TWiST Strengthens PARP Inhibitor Role in Ovarian Cancer

Pam Harrison

March 18, 2019

HONOLULU — A new analysis of the phase 3 NOVA trial strengthens earlier findings that niraparib (Zejula, Tesaro) provides meaningful clinical benefit for patients with platinum-sensitive, recurrent ovarian cancer compared with placebo by prolonging time without symptoms or toxicity (TWiST) until disease progression.

The new data were presented here at the Society of Gynecologic Oncology (SGO) 50th Annual Meeting on Women's Cancer.

As was previously reported by Medscape Medical News, niraparib, a poly ADP-ribose polymerase (PARP) inhibitor, significantly delayed disease progression compared to placebo by 21 months vs 5.5 months in patients with germline BRCA (gBRCA) mutations.

In patients without gBRCA mutations, the PARP inhibitor prolonged disease progression by 9.3 months compared with 3.9 months among placebo control patients.

In addition, quality of life remained stable throughout the treatment interval and prior to progression compared with placebo, as noted by Ursula Matulonis, MD, director and chief of gynecologic oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

In the current analysis, for both cohorts, progression-free survival (PFS) was extrapolated over 20 years to estimate the expected benefits beyond the length of the actual trial, she explained.

The primary objective of the current analysis was to estimate the difference in TWiST between treatment with maintenance niraparib compared with placebo in both cohorts. The main focus was on rates of nausea, vomiting, and fatigue of grade 2 or higher.

"Results for the gBRCA-mutated cohort show that there was definitely an improvement in the mean TWiST in favor of niraparid vs placebo with about a fourfold improvement in mean TWiST for patients receiving active treatment," Matulonis reported.

For the non-gBRAC-mutation group, there was also an improvement in mean TWiST, she added, with about a twofold mean improvement in TWiST for patients who received active therapy compared with those who received placebo.

Table 1. TWIST Endpoints for Niraparib vs Placebo in NOVA

  Mean PFS Mean TWiST Incremental TWiST
gBRCA-mutant cohort with niraparib 4.14 years 3.83 years 2.95 years in favor of niraparib
gBRCA-mutant cohort with placebo 0.91 years 0.88 years  
       
Non-gBRCA-mutant cohort with niraparib 2.59 years 2.46 years 1.34 years in favor of niraparib
Non-gBRCA-mutant cohort with placebo 1.14 years 1.12 years  

 

"Patients taking the PARP inhibitor had a longer time free of progression, and while living without progression, they were also living without nausea, vomiting, or fatigue," Matulonis concluded.

QUADRA Trial

An exploratory analysis of safety data from the NOVA study suggested that baseline body weight <77 kg (approximately 170 lbs) and a baseline platelet count <150,000/uL were predictive of the need to reduce the dose of niraparib early on following treatment initiation.

Interestingly, however, "dose modification did not appear to affect efficacy," Matulonis noted. There were no substantial differences in PFS rates among patients who received the lower dose of the drug compared to those who received the standard 300-mg starting dose.

Among patients whose baseline body weight was <77 kg and whose platelet count was <150,000/uL, the median daily dose of niraparib was 246 mg, she noted.

For those whose baseline body weight was ≥77 kg or greater and whose platelet count was ≥150,000/uL, the median daily dose of niraparib was 295 mg a day.

Because leaner patients with lower baseline platelet counts experienced a greater incidence of grade 3 treatment-emergent adverse events, "our thinking was that individualized dosing regimen could reduce the incidence of toxicities without compromising efficacy in QUADRA," Matulonis noted.

To analyze this hypothesis, Matulonis and colleagues carried out a retrospective analysis involving patients where the average dose given in the first two treatment cycles was dichotomized to those who received ≤200 mg vs those who received >200 mg a day.

From this retrospective analysis, early dose modification did not appear to have a negative effect on efficacy in an all-comer population.

Table 2. Efficacy Outcomes Based on >200-mg Dose of Niraparib vs ≤200 mg

Niraparib Dose >200 mg 200 mg
Body weight ≥77 kg and platelet count ≥150,000/uL ORR: 10.8%; clinical benefit rate at 24 weeks: 23.4% ORR: 8.8%;clinical benefit rate at 24 weeks: 20.6%
Body weight <77 kg or platelet count <150,000/uL ORR: 7.5%; clinical benefit rate at 24 weeks: 15.6% ORR: 7.1%;clinical benefit rate at 24 weeks: 18.8%

 

Moreover, early dose modification did not appear to have an adverse effect on overall survival in the all-comer population or among patients whose baseline body weight was <77 kg and whose platelet count was <150,000/uL, Matulonis added.

Matulonis suggested that on the basis of these findings, if a patient's body weight is <77 kg, physicians should consider a starting dose of 200 mg of niraparib, whereas for those whose baseline body weight is ≥77 kg, they should consider a starting dose of 300 mg a day.

Similarly, for patients whose baseline platelet count is <150,000/uL, a starting dose of 200 mg should be considered, whereas for those whose baseline platelet count is ≥150,000/uL, the 300-mg starting dose should be considered.

An individualized dosing approach for niraparib is being prospectively evaluated in the frontline phase 3 PRIMA study, Matulonis noted.

New Era in Ovarian Cancer Treatment

Asked by Medscape Medical News to comment on these findings, session co-chair John Chan, MD, California Pacific and Palo Alto Medical Foundation, Sutter Health Research, San Francisco, suggested that these findings are "really critical" because they allow physicians to understand the quality of life that ovarian cancer treatment has on patients and how they can perhaps enhance it.

"In addition, these PARP inhibitors are being used in the maintenance setting," Chan noted, "and they shouldn't be giving patients much in the way of side effects yet still keep the disease away," he added.

Instead of taking a standard dosing approach when introducing niraparib, physicians can now possibly mitigate treatment-emergent side effects by adjusting the dose according to baseline body weight and platelet counts, Chan observed.

As to the treatment options that are now emerging for ovarian cancer, Chan noted that physicians have never had so many drugs for the treatment of ovarian cancer than they have today.

"It is absolutely a new era in ovarian cancer treatment," Chan said, "and it's awesome."

The trials were sponsored by Tesaro. Matulonis reports serving as a consultant for Merck, Immunogen, Geneos, Mersana, Fujifilm, and Immunogen. Chan reports receiving speakers fees from AstraZeneca, Tesaro, Clovis, Genentech, and Merck.

Society of Gynecologic Oncology (SGO) 50th Annual Meeting on Women's Cancer: Abstract 1 and 2. Presented March 16, 2019.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....