Selective FGFR3 inhibition represents a promising new approach in bladder cancer

FGFR inhibitors have emerged as an important class of targeted therapies in bladder cancer, with erdafitinib (Balversa) already approved for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least 1 line of prior systemic therapy.

However, the clinical utility of FGFR inhibitors has been limited by significant toxicities, making long-term treatment challenging. Dabogratinib (formerly TYRA-300), a next-generation oral agent, is designed to selectively inhibit FGFR3 while sparing other isoforms, with the goal of maintaining efficacy while reducing FGFR1/2-mediated toxicities.

Early findings from the SURF301 trial (NCT05544552) in metastatic urothelial carcinoma demonstrated encouraging efficacy with a favorable tolerability profile compared with pan-FGFR inhibitors.¹ Building on this, the ongoing SURF302 study (NCT06995677) is evaluating dabogratinib in patients with FGFR3-altered, low-grade, intermediate-risk non–muscle invasive bladder cancer (NMIBC)—a population traditionally managed with endoscopic procedures and intravesical therapies. The results of these studies, particularly in regard to safety and toxicity, will inform the future role for a targeted oral therapy in these spaces.

In a recent interview with Urology Times®, Tom Jayram, MD, outlined the rationale for selective FGFR3 inhibition in bladder cancer as well as what’s needed to bring this treatment modality into routine clinical practice. Jayram is a urologic oncologist at Urology Associates in Nashville, Tennessee.

Urology Times: What is the mechanism of action for dabogratinib?

Jayram: This is in a class of drugs that we would consider FGFR inhibitors. FGFR inhibitors have now been approved in treating advanced bladder cancer. Erdafitinib is a drug that medical oncologists utilize for patients who have an FGFR [mutation] and metastatic disease that may not have responded to conventional earlier stage therapy. We know that there is a rationale for this. FGFR is a group of enzymes that help regulate tumor growth and signal downstream pathways that basically augment tumor growth. Inhibiting these pathways can lead to tumor shrinkage and improvement in cancer outcomes in these patients.

Dabogratinib is a little bit different than erdafitnib and some of the earlier FGFR inhibitors in that it's a selective inhibitor; it only targets FGFR3, as opposed to targeting some of the other isoforms of FGFR. The hope is that the toxicity of the drug will be substantially lower without lowering the efficacy of the therapy. One of the issues with oral erdafitnib is that even though the drug works in the right patient, it is a very difficult drug to keep patients on because of the toxicities involved.

Urology Times: This agent is being explored in the SURF302 and SURF301 trials. Could you highlight these studies?

Jayram: The SURF302 study has just started. [That study is enrolling] patients who have intermediate-risk, low-grade bladder cancer that have an FGFR alteration. If you look at the literature, depending on how you test, we're finding up to 60% to 70% of patients have an alteration in FGFR, so it's a high proportion of patients in the intermediate-risk category. These patients are going to be given daily oral dabogratinib. They have a recent history of diagnosed low-grade, intermediate-risk bladder cancer, and they will have a visible lesion in their bladder that we're following. Over time, we're going to try to understand safety outcomes and efficacy outcomes as it relates to this novel therapy.

This is on the heels of the SURF301 study, which was dabogratinib in a metastatic population. That data showed very good efficacy and tolerability with a much lower likelihood of high-grade adverse events compared with the conventional oral FGFR inhibitors that are not as selective.

Urology Times: The SURF302 study is exploring dabogratinib in patients with FGFR3-altered low-grade, intermediate-risk NMIBC. How significant is the move toward a targeted oral therapy in a space currently dominated by intravesical treatments?

Jayram: That’s the big question: Is there ever going to be a role for an oral systemic therapy in a disease process such as this? This disease is generally low grade, indolent, and usually we manage it with endoscopic approaches, either cystoscopy with bladder tumor resection or fulguration, or now we have new therapies that are FDA approved, where we're placing intravesical gel therapy into the bladder. So, is there a role for systemic oral therapy? Erdafitinib and antibody-drug conjugates are slightly more challenging to give because there are more [adverse] effects. The primary determinant of [the viability of an oral therapy] is going to be the tolerability and toxicity concerns in an otherwise indolent, slow-growing disease process for which we usually don't need to give systemic therapies. I think the answer is to be determined based on the results of some of these trials.

