Expert: Frontline Maintenance With PARP Inhibition Should Be Standard in Ovarian Cancer

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Maintenance treatment with PARP inhibitors should be the standard of care in the frontline setting for patients with ovarian cancer, Kathleen M. Moore, MD, said during a presentation at the 2020 Society of Gynecologic Oncology Winter Meeting.

Kathleen N. Moore, MD

Results from the SOLO-1, PAOLA-1, VELIA, and PRIMA clinical trials demonstrated the value of this treatment strategy in both the studies’ overall populations and prespecified subgroups, she added.

“The rationale is that we may be curing more patients,” said Moore, director of the Oklahoma TSET Phase I Clinical Trials Program and the Jim and Christy Everest Endowed Chair in Cancer Research at Stephenson Cancer Center in Oklahoma City. “If patients are going to benefit from PARP, they're going to benefit most early on. We just need to identify those patients a little bit more accurately.”

In the phase III SOLO-1 trial, first-line maintenance treatment with olaparib (Lynparza) resulted in a 70% reduced risk for disease progression or death compared with placebo in adult patients with newly diagnosed advanced germline or somatic BRCA-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete response (CR) or partial response (PR) to frontline platinum-based chemotherapy (HR, 0.30; 95% CI, 0.23-0.41; P <.001). The median PFS by independent central review was not reached in the olaparib arm versus 14.1 months in the placebo arm (HR, 0.28; 95% CI, 0.20-0.39; P <.001).^1,2The results supported the FDA approval of single-agent olaparib in this setting.

Findings the from the phase III PAOLA-1 trial led to the FDA subsequently granting a priority review designation to a supplemental new drug application (sNDA) for olaparib plus bevacizumab (Avastin) for the frontline maintenance treatment of patients with advanced ovarian cancer who are in CR or PR after first-line platinum-based chemotherapy with bevacizumab. Across the total trial population, the median PFS was 22.1 months with the combination compared to 16.6 months with bevacizumab alone (HR, 0.59; 95% CI, 0.49-0.72; P <.001).³

Patients whose tumors had BRCA mutations derived the greatest benefit from the addition of olaparib with a median PFS of 37.2 months compared with 17.7 months for bevacizumab alone (HR, 0.33; 95% CI, 0.25-0.45). For patients with tumors positive for homologous-recombination deficiency (HRD), the median PFS was 28.1 months versus 16.6 months in favor of the combination (HR, 0.43; 95% CI, 0.28-0.66). The FDA is scheduled to make a decision on the sNDA in the second quarter of this year.

Data from the phase III VELIA trial showed that the frontline combination of veliparib, carboplatin, and paclitaxel followed by maintenance veliparib monotherapy led to a 32% reduction in the risk of disease progression or death compared with placebo plus chemotherapy with placebo maintenance for patients with high-grade serous ovarian cancer.^4,5

The median PFS across all patient subgroups for the combined induction and maintenance phases in the veliparib arm was 23.5 months compared with 17.3 months in the placebo arm (HR, 0.68; 95% CI, 0.56-0.83; P <.001). The benefit was more pronounced for those with BRCA mutations. In this group, the median PFS was 34.7 months compared with 22.0 months for veliparib and placebo, respectively (HR, 0.44; 95% CI, 0.28-0.68; P <.001). For those who were HRD-positive, the median PFS was 31.9 months in those receiving veliparib throughout the trial compared with 20.5 months in the control arm (HR, 0.57; 95% CI, 0.43-0.76; P <.001).

Positive frontline maintenance findings for a third PARP inhibitor, niraparib (Zejula), were demonstrated in the phase III PRIMA study. In the trial, frontline maintenance therapy with niraparib improved median PFS compared with placebo for patients with newly diagnosed, advanced ovarian cancer who responded to platinum-based chemotherapy. In the overall population of the PRIMA study, the median PFS in the niraparib arm was 13.8 months compared with 8.2 months in the placebo group, representing a 38% reduction in the risk of progression or death with the addition of the PARP inhibitor (HR, 0.62; 95% CI, 0.50-0.76; P <.001).^6,7

The median PFS was 21.9 months with niraparib compared with 10.4 months for placebo in patients with germline BRCA mutations (HR, 0.43; 95% CI, 0.31-0.59). In patients with HRD-positive, BRCA wild-type tumors, the median PFS was 20 months with niraparib compared with 8 months for placebo (HR, 0.50; 95% CI, 0.31-0.83).

