Andrew J. Armstrong, MD, MSc

: We now have safety for over 800 patients to really talk about. The good news is that the safety reporting in the study was very complete, and demonstrated a very favorable safety profile. If you talk about all grades of toxicity, the most common side effect of PSMA [prostate-specific membrane antigen] lutetium was fatigue. About half the patients experienced some degree of fatigue. About 7% experienced more severe fatigue. That can result from bone marrow suppression, such as anemia, where about 13% develop the need for transfusions. Cytopenia and the bleeding risk that can happen with low platelet counts occurred in about 8% of patients to that severe degree. PSMA is expressed in the salivary glands and the lacrimal glands, so you do see some dry mouth and dry eyes. This occurs for about 30% to 40% percent of patients. You can see some mild nausea or vomiting. Very rarely can you see renal effects. PSMA can be expressed in the renal tubules. There is only a slightly higher risk of impaired renal function from PSMA lutetium, but it does illustrate the importance of monitoring the GI [gastrointestinal] system, the metabolic system, and bone marrow lab parameters when treating with PSMA lutetium. Despite this, there was no increased risk of infection or neutropenic fever, unlike how it was with cabazitaxel in the randomized phase 2 study, where this was a major side effect.

One clinical trial that has been reported—again, it is a small clinical trial—is called the TheraP study. It was just published in 

. This trial, led by Michael S. Hofman, MBBS,FRACP, FANNMS randomized patients between PSMA lutetium and cabazitaxel, all of whom had a potent AR [androgen receptor] inhibitor, and had a positive PSMA scan. We do see that adverse events really do differ between these 2 therapies as one might expect. For example, the rate of fatigue was very similar, but dry mouth was more common with PSMA lutetium. It was the same with dry eyes. Nausea and vomiting were more common, as was diarrhea, with cabazitaxel. Neuropathy was more common with cabazitaxel. Neutropenia and neutropenic fever were more common with cabazitaxel. There are differing side effects. In general, my experience with PSMA lutetium is that it leads patients to have very good quality of life. By the way, you can use these therapies sequentially. If you chose cabazitaxel first, you can still reasonably try PSMA lutetium as another treatment to improve the survival of your patients, and vice versa. If you started with PSMA lutetium, and a patient starts to progress, cabazitaxel is still an effective agent that can rescue many patients.

A common strategy for treating dry mouth would be chewing gum. This tends to be a mild side effect. Just the stimulation of saliva—the constant stimulation—is one of the tools that can overcome this. This is typically a transient, not durable, side effect because of the radiation that is delivered through the PSMA targeting in the salivary ducts. Certainly, artificial saliva can be used. It would be rare to ever need that. Maintaining hydration and good dental hygiene is critical in this setting; we need to prevent dental caries or other side effects that are dental in origin.

It is always good news to see a PSA [prostate-specific antigen] response, but that is not the whole aspect of treating a patient. For a patient to feel like they are entering remission, you would like to see radiographic and symptomatic responses. Of course, the PSA can go along with that. While it is important to have better PSA declines, it is much more important to have better survival rates, more durable remissions, and radiographic prevention of progression. There are some patients that can progress on imaging, even without a PSA that is rising. We do not want to rely too much just on PSA.

Right now, the VISION study did not have a head-to-head comparison against cabazitaxel. Nor did it have a head-to-head comparison against radium. Right now, we do not know the proper sequencing of PSMA with cabazitaxel or radium. Radium is still a reasonable option for men with bone-predominant disease who have symptomatic progression. Cabazitaxel is still a reasonable option, particularly for patients that have PSMA-negative disease or visceral disease who might not be expected to do as well with PSMA lutetium. There’s going to be a huge demand of PSMA lutetium, however, for the broad PSMA-positive population, due to its efficacy, improved survival rates, good quality of life, and relatively low toxicity, relative to chemotherapy. Many men have the goal of putting off chemotherapy as long as possible. This therapy will not completely replace all our existing therapies. It will add to them and keep our patients alive for much longer. It is giving us, as investigators, time to develop even better therapies that are targeting PSMA or other molecules. We can develop other immunotherapies, other precision medicine treatments, that can then come in afterwards. PSMA lutetium is not curing our patients, but it is prolonging remission, improving survival rates, and maintaining quality of life, which are all major goals of our patients.

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Dr Andrew J. Armstrong reviews the safety of LuPSMA therapy as compared to cabazitaxel as seen in the phase 2 TheraP trial and comments on sequencing strategies for patients with metastatic castration-resistant prostate cancer.

