Exploring novel combinations in the treatment of relapsed ovarian cancer: the MEDIOLA trial results

Ovarian cancer (OC), particularly in the relapsed setting, is a formidable clinical challenge due to its high recurrence rates and limited treatment options. The emergence of PARP inhibitor (PARPi) has revolutionized the management of OC, offering a targeted therapeutic approach; while the benefit is evidently greater in the presence of a BRCA mutation, patients with and without a homologous recombination deficiency (HRD) can also have access to maintenance therapy as it has been clearly shown that there’s an, albeit less impressive, efficacy in these cases (1-4).

However, we are now in need of optimizing the maintenance therapy with PARPi, as we have observed a worrying percentage of patients that are either non responders and have therefore a primary resistance, or later relapse. The PI3K pathway played an important role in chemoresistance and preservation of genomic stability that is mostly upregulated in OC. Inhibition of PI3K may cause genomic instability and mitotic catastrophe by decreasing the activity of the spindle assembly checkpoint protein Aurora kinase B and, as a result, increasing the prevalence of lagging chromosomes during prometaphase (5). The combination of PARPi with other targeted therapies is currently one of the most promising tools to delay or even prevent resistance.

This is especially important, as studies (6-8) have shown a lower efficacy of platinum-based therapies in PARPi treated patients, which is worrisome as we know platinum salts are the cornerstone of chemotherapy in OC and the prognosis of a platinum resistant patients is much worse. The examination of OC proteomics, with mass spectrometry and protein array analysis, and their adaptive reactions to treatment can reveal novel therapeutic options that can delay the development of drug resistance and possibly enhance patient outcomes (9). While the data is still unclear, only coming from retrospective studies, non-platinum-based chemotherapy also seems to be influenced by a previous therapy via PARPi (10).

The MEDIOLA trial (11) has published its expanded results on efficacy and safety recently. The phase II multi-cohort study had the objective of investigating the combination of olaparib plus durvalumab, with or without bevacizumab, in PARP inhibitor-naïve platinum-sensitive relapsed OC.

The early results published in 2018 (12) featuring exclusively patients carrying a BRCA mutation had already been promising, showing a 28-week disease control rate (DCR) of 65.6% [90% confidence interval (CI): 49.6–79.4%], an overall response rate (ORR) of 71.9% (95% CI: 53.25–86.25%). Median progression-free survival (PFS) was 11.1 months (95% CI: 8.2–15.9) with a median duration of response (DoR) of 10.2 months, with no new safety warnings.

An expansion cohort of BRCA mutated patients was added, as well as two cohorts of wild type patients who were sequentially selected to receive olaparib and durvalumab with or without bevacizumab, with the hope of increasing the PARPi sensitivity. The patients enrolled were 51, 31 and 32, respectively.

The combination of olaparib and durvalumab, with or without bevacizumab, represents a novel strategy aimed at enhancing the anti-tumor immune response while simultaneously targeting DNA damage repair mechanisms and angiogenesis. By leveraging the complementary mechanisms of action of these agents, the study sought to exploit synergistic effects that may lead to improved clinical outcomes for patients.

We do already have data regarding the activity of the olaparib and bevacizumab in first line (13), which showed to be more effective than bevacizumab alone in BRCA mutated and HRD OC, and in further lines as a treatment option thanks to the AVANOVA phase II trial (14), where the niraparib plus bevacizumab arm performed better than niraparib on its own in terms of PFS.

A growing body of preclinical evidence showing the immunological properties of PARPi (15), has also prompted the investigation of the combination of this drug with immune checkpoint inhibitors (ICI), with several phase I and II trials mainly focused on resistant OC (ROC) (16).

Of note, the phase III trial DUO-O featured the comparison between olaparib + bevacizumab + durvalumab vs bevacizumab + durvalumab vs bevacizumab in mono therapy in the first line setting. The interim analyses were presented at ASCO 2023 (17) regarding the comparison between the triplet cohort and the bevacizumab, with a significantly greater PFS in newly diagnosed advanced stage OC without tumor BRCA mutations. While a clinically significant difference was also present between the arm containing durvalumab + bevacizumab and the triplet therapy, it has not yet reached statistical significancy and will therefore be reassessed. The phase II BOLD trial also assessed the efficacy and toxicity of the triplet therapy in a relapsed setting, observing a DCR of 70% (90% CI: 56–80%) (18).

In the MEDIOLA trial, PARPi-naïve and ICI-naïve patients with relapsed platinum sensitive disease were enrolled. The expansion cohort featuring BRCA mutated patients received olaparib + durvalumab, with a primary endpoint of ORR, which aimed at confirming the results seen in the initial phase I cohort. Wild-type BRCA OC were also added, and sequentially enrolled into receiving a doublet therapy with or without bevacizumab; DCR at 24 weeks was the primary endpoint, as efficacy had not yet been proven by a previous trial.

The inclusion of multiple treatment cohorts within the study design allows for a comprehensive evaluation of different therapeutic strategies. By exploring various combination regimens, the study not only provides valuable data on efficacy and safety but also lays the groundwork for future research into optimized treatment algorithms.

