GU Oncology Now recently spoke with Dr. Nat Lenzo, Group Clinical Director, GenesisCare-Theranostics (Oncology) Nuclear Physician and Specialist in Internal Medicine Clinical Professor in Medicine, Notre Dame University and Curtin University, Australia, and Dr. Aviral Singh, Clinical Research and Development Manager (Theranostics and Central Imaging) GenesisCare – Theranostics (Oncology), North Shore Health Hub, Sydney, Australia. We discussed how PSMA PET modalities, and Lutetium-177 labeled PSMA therapies, have been ‘game changers’ in the fight against advanced prostate cancer.

GU Oncology Now: Can you provide us with some background on yourself, and your specialty?

Dr. Nat Lenzo: Yeah, thanks Rob. So I’m Nat Lenzo. I’m a nuclear physician and general internal medicine physician, currently based in Perth, Western Australia. I trained in medicine in Australia and also did a fellowship in nuclear medicine at the University of Michigan, United States. I’ve worked in the area of internal medicine and nuclear medicine now for the last over 20 years. Got involved with PSMA PET imaging on the back really of data take PET imaging for neuroendocrine tumors, about 2014, 2015 in Australia. And we’ve been using PSMA PET imaging for prostate cancer staging and restaging and guiding therapy for the last five or six years now. It’s been approved for reimbursement in Australia, and we are due to have our approvals granted, what we call Medicare benefits scheduled reimbursement in the next few months. On the back of the PSMA PET, I’ve also been involved in radioligand therapy with Lutetium PSMA. I’ll leave it at that.

Dr. Aviral Singh: I’m Aviral Singh. So I’m a nuclear medicine physician. I’m currently working with Genesis K Australia in the capacity of a research and development manager. And I’ll be doing a fellowship very soon with the Royal North Shore Hospital. My background is nuclear medicine from UK initially and followed up by a long tenure at one of the ENET Centers of Excellence and a leading center in theranostics, which is Central Clinic Bad Berka. I was there for over seven years where I also completed management medicine training and I’ve recently moved from there. So apart from that, I have pursued clinical medicine from Ukraine, as well as Australia earlier, as physician training. And I’ve also pursued a masters in nuclear medicine from the King’s College London, and I’m currently pursuing a PhD in innovative cancer diagnostics and therapy from Maastricht University, Netherlands. I’ve been involved theranostics of prostate cancer from almost the very beginning, which is 2013. And we have probably one of the largest numbers in the world of gallium PSMA imaging, as well as radionuclide therapy for prostate cancer at the Central Clinic Bad Berka.

What are the challenges of treating metastatic castration resistant prostate cancer (mCRPC), and what is the typical prognosis in this patient population?

Dr. Nat Lenzo: Yeah, look prostate cancer, when you get to this stage of castrate resistance in advanced disease can be challenging. Up until the last few years that were limited therapeutic choices. Chemotherapy has a role often in earlier disease, but the cohort of patients that we treat with advanced metastatic castrate resistant prostate cancer are off often elderly. And so using chemotherapy can be difficult in this patient cohort. The life expectancy of someone who has failed first line chemotherapy and is now in castrate resistance and failed novel antiandrogen drugs is quite limited, usually the order of less than 12 months. At this stage also, there’s a number of symptoms that often patients will complain of, often symptoms related to pain from bone symptoms from bone metastasis. So it’s a group of patients where we have had limited options traditionally, and they start developing symptoms, which can be quite debilitating. And so having a targeted therapeutic approach is a welcome addition to our armamentarium.

How have PSMA PET imaging modalities changed the landscape with respect to prostate cancer?

So essentially PSMA PET imaging has been an absolute game changer. It has really brought about a revolution in the medical imaging of prostate cancer. So say for example, very often one had been focused at the pelvic region. So for example, even for initial staging, mostly the diagnosis was pelvic focused and you do conventional imaging with CT MRI and things, and you would see… or biopsy or ultrasound, you would see the focal or localized disease at best or say primary tubal or some lymph nodes in the area. And usually there were certain metastasis which were not picked up when you do a CT whole body imaging. [inaudible 00:05:56] the known limitations of conventional imaging. What we see with PSMA targeted imaging is A, the resolution is phenomenal. So we can actually pick up very small lesions because it’s not morphological based.

It’s molecular based imaging and PSMA itself. It’s a peptide… I’m sorry, it’s a substance, which is situated on cell membranes. And it’s expression is particularly increased when the tumor is aggressive or metastasized. So having said that, the diagnostics with PSMA PET imaging is both beneficial at initial staging, where when we see PSA could be not very high, but the disease could be spread in other organs or one could have distant metastasis. And this could in itself change the management approaches of prostate cancer because some patients… most patients, yes they’re diagnosed early with low metastatic burden, but there are a lot of patients who are diagnosed at late stage with multiple metastases, which could have been missed by conventional imaging.

