Thomas Powles, MD, MBBS, MRCP, discusses the rationale for the BISCAY trial and what questions still need to be answered.
Thomas Powles, MD, MBBS, MRCP
Results of the biomarker-driven phase Ib BISCAY trial, while it did not meet the prespecified efficacy target, led to intriguing questions about possible future treatment options for patients with metastatic urothelial cancer, explained Thomas Powles, MD, MBBS, MRCP.
In the open-label, randomized, study, investigators explored various combination regimens with durvalumab (Imfinzi) in patients with metastatic disease based on molecular alterations identified via the FoundationOne CDx analysis: durvalumab plus the FGFR inhibitor AZD4547 (FGFR alterations), durvalumab plus olaparib (Lynparza; BRCA1/2, ATM, and homologous recombination repair gene alterations and unselected patients), durvalumab plus the dual mTORC1/2 inhibitor vistusertib (TSC1/2 and RICTOR gene alterations), durvalumab monotherapy, or durvalumab plus danvatirsen for those without gene alterations.
Results showed that the objective response rates (ORRs) were 28.6%, 35.7%, 24.1%, and 27.6% for the AZD4547/durvalumab, olaparib/durvalumab, vistusertib/durvalumab, and durvalumab monotherapy arms, respectively. In patients who received the FGFR inhibitor alone (n = 15), the ORR was 20.0%. However, none of these ORRs met the prespecified efficacy endpoint of 50%, Powles explained.
"We are looking to cure patients," said Powles. "If we are going to use combinations in a personalized approach, we should be using that as our goal. We failed to show consistent signals with this particular trial, but it was a huge effort from the people involved. The trial is ongoing and we have more arms to report in the future."
In an interview with  OncLive  during the 2019 ESMO Congress, Powles, professor of genitourinary oncology, lead, Solid Tumor Research,  director, Barts Cancer Center, in London, England, discussed the rationale for the BISCAY trial and what questions still need to be answered.
OncLive:  What was the rationale for the BISCAY trial?
Powles:  BISCAY is a personalized study looking at novel combinations based on durvalumab in platinum-refractory urothelial cancer. It's an exciting study that was difficult to do. Essentially, we found three exciting targets in urothelial cancer: FGFR, PARP, and mTORC1/2 inhibition.
Inevitably, there was increased toxicity [with some of these agents in combination with durvalumab], but if you are pursuing a personalized combination approach, you're going to want to do better than monotherapy.
We did have a monotherapy arm in this study; however, the arms were not directly comparable because they had different biomarkers. The monotherapy arm had a response rate of 28%, which was a bit higher than we saw with the control arm [at 20%]. It is really a plausible result.
The combination didn't exceed our predefined criteria of 50%. We got to 35% with the PARP combination in patients who had high expression of tumor mutational burden (TMB) and PD-L1 expression. One may say that the immunotherapy may have done better in that arm, but nevertheless, it is an area where we could potentially explore in the future.
We did a randomized phase II [study] in these patients, so we had some patients who had an  FGFR  inhibitor alone, and some patients received an  FGFR  inhibitor plus durvalumab. Again, the addition of the second drug did not make a huge difference and the  FGFR  inhibitor showed activity. Interestingly, the biomarker expression of PD-L1 and TMB was lower in this group of patients. The rationale may be to combine them. The m TORC1/2  arm was not particularly encouraging from our perspective.
Overall, this is a really novel design. It is efficient to bring multiple arms together to test, and knock out the good combinations. We didn't achieve that, but it not necessarily a failure. It means we can move on and use our resources [to move forward].
There may be subtle differences between these [arms]. Perhaps durvalumab plus an  FGFR  inhibitor is 10% to 20% better than durvalumab alone. We haven't been accurate enough to establish that in this study, which is a shortcoming of the trial.
How many patients were screened for this trial versus how many were ultimately involved? Is it feasible to apply this design in a large-scale study?
We screened 390 patients and we enrolled about 120 patients for the trial. It took us a few years to [accrue patients], and there was a big dropout because not all patients were biomarker-positive and there were some exclusion criteria for the individual arms.
We are not entering an era of personalized therapy in urothelial cancer today, but we need to. We know the  FGFR  inhibitor erdafitinib (Balversa) has been approved in the United States, so we have already started the process, but we do not have a randomized trial to support it yet. Could we employ a model such as BISCAY with a personalized approach using drugs like erdafitinib?
We need other promising targets, because erdafitinib [will target] only 15% of patients. It is difficult to screen for 15% of the population so we are currently looking at this in trials today. It is time bladder cancer caught up with other tumor types.
What are the advantages and drawbacks to using liquid biopsy?
There has been some criticism of ctDNA [with regard to] limited availability in some patients. If you go back 10 years, the story was different. We need to explore this avenue properly. Yes, we have not done so in cancer medicine, with cisplatin being the obvious exception in testicular cancer. However, it is unusual to start the journey and answer the question on day one. This is part of the journey.
In 30 years, if we still have to take biopsies from the majority of patients to decide which treatment [to use], that would be a failure. It is not going to be perfect, it may not work for everyone, and there may be some patients whom we need to take biopsies from in the future, but that doesn't mean this isn't an avenue that may be helpful for big groups of patients.
This circulating material is up to date. In the BISCAY trial, we allowed tissue that was 3 years old. Many of those patients had platinum-based therapies and their biomarker expression may be completely different, so this contemporary material may turn out to be a lot more valuable. Perhaps in those patients who do shed tissue, we can find great biomarkers. That would be a step for 50% of patients. It is a “glass half full, glass half empty” discussion, and I am going to be a “glass half full” person.
What are the next steps regarding the BISCAY trial?
The BISCAY trial had a complex design. It also had a comprehensive biomarker program attached to it. We have done FoundationOne CDx analysis looking for DNA alternations on these tumors. We have also monitored FGFR mutations and the presence and absence of ctDNA. I am hoping in the near future we can switch from tumor-based biomarkers into circulating biomarkers, with BISCAY starting that process.
Powles TB, Balar A, Gravis G, et al. An adaptive, biomarker directed platform study in metastatic urothelial cancer (BISCAY) with durvalumab in combination with targeted therapies. Ann Oncol. 2019;30(supp_5). doi: 10.1093/annonc/mdz249.001.