I can tell you anecdotally, in my practice, there are patients who, if you give them the option of an intravesical therapy or an oral therapy, interestingly will choose an oral therapy. They are fatigued from intravesical therapies. They are tired of having cystoscopies and things placed in their bladders, and they have a lot of irritative voiding symptoms. It may represent a nice alternative for these patients who otherwise are [almost] destined to just continue to receive these endoscopic treatments that cause a quality-of-life erosion, as we've seen in several studies that have been published about the burden of bladder cancer, in intermediate-risk or even high-risk disease. I think that absolutely there may be a position here for an oral therapy to come in and add to our options. It doesn't mean that every patient needs it or that every patient has to be on it, but if you present patients the options, I personally think you're going to be surprised by the number of patients who say, "If the side effects are manageable and I don't have a lot of issues with it, I would be happy to try something orally."

Urology Times: How do you see the role of molecular profiling evolving, particularly as we consider selecting patients for FGFR-directed therapies?

Jayram: I'm really excited by this part of the whole diagnostic work-up and shift toward personalized medicine in bladder cancer. We've seen this quite a bit in prostate cancer now, where PARP inhibitors have occupied a very firm role in treating advanced disease in the right patient. Similarly, I think there's going to be this same concept in bladder cancer. We know that there are a lot of molecular alterations that we see in some of these tumors, P53 and RB1, and these alterations can potentially be utilized as a target for some of these novel agents.

We can deliver drugs in novel ways in bladder cancer. We can do it orally, like we're seeing with this trial, or we can do it endoscopically; we can put targeted therapies into the bladder. I think bladder cancer is ripe for a more personalized approach. Urologists, especially those who have been treating advanced prostate cancer, are already familiar with somatic tissue testing. We're now starting to see a lot of new markers in urine to look for tumor DNA, and we’re using ctDNA in more advanced disease. There's a lot coming out now. I think this is a great initial application for tumor profiling, because these patients are very common in urologic practice and a very high percentage are going to have an alteration. It's going to make a lot of sense, I think, to utilize this personalized approach in this disease state.

Urology Times: What are some of the next steps for dabogratinib in both metastatic urothelial carcinoma and NMIBC?

Jayram: We want to build a safety profile and, really, everything hinges on that. The biggest barrier for the uptake of these agents is going to be toxicity. Urologists know how to deal with intravesical toxicity such as irritative voiding symptoms and lower urinary tract symptoms. Although those symptoms can be very bothersome, they don't pose a serious danger to the patient like some of these systemic toxicities, especially in the immune-mediated adverse event realm. But even so, the toxicity is going to drive everything. If the toxicity profile looks to be manageable, and again, from the SURF301 study and some of the earlier data, it does appear to be that way, then I think it becomes an interesting discussion with the patient on the risk-benefit of an oral therapy vs an endoscopic therapy. This step is really important.

I would encourage providers who do research at their facility to look into this study because it's such a novel approach to intermediate-risk, low-grade bladder cancer. We don't have anything like this out there right now, so let's try to get all the data we can [to determine if] this makes sense for our patients in this disease space. Once we get the safety data, I think it's really going to evolve from there.

REFERENCE

1. Tran B, Zhang A, Hansen A, et al. Preliminary safety and anti-tumor activity of TYRA-300, a highly selective FGFR3 inhibitor, in participants with advanced solid tumors with activating FGFR3 mutations/fusions (SURF301). Presented at: 36th EORTC-NCI-AACR (ENA) Symposium on Molecular Targets and Cancer Therapeutics. October 23-25, 2024. Barcelona, Spain. Abstract 500LBA