GU Cancers 2022 | BAYOU: durvalumab plus olaparib for first-line treatment of unresectable advanced UC

The BAYOU study is a randomized Phase II trial that was designed with the knowledge that advanced urothelial cancer, harbors mutations in DNA damage and repair genes in about 20 to 25% of patients. And many of these, most, are homologous for combination of repair genes. And previous data had suggested that the response to immunotherapy might be better in those patients. And we know that in other diseases with these mutations in HRR genes, that patients will respond to PARP inhibitors. And so, based on those several strands of evidence, the BAYOU study was designed.

It was a randomized Phase II trial in platinum-ineligible patients. So these are patients who were ineligible for cisplatin or carboplatin based therapy, and that was defined as, in the investigator’s opinion, not eligible for carboplatin based therapy, and also have renal insufficiency, poor performance status, peripheral neuropathy, or hearing loss, or heart failure. Didn’t have to have all of those criteria, but you had to have at least one of those.

Patients were then randomized, to either, durvalumab alone, or actually, durvalumab/placebo, and durvalumab and olaparib. And patients were stratified by the presence of HRR mutations in their tumor, that was done prospectively, as well as Bajorin risk index, zero one or two, to either durvalumab and olaparib, or durvalumab and placebo. Then, the primary endpoint was progression-free survival in the ITT population, which is all patients who were enrolled and got treated. There was a pre-specified progression-free survival analysis in patients with HRR mutations. And in that patient population, the hazard ratio is .018, and the progression-free survival was about three to four months longer in the HRR subset. But in the entire study population, really, there was no benefit to the combination of durvalumab and olaparib compared to durvalumab and placebo.

Looking at secondary endpoints, the response rate in the HRR mutant durvalumab and olaparib treated patients was 35%, which is quite high. Although, the numbers of patients in that cohort were modest. But there were no responders in the durvalumab monotherapy cohort. And when we looked at the entire population, the response rate was a little higher in the durvalumab and olaparib group, but that was probably driven by the the patients with mutations who were included in the ITT analysis.

And then, looking at overall survival, there’s been some suggestion in the data, that patients with these mutations are a poor prognosis group. And in fact, that was true in this trial, suggesting that survival was shorter, regardless of whether you received olaparib or placebo, if you had a HRR mutation. Although, there was a numerically longer survival in those patients who received olaparib, if they had mutations. Wild type patients did not appear to benefit at all from getting olaparib, and the median survival for the wild type patients was longer, regardless of treatment that they received. And so, it does suggest that this highlights a relatively poor prognosis group of patients in advanced urothelial cancer.

And so the question is going to be more moving forward, seeing the data from the maintenance trial and HRR mutant patients, also showing a progression-free survival advantage as monotherapy, do we consider further trials with these agents in appropriately selected patient populations? And I’m hoping that this will trigger a new wave of trials, looking at HRR altered tumors specifically, and enrolling only those patients, because that’s where the benefit seems to be found. And those are the patients that unfortunately don’t do well with apparently, standard of care therapies based on our data.