Moore said the use of PARP inhibitors for ovarian cancer in frontline remains controversial because some physicians prefer hold PARP inhibition to see if the patient recurs, because hazard ratios in later lines of treatment appear superior to those in frontline in some data, and because of the toxicity related to these agents.

Moore noted that roughly 80% of patients with ovarian cancer recur. She noted a subgroup analysis of patients in SOLO-1 showing that recurrence even occurs among patients with BRCA-associated cancers who are considered cured. Furthermore, only 35% of those who received placebo in SOLO-1 were disease-free at 3 years.

"There is no ‘low-risk’ ovarian cancer,” she said. “These women are all high risk, so there's just no argument, in my mind, for waiting. Until such time that we can identify women who are cured…But we can’t. Because this is the group you'd think was cured and they're not, for the most part.”

Hazard Ratios Must Be Considered in Context

Moore noted that hazard ratios reflect measured risk versus the comparison arm. As such, hazard ratios are highly contextual and cannot be compared across different states of disease to rank how best to use a drug.

She cited earlier studies of bevacizumab as an example. GOG 218 included patients with newly diagnosed stage III or stage IV epithelial ovarian cancer. GOG 213 included patients with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer who had a CR to primary platinum-based chemotherapy and who were disease-free for at least 6 months. AURELIA included women with measurable cancer that had progressed within 6 months of the patient completing platinum-based therapy.

The hazard ratio among a curable patient population in GOG-218 was 0.645. It was 0.628 among an incurable population in GOG-213 and 0.48 among a highly incurable population in AURELIA. No one, she said, would look at those findings and decide to use bevacizumab only in a setting that matched the AURELIA trial.

“That's nonsensical. You want to use [a drug] in the best setting, and that takes the context of the study, the context of the patient, and the control arm all into consideration,” Moore added.

Patients Say PARP Inhibitors Are Tolerable

PARP inhibitors are associated with increased risk for bone marrow toxicities, severe hematologic toxicities, and gastrointestinal toxicity. In PRIMA, 70.9% of patients required a dose reduction in the niraparib arm and 12% of patients discontinued therapy due to adverse events.

However, an analysis of time without symptoms or toxicity (TWiST) data from SOLO-2 published in Lancet Oncology in 2018 showed that the TWiST results clearly favored olaparib over placebo (15 vs 7.7 months).⁸

Furthermore, data from a TWiST analysis of the NOVA trial showed that, compared with routine surveillance, niraparib treatment resulted in a mean TWiST benefit of 2.95 years for patients with germline BRCA-mutated ovarian cancer and 1.34 years for those with nonmutated disease.⁹

“What we know…at least when you consider fatigue, nausea, and vomiting—the 3 adverse events included in TWiST—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.”

References

Moore K, Colombo N, Scambia G, et al. Olaparib maintenance therapy following first-line platinum-based chemotherapy in patients with FIGO stage III—IV ovarian cancer (OC) with a BRCA1/2 mutation (BRCAm): phase III SOLO1 trial. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA7_PR.
Moore K, Colombo N, Scambia G, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Eng J Med. 2018;379(26):2495-2505. doi: 10.1056/NEJMoa1810858.
Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Eng J Med. 2019;381(25):2416-2428. doi: 10.1056/NEJMoa1911361.
Coleman RL, Fleming GF, Brady MF, et al. VELIA/GOG-3005: Integration of veliparib (V) with front-line chemotherapy and maintenance in women with high-grade serous carcinoma of ovarian, fallopian tube, or primary peritoneal origin (HGSC). Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. LBA3.
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;381:2403-2415. doi: 10.1056/NEJMoa1909707.
Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Presented at: ESMO Congress 2019, Barcelona, Spain, September 27 to October 1, 2019. LBA1.
Gonzalez-Martin A, Pothuri B, Vergote I, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med. 2019;381:2391-2402. doi: 10.1056/NEJMoa1910962.
Friedlander M, Gebski V, Gibbs E, et al. Health-related quality of life and patient-centred outcomes with olaparib maintenance after chemotherapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT Ov-21): a placebo-controlled, phase 3 randomised trial. Lancet Oncol. 2018;19(8):1126-1134. doi: 10.1016/S1470-2045(18)30343-7.
Matulonis UA, Walder L, Nøttrup TJ, et al. Niraparib Maintenance Treatment Improves Time Without Symptoms or Toxicity (TWiST) Versus Routine Surveillance in Recurrent Ovarian Cancer: A TWiST Analysis of the ENGOT-OV16/NOVA Trial. J Clin Oncol. 2019;37(34):3183-3191. doi: 10.1200/JCO.19.00917.