The ORR observed in the gBRCA cohort was 92.2% (95% CI: 81.1–97.8%), with a complete response (CR) for 43.1% of patients. DCR at 24 weeks was 28.1% (90% CI: 15.5–43.9%) and 74.2% (90% CI: 58.2–86.5%) in the doublet and triplet non gBRCA cohorts, with an ORR of 34.4% and 87.1% respectively. PFS, a secondary endpoint, was observed to be 15 (95% CI: 12.9–24.1), 5.5 (95% CI: 3.6–7.5) and 14.7 (95% CI: 9.2–18.1) months in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. OS rates at 24 months were 76.7%, 50.8% and 64.5%. No differences were observed when accounting for line of therapy, HRD or programmed cell death ligand 1 (PD-L1) status.

The ORR of the gBRCA cohort is unusually high, as previous data report an ORR of 84.6% to olaparib in monotherapy in the SOLO3 post hoc analyses (19). It could therefore be hypothesized that the addition of an ICI allows to have a higher efficacy, but the small number of patients and the lack of a comparison arm with olaparib in monotherapy does not allow for direct comparisons.

Regarding the non-mutated cohorts, while the doublet arm performed rather poorly, the ORR and PFS were significantly better in the triplet cohort. While the possibility of synergizing the activity of a PARPi and an ICI via the targeting of angiogenesis has a strong preclinical rationale, the lack of randomization in the two cohorts is an evident issue in the reliability of the comparison between them. Generally speaking, the lack of control arms with current standard therapies—PARPi monotherapy, bevacizumab monotherapy and olaparib plus bevacizumab—is an ulterior motive behind a scarce possibility of comparison.

Also worth noting, 50% and 41.9% of patients respectively did not have a known HRD status, due to a lack of analyzable material. As we are now aware that the HRD status is paramount to determine the sensitivity of patients, the lack of this information makes it impossible to stratify the cohorts and therefore know the impact of the HRD population on the overall superiority of the triplet cohort.

As previously said, we now know that combination therapies might be a gateway to diminish PARPi primary and secondary resistance; therefore, the positive results of the MEDIOLA trial are surely very encouraging, especially when partially confirmed by the interim analyses of the DUO-O study.

The addition of immunotherapy to the already tested doublet of PARPi and bevacizumab is a very promising avenue, in contrast with the lack of efficacy observed so far with ICI in OC (20,21). It might allow to finally individuate a clinical setting where immunotherapy is active, as well as improve the already evident benefit of PARPi in all platinum sensitive populations and of olaparib + bevacizumab in the HRD and BRCA mutated patients.

While the results of this phase II study were eagerly anticipated, it is essential to acknowledge the inherent complexities and challenges associated with combination therapies. The potential for increased toxicity, drug interactions, and the development of resistance mechanisms must be carefully considered and monitored. Additionally, the identification of biomarkers predictive of treatment response to immunotherapy will be crucial for patient selection and treatment optimization. Until now CA125 and HE4 are the only approved serum biomarkers for OC. Emerging potential predictors in OC are multivariate index (MVI), the risk of malignancy algorithms (ROMA) and the micro-RNAs (miRNAs) (22).

Today’s therapeutic algorithm features the possibility of treating advanced stage OC in partial or complete response to a first line of chemotherapy with either PARPi, or PARPi + bevacizumab in HRD and BRCA mutated patients; therefore, the majority of relapsed patients have already been subjected to PARPi therapy and/or bevacizumab. While we do have data regarding both the retreatment with PARPi (23) and bevacizumab (24), the potential anticipation of a triple therapy in first line might be more of interest. The updated analyses of the DUO-O trial regarding the durvalumab + bevacizumab arm, as well as the updated overall results, will also be paramount in deciding whether the triplet therapy might be of interest. However, a direct comparison with a PARPi monotherapy is currently not present and would need to be performed in a randomized phase III trial.

Other promising combinations worthy of being explored might be the addition of an antibody drug conjugate (ADC) to ICI, ATR inhibitors plus PARPi, as well as newer forms of immunotherapy such as B cell specific agents. The combination of PARPi with immunotherapies such as anti-CTLA4 and PD-1/PD-L1 is based on the hypothesis that HRD patients, including BRCA1/2 carriers, displayed a higher neo-antigen load compared to homologous recombination proficient (HRp) patients. Furthermore, there is evidence that BRCA deficiency may trigger a STING-dependent innate immune response by increasing type I interferon and pro-inflammatory cytokine levels. Interestingly, clinical models have shown that PARP inhibition inactivates GSK3 while upregulating PD-L1 in a dose-dependent manner. As a result, T-cell activation is reduced, leading to increased cancer cell death (25).

In conclusion, combination target therapies represent a promising avenue to advance the treatment landscape of this challenging disease. By exploring innovative strategies, we have the potential to improve outcomes for patients and pave the way for future advancements in OC therapy.

While the MEDIOLA trial had multiple problematic aspects, namely the lack of the HRD status in more than 50% of patients as well as the absence of randomization, it is certainly a hypothesis provider from which we may be able to gain advanced knowledge on this still relatively unknown topic.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-20/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-20/coif). G.V. has advisory activity with AZ, MSD, EISAI, GSK. The other authors have no conflicts of interest to declare.

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