Discussion
ovarian cancer, NER-deficient ovarian cancer, platinum-specific toxicities, toxicity, platinum-sensitive ovarian cancer
ADVERSE EVENTS, OVARIAN CANCER, EMA
The trial shows that trabectedin/PLD given to extend the TFIp before platinum rechallenge does not prolong the OS in patients with recurrent OC and a TFIp between 6 and 12 months. OS was similar with both regimens and PFS was better with carboplatin/PLD. Grade 3-4 (5) adverse events were reported more in the trabectedin/PLD group than within the carboplatin/PLD. The trabectedin/PLD regimen was associated with a higher prevalence of haematological, gastrointestinal and hepatic treatment-related adverse events than the carboplatin/PLD regimen.Trabectedin in association with PLD for the treatment of platinum-sensitive ovarian cancer was approved by EMA in October 2009, but the use of this regimen was not homogeneous across Europe due to the differences in the National Health Systems policies.This regimen has never been directly compared in a randomised clinical trial with carboplatin/PLD. The hypothesis that prolonging the TFIp by using non-platinum agents could improve response to platinum retreatment was expressed in the ‘90 s but it was never addressed prospectively until the Alvarez Secord’s phase II trial and the MITO-8/ENGOT-ov1 trial were published in 2012 and 2017 [Although the preclinical models of ovarian cancer do not reproduce the complexity and heterogeneity of human ovarian cancer adequately and their predictivity is not fully demonstrated, nevertheless, in vitro and in vivo studies suggested that the exposure to trabectedin induced a selection of NER-deficient ovarian cancer cells that were very sensitive to platinum drugs, providing a further rational for the choice of trabectedin as a non-platinum drug [In the post hoc subgroup analyses shown in Fig. A recently published phase III trial by Monk and colleagues [Another specific area where trabectedin might be taken into consideration for tailoring new therapies emerged from the post hoc analysis of the SOLO2/ENGOT ov-21 trial. In fact, this analysis has recently shown a decreased efficacy of subsequent chemotherapy (particularly platinum-based chemotherapy) assessed by time to the second progression, in BRCA1/2 mutated patients having received maintenance olaparib compared to placebo [Our study has some limitations. First, the absence of information on BRCA mutation status in almost 40% of participants, because this was not yet in standard practice during the inclusion time. Secondly, quality of life was assessed only at baseline and at the sixth cycle of chemotherapy or progression, whichever came first, as we tried to obtain an overall description of the therapeutic burden with the minimum number of assessments. However, we might have missed granularity and overlooked elements possibly exerting pronounced effects on quality of life. Moreover, quality of life assessment was not available for all patients and this may lead to bias since data may be missing not at random but actually in relation to patients’ clinical conditions.This trial was mostly run in the pre-bevacizumab/PARP inhibitors period and these therapeutics are now being integrated into clinical practice and are shaping clinical research. We can only speculate whether trabectedin/ PLD or trabectedin alone might be synergistic with these new medications. A phase II single-arm trial is ongoing in patients with OC on the use of olaparib as maintenance treatment in patients with CR to trabectedin/PLD (NCT03470805). In a randomised phase II clinical trial in patients with TFIp 6–12 months, the combination of trabectedin and bevacizumab showed promising efficacy [This, mature randomised trial did not find any survival advantage compared with standard-of-care platinum-based chemotherapy in the experimental trabectedin/PLD combination. The trabectedin/PLD regimen followed by platinum rechallenge is active in this patient population, showing similar overall survival with respect to platinum-based chemotherapy given first, but it also has higher toxicity and lowers the health-related quality of life. We conclude that a platinum doublet such as carboplatin/PLD combination remains standard practice for recurrent OC patients with a TFIp between 6–12 months; however, trabectedin/PLD can still be considered an option for patients who have received two prior platinum-based lines who show platinum hypersensitivity or may need a longer recovery time from platinum-specific toxicities.