Allison Brodsky, MD, MD Anderson Cancer Center, Houston, Texas, discusses translational results from the phase 1b COPANIRA trial. This study assessed the relationship between molecular profiling and response to copanlisib and niraparib among patients with recurrent ovarian and endometrial cancer.

Dr Brodsky concluded that “PI3K activation within tumors was not directly correlated with PI3K mutation status, but elevated expression of certain AKT substrates and ARID1A were associated with progressive disease” adding “potentially these could be looked at as potential biomarkers when using other types of PI3K inhibitors.”

Transcript: 

Hi, my name is Allison Brodsky. I'm a GYN oncology fellow at MD Anderson and I will be presenting the translational studies of COPANIRA, which was a phase 1b trial of copanlisib and niraparib in recurrent ovarian and endometrial cancer. 

The clinical results of this trial were presented at SGO 2024. A brief summary is this was a phase 1 trial that enrolled 30 patients, and the patients got both copanlisib, which is a pan-PI3K inhibitor, and then niraparib, which is a PARP inhibitor. It was a dose de-escalation trial and the overall response rate for this trial was 13% and the clinical benefit rate, which we defined as a partial/complete response or any type of response with stable disease that lasted more than 4 cycles, and this was 35%. Overall, there was significant toxicity in this combination, the DLT [dose-limiting toxicity] rate was 50% of patients enrolled, with the most common dose-limiting toxicity being maculopapular rash. The final recommended phase 2 dose is 100 mg niraparib and 45 mg of copanlisib but a further trial will not be conducted due to the toxicity. 

For the translational research, we did some exploratory studies to determine if a response to therapy was associated with the molecular profile of the tumor before treatment and to examine if any associations with early changes in functional proteomic biomarkers might help guide who would benefit from PI3K inhibitors and PARP inhibitors in the future. To do this, we used a reverse phase protein array analysis, which I'll refer to as an RPPA, and we took tumor tissue prior to treatment and then after 28 days on treatment. With consent from patients, they had both these biopsies done to look at this further. Since we were looking at a PI3K inhibitor, we created a PI3K score based on 11 proteins that are prominent in the PI3K pathway and then we compared the results of the stable disease to the progressive disease group. 

We found that for PI3K scoring, it was not correlated to stable disease or progressive disease's best response, and so therefore, change in PI3K scoring was not correlated to response, it might not be a useful biomarker in the future. However, when we did an unsupervised RPPA analysis to look for other biomarkers, we found 19 proteins which showed significant difference between the stable disease and progressive disease groups and many of these candidate biomarkers were substrates of the AKT pathway, which is a critical player in the PI3K pathway. We also noted that ARID1A was uniformly elevated in those with progressive disease and minimal in those with stable disease, which has been shown before in prior studies with PARP inhibitors. 

Overall, the key takeaways based on this study is that PI3K activation within tumors was not directly correlated with PI3K mutation status, but elevated expression of certain AKT substrates and ARID1A were associated with progressive disease. Potentially these could be looked at as potential biomarkers when using other types of PI3K inhibitors, whether those are pan class or specific to different classes in combination with PARP inhibitors. Thank you so much.

Source: 

Brodsky A, Asare A, Fellman B, et al. Translational studies of COPANIRA: A phase Ib trial of copanlisib (PI3K inhibitor) and niraparib (PARP inhibitor) in recurrent ovarian and endometrial cancer. Presented at the 2025 SGO Annual Meeting on Women’s Cancer. March 14-17, 2025; Seattle, WA. Abstract 816809