-2402. doi: 10.1056/NEJMoa1910962.

4.     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;381(25):2403-2415. doi: 10.1056/NEJMoa1909707.

5.     Ternyila D. Secord shares data to digest with PARP inhibitors in ovarian cancer. https://www.onclive.com/conference-coverage/sgo-winter-2020/secord-shares-data-to-digest-with-parp-inhibitors-in-ovarian-cancer?p=1. OncLive website. Published February 9, 2020. Accessed February 23, 2020.

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