Discussion
At present, a variety of PARP inhibitors have been used in the clinical
treatment of ovarian cancer patients, covering several stages of
treatment, which has become an epoch-making breakthrough in the history
of ovarian cancer treatment. To our knowledge,
this
is the first study on the therapeutic effect of PARPi monotherapy
compared with platinum-based chemotherapy, and the impact to subsequent
platinum-containing chemotherapy and survival after the progression of
PARPi in BRCA1/2 mutant patients with secondary platinum-sensitive
relapse.
PARPi
monotherapy for relapsed ovarian cancer with BRCA1/2 mutations has been
proven clinically and has been validated in several clinical studies. In
BRCA1/2 mutant patients with platinum-sensitive relapse who received at
least two lines of platinum-based chemotherapy, the ORR ranged from
56.0% with niraparib to 80.0% with
rucaparib15-19.
However, ovarian cancer patients with BRCA1/2 mutations were inherently
more sensitive to platinum-based chemotherapy than patients with
wild-type ovarian cancer20, and the benefits of using
PARPi inhibitors versus platinum-based chemotherapy at the same relapse
stage were still uncertain. In our study, for patients with secondary
platinum-sensitive relapse, the ORR was 77.4% and 84.0%, and the
median PFS was 8.6 and 11.1 months, respectively. The therapeutic effect
of PARPi monotherapy and platinum-based chemotherapy was equivalent.
The mechanisms of PARPi and platinum-based chemotherapy are both related
to DNA damage repair, and the drug resistance mechanisms of PARPi
include alterations in DNA damage repair, reactivation of HR, and
replication fork protection, etc8. Theoretically,
PARPi resistance may lead to subsequent platinum-based chemotherapy
resistance.
In Joo Ern’s study21, BRCA1/2 mutation patients who
received 3-11 lines of platinum-based chemotherapy before Olaparib were
included. After Olaparib resistance, the ORR of platinum-based
chemotherapy was 40% (19/48), and the median PFS was 22 weeks,
suggesting that there was still a partial response to platinum-based
chemotherapy after PARPi resistance. Another study found that both
platinum and non-platinum chemotherapy had a response rate after
resistance of PARPi maintenance therapy, with median PFS of 7.0 and 8.5
months,
respectively22.
In our study, the PFI was significantly prolonged after PARPi
monotherapy, and the median TFST of subsequent platinum-based
chemotherapy after PARPi resistance
was
7.5 months, consistent with patients in control group with
platinum-sensitive relapse after third-line platinum-based chemotherapy.
Further survival analysis confirmed that PRS of patients in the study
group was similar to platinum-sensitive relapse patients, and superior
to platinum-resistant relapse patients after third-line platinum
chemotherapy. This result verified to some extent that although
platinum-based chemotherapy had cross-resistance with PARPi, it does not
negatively affect the efficacy of platinum-based chemotherapy after the
progression of PARPi monotherapy.
PFS
is currently the most widely used primary endpoint in clinical trials of
PARP inhibitors. Most clinical studies have been conducted in recent
years, so data on OS are still limited. In a phase 2 trial of Olaparib
maintenance therapy, for patients with BRCA1/2 mutations, median PFS was
significantly longer than placebo group (11.2 vs 4.3
months)23, but the OS benefit (29.8 vs 27.8 months)
was not statistically significant24. In the Olaparib
SOLO-2 trial, maintenance treatment with Olaparib extended the median OS
by 12.9 months compared with placebo in patients with relapsed
platinum-sensitive BRCA1/2-mutant ovarian cancer6. In
the NOVA study, in the same cohort as the SOLO2 trial, maintenance
therapy with Niraparib provided a 15.5-month benefit for
PFS25, but no benefit for OS (43.6 vs 41.6
months)26.
Results
from the SOLO1 trial showed that Olaparib maintenance therapy extended
the median PFS by 42 months compared to placebo in women with newly
diagnosed advanced BRCA1/2 mutant ovarian cancer, although OS data are
not yet available, it is expected that OS will benefit from a large
increase in PFS as well27.
For
other PARPi, as well as for patients with other indications, the
benefits of OS remain to be determined.
In
our study, patients with secondary platinum-sensitive relapse were
selected and the results showed that the benefit of subsequent
platinum-based chemotherapy was not negatively affected after the
progression of PARPi monotherapy, and there was still a significant
extension of PRS, which reduced the risk of death by 65%.
Factors affecting survival of ovarian cancer patients included tumor
histology, FIGO stage, BRCA mutation status, ascites, and whether no
residual lesions could be achieved after primary debulking
surgery28. In a study with up to 10 years of
follow-up, the initial survival advantage in patients with BRCA1/2
mutations may reflect a higher initial sensitivity to chemotherapy, but
this response does not predict long-term survival, the strongest
predictor of long-term survival was no residual lesions at
resection29. In our study, we found that the factors
affecting PRS included R0 resection and PARPi monotherapy, after
incorporating FIGO stage for multivariate analysis, PARPi monotherapy
was the independent prognostic factor, which also reflected the superior
therapeutic effect of PARPi monotherapy compared with R0 resection.
To a certain extent, our research has significant advantages. First,
this is the first study to evaluate benefits of PARPi monotherapy versus
platinum-based chemotherapy at the same relapse stage of BRCA1/2 mutant
patients. In addition, the four-line treatment information was
collected, at a stage with little evidence for treatment, besides, data
of patients who did not receive PARPi treatment before as control group
were difficult to obtain. However, the most significant limitation of
our retrospective study was the limited number of patients. BRCA1/2
mutations account for less than 30% of ovarian cancer
patients30, and those who did not met the criteria for
secondary platinum-sensitive relapse were excluded, as were those on
maintenance therapy with PARPi or bevacizumab. Although the results of
the analysis in our study were significantly different, further studies
with large samples should be necessary. The findings of this study were
applied only to a specific subset of the ovarian cancer patient
population, not to all patients in general.