So Lutetium-PSMA-617 ((lu psma 617) prostate specific membrane antigen), we'll call it 617 for this discussion, is already an FDA-approved agent for Progressive Metastatic Castrate Resistant Prostate Cancer (MCRPC metastatic castration resistant prostate cancer or advanced prostate cancer). The brand name is Pluvicto. The FDA approval is for men who have progressed despite 1 prior advanced hormonal therapy and at least 1 prior line of Taxane therapy.
And that agent is quite active and well tolerated. The question remains: How and in what is the best way to move this agent earlier and earlier for men with Progressive Metastatic Castrate Resistant Prostate Cancer (MCRPC metastatic castration resistant prostate cancer)? And so there are several studies ongoing. This 1 is specifically investigating the use of PSMA-617 (Lutetium-177–PSMA-617 (lu psma 617) prostate specific membrane antigen) and men who have progressed on 1 advanced hormonal therapy.
Either Enzalutamide or Abiraterone typically, although now a progression on Apalutamide for hormone-sensitive prostate cancer (cells) would also be applicable and eligible patients. And the question is the alternate advanced hormone therapy something that we should be using, or should we be using PSMA-617, particularly in a patient population naive to all Taxane therapy?
And that's the question of this study. So it's a randomized (treatment) study comparing PSMA-617 (Lutetium-177–PSMA-617 (lu psma 617)) to the alternate advanced hormonal. Hormonal agent. And think this is an, it is an important study. It asks a very clinically relevant question.
So the treatment landscape for Progressive Metastatic Castrate Resistant Prostate Cancer (MCRPC metastatic castration resistant prostate) has shifted significantly over the past decade, the major. The driver of that change is the intensification of therapy for men. Metastatic hormone-sensitive prostate cancer (cells metastatic castration resistant prostate cancer), where we're now typically using doublet therapy. So androgen deprivation therapy (ADT or androgen receptor pathway inhibitors) and an advanced hormonal agent, and even in some patients, triplet therapy combining docetaxel with androgen deprivation therapy (ADT androgen receptor pathway inhibitor) and either Abiraterone or Darolutamide based on the recent phase 3 studies that have shown the efficacy there. What about surgically treated prostate cancer in metastatic prostate cancer?
So when patients progress to Progressive Metastatic Castrate Resistant Prostate Cancer (MCRPC metastatic castration resistant prostate cancer), they're now typically progressing, having already received a prior advanced hormonal therapy like Abiraterone or Enzalutamide. So patients in this space still have multiple life-prolonging therapies available, including Sipuleucel-T Radium 223, Docetaxel, the alternate advanced hormonal therapy, and patients typically are going to be treated.
Based on the severity of their disease, and so patients with the relatively indolent disease who are Taxane naive and continue to have indent disease progression, we consider therapies like Sipuleucel-T or alternate AR-directed therapies therapy. And so the PSMAfore clinical trial is asking the question of patients where we're considering.
Their disease is manageable with an alternate AR, are they better served? Do they have better response rates and more durable responses to a more aggressive therapy like this? Radiopharmaceutical targeting PSMA, or perhaps are there issues related to toxicity? That would make an alternate AR therapy potentially even more effective.
And so that's why it's an important study that's being appropriately addressed in a randomized fashion.
So PSMA-617 was a molecule synthesized in Germany and has been used there for quite a while. Multiple phase 2 studies were presented there, and there have been randomized phase 2 studies presented with this agent from the Peter MacCallum Cancer Centre in Australia, all showing impressive response rates.
And even head to head against Cabazitaxel in a significantly higher response rate in a selected patient population. Those studies led to the VISION clinical trial, the registrational phase 3 trial that led to the FDA approval of this agent for Progressive Metastatic Castrate Resistant Prostate Cancer (MCRPC metastatic castration resistant prostate cancer) that has progressed on one AR-directed therapy and at least one, if not two of Taxine based chemotherapy.
Prior clinical data led to the design of this study comparing PSMA-617, the only approved radiopharmaceutical agent targeting PSMA in the space right now, to an appropriate standard of care for a selected patient population progressing on the first line of AR-directed therapy.
PSMA is a very commonly expressed tumor-associated antigen. That is a transmembrane protein with an extracellular domain. And it is frequently upregulated in prostate cancer (cells) and is expressed in upwards of 90% of men with Progressive Metastatic Castrate Resistant Prostate Cancer (MCRPC metastatic castration resistant prostate cancer). And so, it is a common tumor-associated antigen. The trial's design is in keeping with a VISION trial (in prostate cancer cells) in that it is a precision trial in which prostate cancer patients treated need to have evidence of the predominant PSMA disease as detectable on a PSMA. One of several PSMA PET scans. In common practice for men who are Taxane resistant, we commonly have several PSMA agents that we image with, but for the trial specifically, Gallium Ga 68 PSMA-11 (prostate specific membrane antigen) was the (PSMA) imaging agent used to detect PSMA expression.
