MEDIOLA Highlights Importance of BRCA Testing in Advanced Ovarian Cancer

Susana K. Banerjee, PhD

The combination of olaparib (Lynparza) and durvalumab (Imfinzi), and olaparib plus durvalumab and bevacizumab (Avastin) was well tolerated in patients with non-germline BRCA-mutated platinum sensitive relapsed ovarian cancer, according to findings from the phase 1/2 MEDIOLA trial (NCT02734004).¹

The phase 1/2 MEDIOLA trial is an open-label, multicenter study which evaluated these 2 combinations in patients with advanced solid tumors who harbor BRCA mutations, including non-germline BRCA-mutated platinum sensitive relapsed ovarian cancer.

Patients enrolled in the trial had progressed after receiving 1–2 prior lines of platinum-based chemotherapy. Olaparib was administered at 300 mg orally twice a day, durvalumab was given at an intravenous dose of 1.5g every 4 weeks, and bevacizumab was given at 10 mg/kg once every 2 weeks (triplet only) until progressive disease.

The primary end points of the trial included safety and disease control rate (DCR) at 24 weeks. Secondary end points were objective response rate (ORR), median duration of response (mDOR) and progression-free survival (PFS).

Data presented at ESMO 2022 showed that the DCR for patients who received the doublet did not meet the prespecified target of 80% while the DCR for patients in the triplet cohort included the prespecified target. The ORR and PFS in the triplet cohort demonstrated promising activity in this patient population

At the data cut-off of February 13, 2020, 22% of patients who received the doublet of olaparib and durvalumab and 42% of who received the triplet of olaparib, durvalumab, and bevacizumab remained on treatment. The most common grade 3 or greater adverse events (AEs) in the doublet arm included anemia, lipase increased, and neutropenia. In the triplet arm, the most frequent AEs were anemia, hypertension, fatigue, lipase increased, and neutropenia. Two patients (6%) receiving the doublet and 5 (16%) receiving the triplet discontinued 1 or more of the study drugs as a result of their AEs.

In an interview with Targeted Oncology^TM, Susana K. Banerjee, PhD, a consultant medical oncologist and research lead for the Gynecology Unit at The Royal Marsden NHS Foundation Trust, further discussed the updated results of the MEDIOLA trial and the implications of these findings.

Targeted Oncology: Can you discuss the prognosis of patients with non-germline BRCA mutations? What are the clinical implications of having this mutation?

Banerjee: It's such an exciting time treating patients now with advanced ovarian cancer because thanks to BRCA testing, we're able to tailor our therapies. There's been a lot of progress in BRCA-mutated ovarian cancer with PARP inhibitors in the first-line and recurrent disease. Then in non-germline BRCA-mutated ovarian cancer, we also know that PARP inhibitors can help some women in that situation. There have been studies of PARP inhibitors as monotherapy as treatment and as maintenance therapy. One of the key questions is whether we can enhance the response, the survival, the progression-free survival, in patients with non-germline BRCA-mutated ovarian cancer where the clinical outcomes are not as good as with women with BRCA mutations.

Can you explain the background of the MEDIOLA trial?

MEDIOLA is a phase 2 study, and it was designed to evaluate combined treatments with the PARP inhibitor olaparib plus the PD-L1 inhibitor durvalumab in women with platinum-sensitive relapsed ovarian cancer. The latest update is of a triplet combination of olaparib plus durvalumab and the antiangiogenic agent bevacizumab. We also updated the combination of the doublet of olaparib plus durvalumab. This was specifically in women without a germline BRCA mutation.

We already knew from our presentation back in 2020 at the ESMO Congress that the response rate was around 34%, and median progression-free survival was just over 5 and a half months with a doublet combination. With the triplet, it showed promising efficacy with a response rate of 87%, and a median progression-free survival of 14.7 months. What I updated in terms of the MEDIOLA study at the 2022 ESMO Congress was the overall survival and the disease control rate at 56 weeks.

What are the key takeaways from the primary analysis of MEDIOLA?

What we saw was that in the triplet cohort, the median overall survival was 31.9 months, and the 56-week disease control rate was almost 39%. Now in the doublet cohort of olaparib plus durvalumab, the median overall survival was 28 months, and the 56-week disease control rate was around 9%. What's important is to also look at potential biomarkers when looking at homologous recombination deficiency states and immunotherapy, so looking at genomic instability status, and PD-L1 status. What we found was that there was no clear association between clinical outcomes, so survival, progression-free survival, and response, with either genomic instability status or PD-L1 status, but it’s important to point out that there were small event numbers and there are patients with unknown biomarker status. That limits the interpretation, and further investigation is warranted.

What are the implications of these findings?

An important aspect is we're looking at combination treatments, and also the safety. What we learned with the long-term follow-up is that the safety profile was consistent with a known safety profile of the single agents. The real implication of this treatment shows proof of concepts looking at signals, which is important in earlier phase studies to see if there's some clinical activity, which is important to take forward in further clinical trials. That's what I think MEDIOLA brings to the table, looking at the combination of PARP inhibitors with immunotherapy, and also the triplet combination with antiangiogenic treatments. The next steps are that the olaparib plus durvalumab and bevacizumab combination is under investigation in the first-line setting for newly-diagnosed advanced ovarian cancer as a maintenance treatment in patients with non-BRCA-mutated advanced ovarian cancer in the phase 3 study.

Are there currently any other studies for patients with BRCA-mutated disease that seem hopeful?

At the 2022 ESMO Congress, we heard the 7-year follow-up from the SOLO-1 trial [NCT01844986]. What we saw was that there was a clinically meaningful prolongation of survival in women treated with olaparib as maintenance therapy for 2 years and these patients had a BRCA mutation. We also saw in the PAOLA-1 study [NCT02477644], an improvement with the addition of olaparib to bevacizumab of an overall survival at the 5-year point. It's an exciting time for the treatment of women with BRCA-mutated ovarian cancer and those without BRCA mutation. I think the important message is that we should be considering maintenance PARP inhibitors in the first-line setting for women with newly-diagnosed advanced ovarian cancer, and that BRCA testing is essential in clinical practice.

REFERENCE:

Drew Y, Penson RT, O'Malley DM, et al. Phase II study of olaparib (O) plus durvalumab (D) and bevacizumab (B) (MEDIOLA): Initial results in patients (pts) with non-germline BRCA-mutated (non-gBRCAm) platinum sensitive relapsed (PSR) ovarian cancer (OC). Ann Oncol. 2020;31(suppl_4):S551-S589. doi:10.1016/annonc/annonc276