Safety Profile of LuPSMA Therapy in mCRPC

A great question is which patients are most appropriate for Luetetium-177 PSMA (Prostate-specific membrane antigen)-617? The FDA [Food and Drug Administration] has yet to approve this PSA [prostate-specific antigen]-based therapy yet. We do not know for sure what the FDA label will have. For example, in the VISION trial, all patients were required to have a PSMA PET [positron emission tomography] scan, demonstrate PSMA positivity, and a lack of disease that was PSMA-negative. I would expect 1 possible indication for this therapy would be very similar to the VISION type patient: a patient with metastatic castration resistance, who has progressed, despite a potent AR [androgen receptor] inhibitor and docetaxel. Another possible patient would be unfit for docetaxel and have positive PSMA disease on a PSMA PET scan. One could argue that this was such a broadly effective therapy, and that so many patients are positive for PSMA anyway—nearly 85%—that this may be effective, even without the need for a PSMA PET, which would increase barriers to access, and add cost to this therapy. Since it is such a broadly effective agent, it remains to be determined whether the PSMA PET will be required. The patients, in my experience, who tend to have PSMA-negative disease, which you need to watch out for—because this may not be an appropriate therapy for such patients—would be those with small cell or neuroendocrine prostate cancer. These patients are known to lack PSMA. This would not be an appropriate PSMA-targeting strategy for these patients. They are likely not to respond. These such patients are more likely to have liver or visceral metastases. While some patients with visceral metastases can have PSMA, most patients with liver metastases have very scattered or low PSMA expression. This would be a word of caution for these patients. If you know that a patient has small cell or neuroendocrine differentiation, it would be more appropriate to consider alternatives to this approach.

The impact of this for our patients, once the FDA has approved this, would be that this adds another life-prolonging therapy to the armamentarium of what we have already. The life-prolonging therapies that we have available to us in the mCRPC [metastatic castration-resistant prostate cancer] setting are abiraterone, enzalutamide, and sipuleucel-t. We use olaparib for DNA [deoxyribonucleic acid] repair-deficient patients and radium for patients with bone metastases that are symptomatic. We use docetaxel and cabazitaxel more broadly.

Then, PSMA lutetium would be for patients who have failed with an AR inhibitor and a taxane. The question will be, where do you fit this in? Some studies have compared, in small phase 2 trials, PSMA lutetium against cabazitaxel. And PSMA lutetium performs comparably to cabazitaxel, with improved PSA outcomes, better quality of life, and improved tolerability. There are many patients in our clinics that are not candidates for further chemotherapy, or have exhausted their chemotherapy outcomes, because of side effects, comorbidities, and age. They prefer not to get more chemotherapy. This represents a very good therapy regarding quality of life. The toxicities of PSMA lutetium do include some bone marrow toxicities, such as platelet counts, some dry mouth, dry eyes, and fatigue, due to the marrow suppression, but not to the degree that typically cabazitaxel or docetaxel produces. There are no impacts, generally, on infection risk. There is no hair loss. There is not the typical side effects of chemotherapy that most men are accustomed to experiencing.

An expert in prostate cancer comments on the appropriate patient population for Lutetium-177 PSMA-617 therapy for the management of metastatic castration-resistant prostate cancer.

Patient Selection of LuPSMA Therapy in mCRPC

: The VISION clinical trial was a phase 3 global study that looked at the safety and global efficacy of PSMA [prostate-specific membrane antigen] lutetium 177, which is a small molecule that binds to PSMA on the cell surface of prostate cancer cells, and delivers a beta emitter, called lutetium-177, that emits radiation selectively to PSMA-expressing tissues. This trial selectively enrolled patients with mCRPC [metastatic castration-resistant prostate cancer], who had failed with at least 1 prior AR [androgen receptor] inhibitor or ongoing androgen deprivation therapy [ADT] and had also progressed on at least 1 prior taxane, mostly docetaxel. Patients who were not considered fit or optimal for further chemotherapy, such as with cabazitaxel or with radium 223, were also enrolled. These patients underwent PET [positron emission tomography] imaging as part of their screening. If they had PSMA-positive disease and lacked PSMA-negative disease—which was, again, about 82% to 83% of all the randomized screened patients—then they would be eligible for the VISION study approach, in which patients were, again, randomized to the best supportive care, standard of care, that they could receive, provided that was an oral agent, such as a steroid or a second AR inhibitor. Alternatively, they could receive the best supportive hormonal therapy, with ongoing ADT, with up to 6 cycles every 6 weeks of PSMA lutetium. The final sample size for this trial was over 800 patients, specifically 831 patients. The primary end point of this trial was radiographic progression-free survival, but the most impressive results occurred in reference to—and a key co-primary end point was—overall survival. Both end points were met in this study.

