Zachary Klaassen: Hello. My name is Zach Klaassen, urologic oncologist at the Georgia Cancer Center, in Augusta, Georgia. I'm delighted to be joined on UroToday by Dr. Srikala Sridhar, who is a medical oncologist at Princess Margaret Cancer Center, in Toronto, Ontario. We'll be discussing her ESMO 2025 oral presentation discussing the ALPACA trial, a key trial looking at other options other than chemotherapy for advanced penile cancer. Kala, thanks so much for joining us on UroToday.

Srikala Sridhar: Thanks for having me, Zach, and bringing some attention to this rare cancer.

Zachary Klaassen: Absolutely. Orphan disease, and I'm glad they recognized it with an oral presentation at ESMO.

Srikala Sridhar: Yeah, absolutely. So maybe I'll just run through it for you, if that works.

Zachary Klaassen: Absolutely.

Srikala Sridhar: Yeah. So this was a Phase 2 study of avelumab, which is a PD-L1 inhibitor, in locally advanced or metastatic penile cancer patients who were either unfit for standard platinum-based chemotherapy, or had progressed on platinum-based chemotherapy. I have some disclosures, of course. So this trial actually took almost seven years to complete. It faced a number of challenges, including the pandemic, including loss of the sponsor. I was super pleased that we were able to get it done, especially for this patient population that is so rare, and doesn't have a lot of trials available to them.

By way of background, we know that penile cancer is a rare and aggressive malignancy, and will account for about 38,000 new cases per year, worldwide. There is significant geographic variability, with most cases being seen in Latin America, Africa, and India. This is largely due to sociodemographic factors. Up to 50% are HPV-related, and 30 to 60% express PD-L1. And so, for patients with metastatic disease, unfortunately, median survival remains less than one year. It's pretty dismal. Platinum-based chemotherapy has limited efficacy, with response rates in that 30 to 40% range, low durability of progression-free survival of only about three months or so, and is relatively poorly tolerated. There are currently no standard second-line options, which really highlights a significant unmet need. The immune checkpoint inhibitors have shown activity in other HPV-related cancers, and as you know, are fairly well-tolerated. And so, it really set the stage to conduct this investigator-initiated multicenter single-arm Phase 2 trial, to determine the efficacy and tolerability of the PD-L1 inhibitor avelumab, in patients with penile cancer refractory to, or unfit for platinum-based chemotherapy.

You see we kept the criteria fairly open. Because there's not that many of these patients around, we didn't want to restrict too much, in terms of the eligibility criteria. So here you see the study design. It was a multicenter, single-arm Phase 2 study. We took patients with locally advanced inoperable, or metastatic penile cancer. They had to be refractory or unfit for platinum-based chemotherapy, having an ECOG performance status of 0 to 2, and no prior immune checkpoint inhibitors. And so, they went on to receive avelumab at a dose of 10 milligrams per kilogram IV every two weeks, which is fairly standard dosing for this drug. This was given until toxicity or progression. Tumor assessments were done every eight weeks. The primary endpoint was objective response rate by the investigator, using the iRECIST criteria. Secondary endpoints, progression-free survival, overall survival, safety and tolerability. We tried to incorporate some correlative studies, as well, which of course, in investigator-initiated studies, that's always a little bit extra, and hard to do these correlative studies, because the funding really is for the trial, very little leftover for these. We used a Simon 2-Stage design, and overall we accrued 25 patients during the accrual period of August 2018 to January 2025, of which 23 patients were deemed evaluable, and that's the group in whom we reported on.

So, in this patient population, median age was 58. So it's a young-ish patient population, if you think about it. Majority of patients were ECOG 1 or 2, and 30% were actually ECOG 2. So, these patients were quite sick and quite unwell. About 83% had visceral metastatic disease, and all but one patient had prior platinum-based chemotherapy. So, they were all very solidly in the sort of platinum-refractory setting. Then we looked at HPV status. Interestingly, in about half the patients it wasn't available. And in the half in whom it was available, about half of those were HPV-positive. So, that's something that we're trying to get a little bit more information on, as we look further into getting HPV status established.

Here, you can see the primary endpoint was objective response rate by the investigator. Four patients had a partial response, so, four out of 23, about a 17% response rate. The disease control rate, five out of 23. So, one patient had prolonged stable disease, so it comes into that category. But I think what's perhaps important to keep in mind is, for those patients that did respond, median duration of response was about 15.9 months. So, if we can figure out who those patients are that are responding, there's a chance they'll get a good response. And again, this drug is well-tolerated. When we looked at the secondary outcomes, so, progression-free survival, really short, 1.7 months. Median overall survival, 3.9 months. So, this is not transformative data. I mean, there's a lot of patients who just didn't respond to treatment, and just had disease progression throughout. The median number of cycles was about three cycles. Ongoing treatment in about three patients, they continue on treatment, and about 20 patients have come off treatment. The majority of those have come off because of disease progression. Again, not that surprising, given this disease.

