Andrei Iagaru, MD, Professor of Radiology – Nuclear Medicine and the Chief of the Division of Nuclear Medicine and Molecular Imaging at Stanford Health Care, discusses current trials exploring new indications for prostate-specific membrane antigen (PSMA) and GRPR, as well as what’s currently in the prostate cancer treatment pipeline and some key differences between Axumin and PSMA.
GU Oncology Now: Could you discuss the premises of the trials currently underway at your institution evalu- ating PSMA and GRPR imaging for indications beyond biochemical re- currence and the presurgical setting?
Dr. Iagaru: First of all, thank you for the invitation to be a part of your series. This is a very important area, imaging, and treatment of prostate cancer, and it’s great that Nuclear Medicine now plays a significant role in both imaging and therapy. We started at our institution providing expanded access program to PSMA radiopharmaceuticals for diagnosis. We currently use F-18 DCFPYL for these purposes, both biochemical recurrence and pre-prostatectomy. But as you asked about other indications beyond these, we do have trials with Gallium-68 PSMA-11 under an IND, as well as Gallium-68 RM2, a gastrin-releasing peptide receptor antagonist also on under an IND for the indications of biopsy guidance, as well as guidance in patients with either suspected prostate cancer in the case of pre-biopsy or newly diagnosed prostate cancer in the case of treatment guidance.
What are some of the preliminary findings of these trials?
As far as biopsy guidance, we just finished analyzing the data from the first 10 participants who were involved, so it is a pilot study, but overall, both PSMA and RM2 had accuracy in the mid-80% range. We saw a sensitivity of 100% for both of them and specificity of also mid-80%. What we’ve observed is that in this cohort, the sensitivity of multi-parametric MRI of the prostate was 50%. And this is not surprising because we are selecting patients who had equivocal or negative MRI. So not everyone with suspected prostate cancer should get these tests, but those where MRI and prior biopsies are inconclusive are likely to benefit from PET imaging, either with PSMA or gastrin-releasing peptide receptor, or both.
How can additional indications for PSMA and GRPR imaging fill an unmet need in prostate cancer treatmeant?
Beyond biopsy guidance, as I indicated earlier, guiding what area of the prostate to treat with high-intensity focused ultrasound (HIFU) or high-dose-rate brachytherapy are of great interest to our group. And not only to guide what needs to be treated but also six months later after treatment to see if we can avoid biopsying these patients again to evaluate the response to treatment.
And then if we expand beyond that, the spectrum of prostate cancer patient covers many years. So we can look at earlier stages of biochemical recurrence like an oligometastatic disease. We can think of combination with radioligand therapy. So Lutetium-177 or alpha emitters labeled PSMA combined with immunotherapy, for example. Or we can think of combining disease-targeted therapies with external radiation therapy. At my institution we installed the first biology-guided radiation therapy from a company called RefleXion. So instead of using the anatomical signal to guide the X-ray beam for external radiation you use the PET signal to do that, which has many advantages.
What are some treatments for prostate cancer cur- rently in the pipeline that you are interested in?
On the side of radiopharmaceuticals, there are several versions of PSMA agents each with their own potential advantages. In addition to beta emitters like Lutetium-177, we also have alpha emitters that are in the pipeline. Those are of great interest as well, but we also have to keep in mind that there are also drugs that are
non-radioactive, that are expected to, for example, target PSMA and block those cancer cells in other ways than radiation does. So the field is evolving rapidly and there is a lot of excitement about all of these treatments.
I would also add again that the combination of biology-guided radiation therapy through a device like RefleXion and intravenous radiopharmaceutical therapy holds a lot of promise for many of these patients.
What are the most significant difference between Axumin and PSMA?
Well, there are many and I don’t know if we have time to discuss all of them, but Axumin (fluciclovine) has an advantage of little-to-no urinary excretion. For many of the PSMA agents, evaluation of the prostate bed may be limited by the fact that the urine contains the drug. So one potential benefit for Axumin is evaluating the prostate bed. There are PSMA agents like PSMA-1007 with less urinary excretion that do not have the disadvantage.
However, I would say that the PSMA agents have significant advantages over fluciclovine in terms of detection of disease at low PSA levels, such as <1 ng/ml. So it’s there where PSMA has significant advantages. If you go to lev-els of PSA greater than five, the positivity rate between the two I think is comparable. PSMA targets an enzyme that’s overexpressed in many prostate cancers, while Axumin targets the amino acid transporter present in cancer, but also other cells.
I think that as far as image interpretation, PSMA scans are likely to be easier to interpret than Axumin scans because of less non-specific activity. My prediction (and of course, you have a 50% chance of being correct when you make a prediction about the future, but I think in this case it’s higher than 50%) is that PSMA would largely replace Axumin in the United States after FDA approval, but Axumin will retain a role for certain patients. Remember PSMA is a great tool but not 100% sensitive or specific.