How LuPSMA is changing the prostate cancer space

At the recent 2021 Prostate Cancer Foundation Scientific Retreat, Michael S. Hofman, MBBS (Hons), FRACP, FAANMS, FICIS, presented the latest research on LuPSMA for the treatment of advanced prostate cancer.¹ He gives an overview on current LuPSMA clinical trials and what these trials hope to accomplish in the prostate cancer space. Hofman is a nuclear medicine physician and director of the Prostate Cancer Theranostics and Imaging Center of Excellence (PROSTIC), Melbourne, Australia.

Please describe the work being done by the Prostate Cancer Theranostics and Imaging Center of Excellence.

PROSTIC is the Prostate Cancer Theranostics and Imaging Center of Excellence, and we seek to do state-of-the-art research to deliver new paradigms for treatment of prostate cancer by seamlessly integrating clinical trials, preclinical, and discovery research. We have a multidisciplinary team, including nuclear medicine, medical oncology, radiation, oncology, urology, and laboratory-based doctors and researchers in our hospital and we have a strong patient-centered philosophy.

PROSTIC has 3 main aims that we're really working on every day. [The] first aim is to accelerate clinical trials. When we started this program, we had around 5 clinical trials open and we're hoping by the end of next year to have 10 clinical trials open. These are using PSMA imaging or PSMA-targeted therapy theranostics to treat men with prostate cancer. And with these investigator-initiated trials, we're trying to find areas of high-impact need that are not being addressed by other global trials being done to date.

A second aim is around education and leadership. This is a technology that's taking off very quickly, again, both on the imaging and the therapy side. PROSTIC will serve as a global hub of excellence to educate doctors, scientists, patients, and the community about this new technology and how to adopt it. So, next year, we're going to have a PROSTIC preceptorship in April, which will be an in-person and hybrid meeting, where we're really going to go through how we do the imaging and the therapy in our hospital.

The third aim is discovery research. We hope to further investigate next generation PSMA-targeting molecules, develop new biomarkers to try to predict and monitor response to these novel therapies, optimize combinations with other treatments, and do some discovery research, including artificial intelligence [and] deep learning of our images. So, [it's] a large program and it's really thanks to a large grant from the US-based Prostate Cancer Foundation [who have] made this possible, combined with local support from the Peter MacCallum Foundation in our hospital.

At the recent Prostate Cancer Foundation Scientific Retreat, you gave a presentation titled, “LuPSMA: The Newest Treatment Class for Advanced Prostate Cancer.” Can you provide a brief summary of this presentation, as well as the PSMA-targeting products that are currently available?

Lutetium PSMA is a new treatment option for men with prostate cancer, and it's a radioactive molecule that targets prostate-specific membrane antigen, PSMA being a cell surface receptor that sits on prostate cancer cells. So, this is a way for us to get high doses of radiation to sites of tumors, wherever they are in the body. This year, in the last 6 months, 2 randomized control trials have read out in this area. This treatment [has] been in evolution for the last 6 to 7 years, but now we have these 2 randomized control trials, 1 being our own Australian phase 2 trial called the TheraP trial.² This was a randomized trial compared to cabazitaxel [Jevtana] chemotherapy. We also have the VISION trial,³ which is the phase 3 industry trial run by Novartis comparing lutetium PSMA to best standard of care. What both these trials showed is a significant advantage for lutetium PSMA 617, and this was really the subject of the talk. Those advantages are, in the VISION trial, improved survival by approximately 4 months and improved quality of life. Both trials showed improved PSA response rates, improved responses on CT, like RECIST responses, and really all end points favoring lutetium PSMA. It's really quite well tolerated. There's not a lot in the way of side effects. We do have some off-target effects, the main ones being salivary toxicity, which causes mild dry mouth, but this was really only grade 1 and 2 in both of those studies. We see a little bit of hematotoxicity, again, mostly grade 1 and 2, with about a 10% incidence of grade 3 thrombocytopenia. Nausea is another side effect but compared to existing treatments or just standard of care, we really improved quality of life with this treatment.

The setting where this was studied was men with metastatic castration-resistant disease, who had progressed after docetaxel chemotherapy and also after an anti-androgen targeted therapy, like enzalutamide [Xtandi] or abiraterone [Zytiga]. So, this is a third-line treatment option. In the TheraP study, it was vs cabazitaxel. In the VISION trial, some patients had progressed after cabazitaxel, some patients weren't suitable for cabazitaxel. So, this is now providing a strong evidence base for lutetium PSMA 617. The treatment recently received FDA breakthrough status, which means it will be more rapidly reviewed. We expect an outcome from the FDA next year and if that's positive, we expect global, widespread availability of this as a new option for men with metastatic castration resistant prostate cancer.

In what ways do PSMA-targeting agents meet an unmet need in prostate cancer?

Men with metastatic castration-resistant prostate cancer have a limited number of therapies available at the moment and that's really chemotherapy, like docetaxel or cabazitaxel, anti-androgen targeted therapies, like abiraterone or enzalutamide, and there are some new drugs, like PARP inhibitors. But it is a lethal condition, and the survival of men in this state is really quite poor in the order of only a few years. So, we need to do better than that. This is a totally new class of treatment. The mechanism of action is completely different to all these other treatment options, working by delivering radiation to all sites of disease. So, it's got some analogies to external beam radiation, which is an effective palliative treatment, but [with] external beam radiation, you can target a single side of disease. Here, we're giving the injection intravenously, it travels around the body, it's taken up directly into the tumor sites, delivering really high doses of radiation, specifically to tumors. Now, the lutetium 177 travels only 1 mm, so once it's taken up into the tumors, there's not a lot of damage to surrounding normal tissue. It's a truly targeted therapy and that's why it's so well tolerated.