From a correlative standpoint, we didn't see a clear correlation between HPV status and outcomes. But then again, half the patients we didn't know their HPV status. So, I think that really needs to be looked into further. We found also a high neutrophil to lymphocyte ratio may predict worse outcomes. This is a simple thing that you can find on the blood test. So, if it helps us to understand, then that might be something to look at going forwards, as well. We have a number of correlative studies still ongoing at this time.

When you look at the adverse events, really no new safety signals. No treatment-related grade five events. I know when we treat with upfront chemotherapy, infection is a common problem in these patients. We didn't really see that, related to the immunotherapy. That certainly is a bit encouraging, I would say.

So really, in conclusion, we felt that in patients with advanced penile cancer refractory to platinum-based chemotherapy, avelumab was well-tolerated and achieved an objective response rate of 17%. Median duration of that response was about 15 months, suggesting a small subset of patients may benefit. But we really need biomarkers to understand who these patients are, and maybe to refine patient selection accordingly. Progression-free survival and overall survival, as I mentioned, were short, suggesting this is not transformative data. But I think we'll have to look in the future to see if these agents should be evaluated, maybe, in earlier disease settings, maybe in the neoadjuvant setting, maybe in combination with chemo, or even drugs like the antibody-drug conjugates, which we've seen move quite nicely ahead, in diseases like urothelial cancer. So, maybe we have to start looking at things like that in this setting.

Ultimately, I felt, though, that large-scale collaborations, innovative study designs, and increased funding would be really essential to accelerate drug development to improve outcomes for patients with rare tumors, including penile cancer. And then, as always, I want to thank the patients and their families who agreed to participate, the three research cancer centers that were involved, Pfizer, who supported and provided study drug, and some of my colleagues who helped me with the presentation. It was such a pleasure to present this, and to finish this study, and we're working on writing it up now. Thank you.

Zachary Klaassen: So, Kala, fantastic work. Congratulations to you and your colleagues in Toronto, also in London and Hamilton, to get this study done. These are not easy, when, by definition, orphan disease for penile cancer. But it really goes to show, I believe 22 of the 23 were platinum refractory, so these patients have no other option. So when you look at objective response rates of 17%, modest. But for those few that do have a response, certainly transformative to try to help them have a little quality of life and quantity of life. How do you think this data with avelumab maybe informs future trials, future IO options? You mentioned the ADCs. How do you take this data and move forward?

Srikala Sridhar: Yeah, I think that's a great question. So, I think we've seen these combination studies now. I treat a lot of urothelial cancer as well, things like enfortumab vedotin plus pembrolizumab really moving frontline metastatic bladder, now moving into the perioperative setting, based on data. At ESMO, there is nectin expression in penile cancer. So, can we look at enfortumab vedotin? Can we look at enfortumab vedotin plus pembrolizumab? Can we look at these combination approaches? Because this is such an aggressive disease that moves so quickly, that we need something really effective upfront. I think that's where this came in, in second line, as you said in the platinum-refractory setting, their disease is quite aggressive at that point. Their clinical status is quite poor at that point. We know immunotherapy often takes a little bit longer to work. And so, maybe you ran out of runway for that to work. So, I think if we move these drugs earlier, perhaps we will get a little bit more efficacy, and perhaps in combination is the way to go. I think we really need to understand, what are the biomarkers in those tumors? What's being expressed? I don't think we have a lot of that. And even to have wide-scale collaborations where we collect tissue maybe across Canada, or whatever, from all penile cancer patients, and do a deep dive and understand some of the molecular drivers may set the stage for the next line of treatment. But the fact that we can get these trials done is going to be really important for the future.

Zachary Klaassen: Yeah, no question. I think if we look at penile cancer in this setting, chemo is not a cure for these patients. I mean, if we can get something like an enfortumab vedotin plus pembrolizumab or maybe there's something out there we haven't figured out yet, run those Phase 2s, and start to get a signal to even just eliminate the chemo and go upfront. I think that's, like you said, getting them moved up to where we can get a response rate would be great.

Srikala Sridhar: Yeah. Absolutely.

Zachary Klaassen: Always great chatting with you, Kala. Any take-home messages? Anything we haven't hit on yet before we conclude?

Srikala Sridhar: No. I mean, I think that it's just this idea that when we're doing trials, I'd encourage our industry colleagues to really think about diseases like penile cancer that are orphan diseases, as you said at the outset, where there is no standard of care. There's not a whole lot. So if you found something that was effective, I think you'd get an indication fairly quickly. I think these patients are so desperate, that I would just encourage all of us to try to put a bit of a focus, and try to advance the field in these rare cancers.

Zachary Klaassen: Yeah, absolutely. Kala, thanks so much. Congratulations, again. Appreciate you joining us on UroToday.

Srikala Sridhar: Absolutely. Take care.