Now with PSMA targeted imaging, these metastases can be picked up earlier rather than late. B, when a patient treated with conventional therapies that are there today, at late stages when the disease is advanced and progressed and [inaudible 00:07:50], at late stage heavily metastasized or advanced disease, recurrent, past all possible treatments, at that point, PSMA targeted imaging can also help in patient selection for PSMA targeted therapy for which there have been clinical trials now. And hopefully this is going to be FDA approved very soon in the near future.

Can you talk to us about Lutetium-177 labeled PSMA and how this agent can be used as a diagnostic and therapeutic target in mCRPC?

Dr. Nat Lenzo: Yeah, thanks lutetium-177 is a beta emitting radio re-client, it’s been around for a long time. And in fact, the whole paradigm of lutetium PSMA for the targeted therapy of prostate cancer, based on the PSMA target, goes down to a similar scenario that we’ve been using in neuroendocrine tumors now for about 20 years. So in neuroendocrine tumors, we look for a different target called the somatostatin receptor and we use lutetium-177 coupled with gallium imaging as well. So we use gallium PET to look for the targets usually. And then once we find a target, we move from a diagnostic type of imaging agent with gallium to a therapeutic type of treatment with lutetium. So that sort of gallium for imaging, lutetium for therapy has been around a long time. We can use lutetium more so as an imaging agent, but it’s not a very good imaging agent.

It does give some type of radiation that we can pick up on a gamma camera or a SPECT camera. And we do that routinely more so to see if the therapy has gone to the targets that we wanted and also to do what we call dosimetry, where we try and work out doses. Doses to relevant organs like bone marrow or kidneys, and also doses to the tumor. So by and large, in modern practice of radioligand therapy, we’ll use a PET imaging agent, either gallium or now fluorine PSMA to look for the target. And then if you have sufficient target, then we can offer a therapy with lutetium PSMA, which will go to those areas and deposit a radiation dose to those areas.

Are there any studies you’re currently involved in that you would like to make our audience aware of?

Dr. Nat Lenzo: Yeah, we’re involved in a number of trials. Of course the vision trial has been reported out of the United States and Europe, which showed the benefit of this targeted approach to metastatic prostate cancer using lutetium PSMA therapy. In Australia, there’ve been a few trials, the therapy trial that’s also been reported. That was a trial done at a number of institutions. We’ve currently got a trial called the ENZA-p trial, which is a combination trial of enzalutamide and lutetium PSMA.

It’s been done throughout Australia and Genesis Care is involved at our site in New South Wales at the North Shore where Dr. Singh practices. We also have a number of trials, both imaging, and therapeutic in this area. We have trials with Clarity pharmaceuticals, looking at a new type of imaging agent called copper PSMA. We have trials with Telix pharmaceuticals looking at their gallium PSMA imaging agent, but also some of their new PSMA targeting agent called TLX 591. And that’s a slightly different agent, but once again, it works on the same principle of targeted radioligand therapy. That agent is a monoclonal antibody that targets the PSMA with lutetium coupled to the monoclonal antibody to bring D lutetium once again, to the PSMA target on the tumor. So we have a number of trials currently ongoing in Australia.

Dr. Aviral Singh: The most important trial that we have so far was the vision trial. The results are pretty supportive before, the success of… or reflecting the usefulness, effectiveness, and safety of lutetium PSMA therapy. However, of course, there are certain… patients usually reach a saturation point or they become resistant to therapy. So in the future, there would be areas of… there are areas of interest with, say, for example, imaging and therapy with other radionuclides, say for diagnostic purposes, we’ll probably have the same, but there are other ones that are being worked up. What would be more important is therapy say, for example, alphas images such as thallium, it’s being used a lot real world for patients who are resistant already to lutetium therapy. However, due to logistic reasons where there’s shortage of thallium, it’s difficult to produce and distribute.

These are the areas which one would need to look into in the future. There are other radionuclides, such as terbium, which we worked with. And scandium back in Europe, where imaging could be performed, very high quality, high resolution PET images can be acquired as well as these can be… they have what we call telenostic pairs. So the similar radionuclide, with a different number or quality, so it has different qualities of emission. So the other isotope, lets say emits beta radiation, which could then be used for treatment. So same with scandium 44, 47 with terbium 152, 167. So these are different avenues to look for in the future. There are also different combination therapies to be looked into future, say combining PSMA radioligand therapy with radiosensitizer and chemotherapy, which professor Lenzo has already mentioned. There are certain trials ongoing. So these are the works for the future of theranostics and prostate cancer.

Any closing thoughts?

Dr. Nat Lenzo: Look, I think it’s an exciting time for theranostics in prostate cancer. There’s a lot happening in the space, as Dr. Singh said, combination therapies, we think are the way forward. There’s been some very exciting work out of the United States, looking at combining the immunotherapy with radioligand therapy. And there’s a number of trials happening in Europe and the United States with a number of companies such as Novalis pushing this area. So I think it’s a very exciting time and it bodes well for future prostate cancer patients.