NEW YORK (Reuters Health) – Maintenance therapy with rucaparib prolongs progression-free survival (PFS) in women with recurrent ovarian carcinoma responsive to platinum therapy, according to results from the ARIEL3 phase 3 randomized trial.
“Overall, the most compelling aspects of the trial is that the efficacy in delaying progression was seen across all cohorts – those we expected based on prior work – somatic BRCA alteration, and non-BRCA loss of heterozygosity (LOH)-high – as well as those we didn’t, e.g., LOH-low,” Dr. Robert L. Coleman from the University of Texas MD Anderson Cancer Center, in Houston, told Reuters Health by email.
Rucaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved in the U.S. for treating women with deleterious BRCA mutation-associated advanced ovarian carcinoma who have received two or more chemotherapy regimens. In an earlier trial, rucaparib was also effective in women with BRCA wild-type carcinomas with high LOH.
Dr. Coleman and colleagues from 87 hospitals and cancer centers in 11 countries assessed the efficacy and safety of rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in 564 women with high-grade, platinum-sensitive ovarian carcinoma.
Among women with a BRCA-mutant carcinoma, median PFS was 16.6 months with rucaparib versus 5.4 months with placebo (P<0.0001), the team reports in The Lancet, online September 12.
Similarly, in women with homologous recombination deficient (HRD) carcinoma, median PFS was significantly longer with rucaparib (13.6 months) than with placebo (5.4 months).
In the overall intention-to-treat population, median PFS was significantly longer in the rucaparib group (10.8 months) than the placebo group (5.4 months).
All clinical subgroups experienced a PFS benefit for rucaparib versus placebo, irrespective of measurable or multi-disease at baseline, response to last platinum-based regimen, LOH, or BRCA mutation.
All rucaparib recipients and 96% of placebo recipients experienced at least one treatment-emergent adverse event. Serious adverse events arose in 21% and 11%, respectively.
Treatment-emergent adverse events (excluding disease progression) led to treatment discontinuation in 13% of rucaparib patients and 2% of placebo patients.
“In the clinic, only about a third of platinum-sensitive recurrent ovarian cancer patients achieve a complete remission after platinum-based chemotherapy, so a decision needs to be made as to what to do next,” Dr. Coleman explained. “Usually, it’s continuation of that therapy or switching to a different therapy due to toxicity concerns. It is rare in this country to just stop treatment and wait, which is essentially the point of placebo in all of these trials.”
“This trial and the others suggest something is better than nothing, and the expectations of that treatment are now becoming very well defined,” he said. “But our aim is to do even better, because even those patients expected to do best still have treatment needs down the road and, thus, rely on us to improve their care by developing better combinations and therapeutic strategies.”
“Given the two other approvals in this setting (niraparib and olaparib), the impact will be more choice, utilization, and hopefully lower costs in the long run,” Dr. Coleman concluded. “Since the current treatment of recurrent disease is ever-changing, I expect new paradigms to be developed in the approach for not only platinum-sensitive ovarian cancer, but also for strategic placement of these active agents in the overall management of the disease.”
Dr. Don S. Dizon from Lifespan Cancer Institute, Alpert Medical School of Brown University, in Providence, Rhode Island, who wrote an accompanying editorial, told Reuters Health, “ARIEL3 gives us a good indication that even as a maintenance treatment, PARP inhibitors are active, yielding a pretty encouraging response in women with a known germline mutation in BRCA (38%) and 27% in those with homologous recombination deficiency (HRD) cancers (with 18% responders using the intent-to-treat population).”
“This could be interpreted two ways: either (A) the results of ARIEL-3 are better than expected because the placebo preparation included patients with bulky disease, or (B) that it may be okay to stop chemotherapy earlier than you intend, provided that women show they have responded to treatment,” he said in an email.
“I think the latter interpretation is reasonable, and gives me more comfort in stopping chemotherapy early and starting maintenance. Of course, even though a woman may trade IV chemotherapy for maintenance treatment using pills, ARIEL3 (as with other PARP inhibitor trials) shows that this is still a toxic treatment, particularly as it relates to bone-marrow effects,” he added.
“PARP inhibitors are likely to improve the survival of women with recurrent ovarian cancer, and access to these agents is not restricted to hereditary BRCA mutation-associated ovarian cancer,” Dr. Dizon concluded. “Anyone with recurrent ovarian cancer showing evidence of a response to platinum should be considered for maintenance PARP inhibitors, two of which are approved already. It may be that this clinical characteristic – platinum sensitivity – is a better predictor of who will benefit.”
Dr. Bradley J. Monk from Arizona Oncology and the University of Arizona and Creighton University, in Phoenix, who earlier showed the effectiveness of the PARP inhibitor niraparib in this setting, told Reuters Health by email, “This study adds confidence to the therapeutic paradigm of using a PARP inhibitor as maintenance following response to platinum-based therapy, since it is now the third positive phase 3 trial to be reported.”
“All patients with a response to re-treatment with platinum-based chemotherapy should discuss PARP inhibition as a maintenance strategy with their doctor,” he said. “Although PARP inhibitor maintenance works best among those with BRCA mutations, there is still significant clinical activity among those without mutations.”
Dr. Monk added, “Although PARP inhibitors are exciting new agents, I am concerned that their novelty might detract from using other active targeted agents, such as bevacizumab. In other words, there are many unanswered questions as we attempt to optimally sequence the available active agents and personalize ovarian cancer care.”
Clovis Oncology funded the study, employed 9 of the 34 authors and had various relationships with 14 other authors, including Dr. Coleman.
SOURCE: http://bit.ly/2xVUaJo and http://bit.ly/2fmqrSb
Lancet 2017.
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