The potential of HER2 targeting in prostate cancer: A case study with trastuzumab deruxtecan

In this interview, Maneesh R. Jain, MD, details a case study on the use of trastuzumab deruxtecan-nxki (Enhertu) in a patient with Human Epidermal Growth Factor Receptor (HER) 2-positive prostate cancer.¹ Jain is an oncologist at the Washington DC VA Medical Center and an associate professor of medicine at George Washington University.

This transcript was AI generated and edited by human editors for clarity.

Maneesh R. Jain, MD

Could you provide some background on this case and describe the rationale for turning to this treatment option?

This is a 59-year-old, currently 60-year-old veteran who had been seen by other large academic centers in the Washington, DC area, and had been coming to see me for the past few years as a third opinion. It turned out that his prostate cancer was extremely aggressive. After undergoing several treatments, it can be converted or changed to what they call neuroendocrine prostate cancer, which tends to be extremely aggressive. Patients usually have less than a year to live. His cancer had gone to the neck and brain, and he had it resected at an academic university in the area in October/November. He came back in January and had mentioned to me that the cancer had grown back in the neck and brain. So, he had disease in the brain, neck, abdomen and all over his bones. At the other hospitals, they had basically told his wife and him that they had ran out of standard-of-care options. He came in [to see me] and was fatigued and withdrawn and had a poor performance status. That's when I talked to him about using this drug off-label.

Things that people need to recognize is we do not check protein expression or immunohistochemistry expression in prostate cancer. We check it in breast cancer and a lot of other solid tumors, but not in prostate cancer. We rely on next-generation sequencing to get a tumor profile of the tumor. What's interesting about this particular target of HER2 in prostate cancer is you cannot see it in the next-generation sequencing; you have to be able to check it using immunohistochemistry. At the other hospitals, they had checked next-generation sequencing, but had not seen this biomarker. The reason we were doing biomarker research that led to HER2 was we have a minority cohort at the Washington DC VA Medical Center, and we wanted to look at certain targets using immunohistochemistry. When these data came out 2 years ago [and were] very promising in breast cancer, we thought to re-look at HER2 in prostate cancer. Before that veteran had come and saw me, I had known that his HER2 expression was high. I had checked it in his tumor, knowing that this could be a relevant pathway and we have an upcoming clinical trial. We knew he was positive. So, when he came and saw me in February, we knew this was a potential area or target to treat.

What was the patient’s response to treatment?

He started therapy in February of this year, and within 2 to 3 cycles of treatment, he had a dramatic improvement in his fatigue and his appetite. His energy had increased because his hemoglobin had increased. There was a huge tumor on his left side of his neck, and that had decreased so you could no longer palpate it. He no longer had bone pain. The tumor was on his neck, so he couldn’t swallow that well on that side, and his vision was impaired on the left side. A lot of those symptoms went away within a few months. It's very dramatic. I mean, he failed 7-8 lines of therapy.

The family gets very emotional. There was a trip that they wanted to go on, a mission trip. They were going to go to the west coast to Utah. He has 5 sons and a daughter. They were not sure that they were going to be able to go on this trip, because of all the news that they heard in January/February. When he had that dramatic improvement from the trastuzumab deruxtecan, he was able to go on this trip in June. And he's still doing well.

What's amazing about this therapy is his prior lines of therapy only worked for 3 to 4 months. He's been on this therapy from February to now November, and he's still doing well. So, he's been on it now for almost 9 months. Even though he has a very aggressive prostate cancer [that] involved the neck and brain, and his prior lines worked 3 to 4 months, this therapy has been working for 9 months and he's doing well. There was 1 lesion in the brain that they were a little concerned whether it was responding to trastuzumab deruxtecan, [but] the rest of his disease was doing well. So, they resected it at an academic institution in our area, and a few days afterwards, which just happened last week, he was like, “When can I resume my trastuzumab deruxtecan?” He actually wanted to come in last week because he was doing that well. I feel like it's an incredible turn-around from February to now. Like I said, he's been on it for 9 months. I feel in my heart he might be on it beyond a year, which is incredible, being so late-stage and having such an aggressive cancer.

