Weekly dose-dense CT does not confer survival benefit for ovarian cancer patients

In the final analysis of the phase III ICON8* study, a weekly dose-dense chemotherapy (CT) regimen comprising paclitaxel and carboplatin did not improve survival outcomes in women with epithelial ovarian cancer** compared with the standard first-line (1L) paclitaxel-carboplatin regimen given once every 3 weeks (Q3W).

“[I]n a predominantly European population with high-risk epithelial ovarian cancer, the incorporation of weekly dose-dense paclitaxel in combination with either Q3W or weekly carboplatin into 1L multimodality treatment does not improve either progression-free survival (PFS) or overall survival (OS),” said the researchers.

Participants (n=1,566; median age 62 years) were randomized 1:1:1 into three*** CT arms: the standard Q3W regimen (arm 1), Q3W carboplatin and weekly dose-fractionated paclitaxel (arm 2), or a weekly regimen (arm 3). All agents were administered via IV infusion for six 21-day cycles. [Lancet Oncol 2022;23:919-930]

After a median follow-up of 69 months, median OS in the respective arms 1, 2, and 3 were 47.4, 54.8, and 53.4 months. Comparisons between arms did not yield significant differences (hazard ratio [HR], 0.87; p=0.092 [arm 2 vs 1] and HR, 0.91; p=0.24 [arm 3 vs 1]).

There were also no significant differences in either comparison in terms of PFS (HR, 0.92; p=0.39 [arm 2 vs 1] and HR, 0.94; p=0.49 [arm 3 vs 1]). Overall, three-quarters of participants had disease progression. Restricted mean survival times were 23.9, 25.3, and 24.8 months for arms 1, 2, and 3, respectively.

Arm 2 had the highest incidence of at least one grade ≥3 AE adverse event (AE) compared with the other two arms (62 percent vs 42 percent [arm 1] and 53 percent [arm 3]). The most common grade ≥3 AEs were reduced neutrophil (15, 36, and 30 percent for arms 1, 2 and 3, respectively) and white blood cell counts (4, 16, and 14 percent, respectively). There were also more treatment-related deaths in arm 2 than in arms 1 and 3 (n=4 vs 2 and 1).

The role of race, ethnicity

However, the findings digress from those seen in the Japanese JGOG 3016 trial. [Lancet Oncol 2013;14:1020-1026; Lancet 2009;374:1331-1338] “ICON8 was developed after the results of [JGOG 3016] were reported,” they said. “The disparity in survival outcomes … emphasize the potential importance of racial and ethnic differences in ovarian cancer biology or pharmacogenomic factors.”

“Notably, pharmacogenomic studies have shown lower incidence of polymorphisms in drug-metabolizing enzymes that might negatively affect paclitaxel activity in Asian than in Caucasian populations,” said the researchers. In a lung cancer trial, the racially associated single-nucleotide polymorphisms CYP3A4*1B and ERCC2K751Q were tied to improved outcomes in Japanese vs US patients. [J Clin Oncol 2009;27:3540-3546]

It thus appears imperative to look into the role of race and ethnicity in future studies. “[D]etailed race and ethnicity data capturing sufficient information to allow granular analyses should be incorporated into routine baseline demographic data collection in future phase III ovarian cancer trials,” they added.

1L weekly regimen not recommended

“ICON8 is the only study to our knowledge that has assessed OS as a coprimary outcome measure and provides the largest and most mature dataset to date,” said the researchers. “[The study] was adequately powered to detect a clinically relevant survival difference between either of the two dose-dense weekly paclitaxel-containing experimental regimens and standard treatment scheduling.”

“[As such, weekly dose-dense CT] should not be used as part of standard multimodality front-line therapy in this patient group,” they concluded.