In terms of an unmet need, we want to do 2 things for men with metastatic castration-resistant prostate cancer. One is to prolong life, improve survival, and the second one is to improve quality of life. They're really the 2 main aims. This is not a curative treatment, so some men are having really exceptional responses and potentially living several years longer than they would, but eventually the prostate cancer recurs. But what the VISION trial and the TheraP trial [tell us] is that this is a life-prolonging therapy. We improve the duration of life. That's only good if we also improve the quality of life, and we do that in 2 ways with this treatment. One is by having good responses, so tumor shrinkage if you've got pain, and men with castration-resistant prostate cancer very often have spread of cancer to bones and that causes bone pain, requiring opiate analgesics or other forms of pain relief, or can lead to pathologic fractures. By shrinking the tumors in bone with lutetium PSMA, we often get a rapid reduction in pain, and we also delay consequences like fractures. That's a really important way to improve quality of life. The other way we improve quality of life with this treatment is by just having a low side effect profile compared to other drugs. So, compared to cabazitaxel chemotherapy, which causes [a] range of chemotherapy side effects like nausea, vomiting, neuropathy, hair loss, a whole range of those chemotherapy-related side effects, which can decrease quality of life whilst you're on the treatment, we just don't see those side effects with lutetium PSMA. Whilst you're on the treatment, you can usually continue what you're doing. Many people [are] still playing golf or doing their work whilst on this treatment.

What innovations in PSMA do you expect to emerge in the near future?

In the near future, firstly, we want to see this treatment FDA approved and globally available. So, that's step 1 because, at the moment, in some jurisdictions like ours this treatment is already available, but in much of the world this isn't available yet. We hope that'll happen pretty soon. Now, we have a whole range of other clinical trials that are already open, some industry sponsored, some, like ours, investigator-initiated, and these are looking at using lutetium PSMA earlier in the treatment paradigm. So, the vision of the TheraP trial [is] really [the] last lines of therapy after you've failed chemotherapy and antiandrogens. And the question is, "Well, it works well in that setting. Can we bring it back earlier? Can we use it before chemotherapy? Can we use it in men even with newly-diagnosed prostate cancer?" [In] Peter Mac[Callum] and around Australia, we have a few clinical trials open in this setting. One of them [is] called the UpFrontPSMA trial,⁴ which is looking at men with newly diagnosed prostate cancer with high-volume disease and comparing lutetium PSMA followed by docetaxel to docetaxel alone. We have a trial called the PRINCE trial,⁵ combining lutetium PSMA with immunotherapy, and another trial LuPARP,⁶ combining it with a PARP inhibitor. Can we improve outcomes by combining rotation PSMA with other treatments? Because we know the history of oncology is often that these combination treatments work better. [There's] a lot of emphasis on these combination treatments, and another trial looking at [lutetium] in combination with enzalutamide. We do know that enzalutamide, or novel antiandrogen-targeted treatments in general can result in increased PSMA expression. So, there's a hope that we can modulate PSMA expression with some drugs, increase the amount of PSMA on the tumors, [and] therefore increase the amount of radiation that we can target. A lot of clinical trials underway using lutetium PSMA earlier or in combination with other treatments.

Is there anything else you feel urologists should know about this topic?

It's probably also worth mentioning that all the clinical trials that I was describing use lutetium PSMA 617, which is the Novartis product. There is another product in active development called lutetium PSMA INT, which is very, very similar, has some minor differences, and there are a few companies around the world commercializing lutetium PSMA INT. There [are] other groups working on next-generation targeting molecules. So, they're the 2 first cabs off the rank, and now we'll have a newer generation. Can we improve targeting by modifying the PSMA targeting molecule further?

Another way we're trying to improve this treatment is by using different radioactive substances other than lutetium 177. There's a lot of interest in actinium 225, which is an alpha emitter, a different type of radioactive substance. And there's a whole myriad of different radioactive substances that can be used that are going to be evaluated over the next few years. I think this is going to be an area of really explosive growth and interest, but most importantly, a new treatment option to both improve survival and improve quality of life for men with prostate cancer.

References

1. Hofman. PSMA Theranostics: The New Age of Prostate Cancer Imaging and Treatment. Lecture presented at: 2021 Prostate Cancer Foundation Scientific Retreat; October 28-29 and November 4-5, 2021; Virtual.

2. Hofman MS, Emmett L, Sanhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. The Lancet 2021;397(10276):797-804. doi:10.1016/S0140-6736(21)00237-3

3. Study of 177Lu-PSMA-617 in metastatic castrate-resistant prostate cancer (VISION).ClinicalTrials.gov. Updated July 27, 2021. Accessed November 11, 2021. https://clinicaltrials.gov/ct2/show/NCT03511664

4. In men with metastatic prostate cancer, what is the safety and benefit of lutetium-177 PSMA radionuclide treatment in addition to chemotherapy (UpFrontPSMA). ClinicalTrials.gov. Updated January 8, 2021. Accessed November 11, 2021. https://clinicaltrials.gov/ct2/show/NCT04343885

5. PRINCE (PSMA-lutetium radionuclide therapy and immunotherapy in prostate cancer) (PRINCE). ClinicalTrials.gov. Updated December 3, 2020. Accessed November 11, 2021. https://clinicaltrials.gov/ct2/show/NCT03658447

6. 177Lu-PSMA-617 therapy and olaparib in patients with metastatic castration resistant prostate cancer (LuPARP). ClinicalTrials.gov. Updated June 16, 2020. Accessed November 11, 2021. https://www.clinicaltrials.gov/ct2/show/NCT03874884