Given this patient’s response to therapy, are there plans to explore this treatment option in prostate cancer?

We had our concept endorsed to our pharma sponsor, Daiichi Sankyo. We have an upcoming trial called the CaRPET trial (NCT06610825). It's a multi-VA site trial between us and 6 other VAs and then our academic affiliate, George Washington University. Our hope is to start this trial in December of this year. What we're looking at in that trial is different levels of HER2 expression. In some of the other solid tumors, this drug worked very well if you had higher expression, like IHC 2+ and IHC 3+. We will have arms of IHC 3+, IHC 2+, and IHC 1+, just to stratify response to therapy. Our hope [is] that the majority of the patients respond, but bare minimum, that they respond in the higher expressing group, the IHC 2+ and the IHC 3+. We're going to try to see, by different levels of immunohistochemistry, who responds in this trial. We're very excited about it. It's a 60-patient trial.

Could you touch on the importance of HER2 expression testing?

In April of this year, the trastuzumab deruxtecan got an FDA pan-tumor approval that [says that] anybody that is IHC 3+ can go on this drug.² That pan-tumor approval and this patient case really highlight that in prostate cancer, we should be checking HER2 by immunohistochemistry so that we can identify patients to get this treatment, either by participating in the clinical trial or getting trastuzumab deruxtecan based on the pan-tumor FDA approval.

I will make a note that some people in prostate cancer use a breast scoring system or a gastric scoring system. Based on how we score it using our institution scoring system, we scored him as an IHC 3+. But if you use the breast or gastro scoring system, he would not have been IHC 3+. That would have meant that if the pan-tumor approval was there and somebody had seen him and done immunohistochemistry, he would have not been scored IHC 3+. Therefore, he would not have been able to benefit from that pan-tumor approval. Another thing that we're trying to illustrate in the case is not only to test for HER2 by immunohistochemistry, but also to consider an alternative scoring schema that takes into consideration the morphology that you see in prostate cancer. We're utilizing that scoring schema in our clinical trial. By no means are we saying that this is the right scoring schema, we're just saying that we should just not be using a breast scoring schema or another solid tumor schema and applying it in prostate. That is our argument.

Is there anything else that you wanted to add?

It's a very incredible drug. It's an antibody drug conjugate, so it's linked to topoisomerase inhibitor. As long as there's expression of HER2 in prostate cancer, or any other solid tumor, then the drug will work, because it kills that target and the neighboring cancer cells. I feel like we're a little bit behind [in prostate cancer]; we have data on all the other solid tumors. You could say to yourself, with such a common cancer in men, why are we starting the trial now?

The reason for that is they tried other HER2-directed drugs like herceptin [trastuzumab] and lapatinib [Tykerb] in the past, and it didn't work in prostate cancer. Because it's not a mutation or amplification you can't use a signal transduction inhibitor. You need to focus on this low level of expression.

Where this antibody drug conjugate comes into play is as long as there's expression in the cancer cells, there's a chance that this could work. Because prior drugs in prostate cancer utilizing HER2 did not work, maybe that is why in prostate cancer we are the last major solid tumor to have this checked on. In breast there's an approval, gyn, lung, upper GI, and even in the pan-tumor trial, they included pancreatic—they included everybody. So, why did they not include prostate? I think it was just because it's a low level of expression, and the prior therapies on HER2 did not work.

References

1. Lap CJ, Rajendran R, Martin JM, et al. Response of Human Epidermal Growth Factor Receptor 2-expressing prostate cancer to trastuzumab deruxtecan. Ann Intern Med. 2024.doi:10.7326/ANNALS-24-01409

2. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. News release. US Food & Drug Administration. April 5, 2024. Accessed December 3, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2