So it's a precision trial (in prostate cancer cells) patients need to have PSMA avid disease on PET imaging, and then patients are randomized. And the trial does allow crossover at radiographic progression. And the primary endpoint of the study is radiographic progression-free survival (radiographic disease progression or overall survival), which has been accepted by the FDA as a clinically relevant primary endpoint sufficient for drug approval.
So the specific inclusion and exclusion for this trial are similar to the VISION trial (in prostate cancer clinical trials) patients need to have PSMA predominant disease. So they cannot have any PSMA negative visceral disease or bulky osteons PSMA negative disease that's defined. In the VISION eligibility criteria, patients cannot have had any prior PSMA targeted therapy.
Patients cannot have had any prior Taxane-based therapy used in the hormone-sensitive or hormone resistance space. And the idea here is really to focus on this patient population with a relatively indolent disease where we can best appropriately compare The PSMA-617 versus the alternate AR-directed therapy.
The promising attributes of PSMA-617 are the ability of the agent, what we've seen, to prolong life and to help patients with symptoms. Number one and number two are to be well tolerated and to have a low rate of high-grade toxicity and a low rate of fatigue. And so those are the key endpoints that I think oncologists are gonna be looking at.
They are going to be looking at the extent of delay in radiographic progression-free survival (overall survival). They are going to be looking at the response rate, and they're gonna be looking at the durability response, and of course toxicity now with this agent, the main toxicity of note is that is dose-limiting is typically marrow toxicity.
And so thrombocytopenia is the data point that, that oncologists will have their eye on. There is a concern about multiple neurotoxic agents in sequence, eventually leading to bone marrow failure. And so the use of this agent earlier and earlier in the disease trajectory, I think, needs to be tested for precisely that reason. What is the impact on the bone marrow?
In the long run, though, I think that the main outcome of note will be the delay in radiographic progression-free survival, and we're hopeful that using this agent in an earlier taxi naive setting will give us an even bigger improvement in that critical.
Like many, I had a close family member with cancer at a very young age. And so that was a very memorable experience that has stayed with me both the experience of my experience, my family's experience, of course, but also our relationship with the oncologist and our reliance on and dependency on the healthcare system in order to manage through that experience, that had a big impact on me. And that was one of my major motivators just to help others through that experience. I also became very interested in understanding the science of cancer the science of cell biology.
And trained as an MD, Ph.D. in that space, trying to understand the disease from all angles. And as I progressed through my training and learned about different types of cancer and got to interact with different types of patients, I was very struck by the treatments that we had for prostate cancer and felt very proud of what the medical community has been able to develop and be able to help patients with those very effective treatments that, that felt like that was the right place for me to be at the same time.
We still had patients who did not do well with our treatments from a side effect standpoint and from. The standpoint of disease continues to be not well managed. And that's where research came in. And I worked with some influential mentors who greatly impacted my career, particularly in prostate cancer.
And that solidified my career in that area, both in prostate cancer and clinical research and trying to develop better treatments and taking care of men with prostate cancer and taking care of people with other urologic cancers. So that's that was my development and my evolution into that space.
I think that to oncologists. I think that our patients who are being treated with prostate cancer fundamentally, on the one hand, have treatments that are available and effective. On the other hand, these treatments are often very difficult to manage for some men, and we need to do better in intensifying cancer therapy treatments that are more targeted and less toxic for patients with aggressive diseases.
And we need to de-escalate or make the treatments more gentle for patients who do not have aggressive disease. And I think those are both. Key goals for the community over the next several decades. And it's tough to go back and forth, and that's all of us, trying to strike that balance of bringing the right patient and treatment to the right patient at the right time.
And I think that PSMA4 and PSMA-617 are other key treatments we're going to have available. That's gonna really for the right patient is gonna help. And I think we need to do more research with clinical trials and good clinical research to understand better who most clinical benefit and who might be better served with something else.
David Wise, MD, Ph.D. - DASL-HiCaP Phase 3 Trial : Update
David Wise, MD, Ph.D. - About The Author, Credentials, and Affiliations
David R. Wise is an assistant professor in the Department of Medicine and the Department of Urology at NYU Langone's Perlmutter Cancer Center focusing on clinical oncology. He holds a doctorate and a medical degree. Dr. Wise practices medicine in New York, New York, and specializes in clinical oncology. He has more than 11 years of expertise in the field of medicine. In 2011, he received his medical degree from the University of Pennsylvania School of Medicine. Appointments with his office can be made via telehealth.