All these patients were heavily pretreated. Most patients had already had, again, an AR inhibitor. All patients had a taxane regimen, but some patients had several taxane regimens. And many patients had already had multiple AR pathway inhibitors. The topline results for overall survival demonstrated that PSMA lutetium plus the standard of care improved overall survival, over standard of care alone, by about 4 months. The hazard ratio was .62, with a very significant 

 value that was less than .001. This met the primary analysis for all the randomized patients. This was also held up in an analysis set that was restricted to just those patients that were evaluable for a key primary end point of radiographic progression-free survival. In both subsets of patients, including the overall group of patients, overall survival was significantly improved by about 40%.

PSA [prostate-specific antigen] is one of the proteins made by prostate cancer. PSMA is expressed on the cell surface. PSA is a secreted protein. We often use PSA declines with hormonal therapies and chemotherapies to update the prognosis of our patients, and to reassure them that they are doing very well with the therapy that they are on, that they are having a robust response to treatment. We can follow PSA over time, to detect the time until PSA progression, for example. Other aspects of the disease that are important are objective and soft tissue responses. Let me start with PSA declines. When we characterize PSA declines, there is really a continuum. The lower the PSA drops, the better the prognosis of a patient. With PSMA lutetium in the VISION study, we observed a confirmed 50% or greater drop from baseline in nearly half of the patients, or 46%.

With the standard of care, it was only 7%, illustrating that this is having an on-target effect. It is reducing PSA, and many more patients had a very robust decline, to 80% or more. A third of the patients had an 80% or more decline that was confirmed, as compared to only 2% of patients receiving standard of care alone. On imaging, which is equally important to PSA declines, you see 9% of patients had complete remissions and 41% had partial remissions. This was very rare with supportive care or the standard of care alone. Only about 13% of patients did not respond to PSMA lutetium, where their best response was progressive disease. Nearly half the patients treated with this standard of care alone had a best response of progressive disease, illustrating that this treatment is very effective in establishing disease control. The radiographic progression-free survival was substantially improved for these patients with an improvement of about 5 months over standard of care.

Dr Andrew J. Armstrong reviews the phase 3 VISION trial evaluating the use of LuPSMA therapy in patients with progressive PSMA-positive metastatic castrate-resistant prostate cancer.

Phase 3 VISION Trial in PSMA-Positive mCRPC

: Michael Morris, MD, while presenting the VISION trial at ASCO [American Society of Clinical Oncology] conference, mostly covered the outcomes according to overall and progression-free survival according to subgroups based on age, based on prior AR [androgen receptor] therapies, as compared to LDH [lactate dehydrogenase] levels, liver metastases, functional status, and race. There was no clear heterogeneity in outcomes based on those factors for progression-free survival. There were benefits to the approach of the VISION trial in basically all of the subgroups that were identified and explored in this ASCO abstract. For overall survival, however, what I would say is that while almost all the subgroups benefitted, the patients with liver metastases seemed to have a diminished survival benefit. This was based on a small subgroup of patients. Only about 80 patients had liver metastases, so take that with a big grain of salt. But again, like I said, patients with liver metastases tend to be enriched in PSMA [prostate-​specific membrane antigen]-negative disease. All the other subgroups tended to have a survival benefit.

The main comparison that I look at for this VISION trial, in this more third-line setting, would be the PSMA lutetium against cabazitaxel, or PSMA lutetium against radium 223. Both agents are FDA [Food and Drug Administration]-approved. Both are life-prolonging. Both improve survival by about 20% to 30% for this patient population. However, radium is really selective, and it is only for patients that have a bone-predominant pattern of spread. It would not be appropriate for patients with bulky soft tissue disease or visceral metastases. That is where PSMA lutetium and cabazitaxel are more active. Now, cabazitaxel is an active agent. In a randomized trial, called the CARD trial, cabazitaxel did improve progression-free and overall survival as compared to a second AR inhibitor. That was published in the

 We do not have a formal phase 3 comparison of PSMA lutetium against cabazitaxel. We have smaller randomized trials, where the progression-free survival was nearly identical between these 2 approaches. However, the toxicities differed. The PSA [prostate-specific antigen] responses did differ, and they favored more PSMA lutetium. There was lower toxicity, so there were probably better quality of life and better PSA outcomes.

Andrew J. Armstrong, MD, MSc, discusses the survival benefit of LuPSMA therapy in patients with metastatic castration-resistant prostate cancer and evaluates the response to therapy compared with other agents.

Response to LuPSMA Therapy in mCRPC

: When we talk about unmet needs in the field of advanced prostate cancer, most patients are, nowadays, offered a very potent androgen receptor [AR] inhibitor as one of their front lines of defense, either in the hormone-sensitive or non-metastatic castration-resistant setting, or in the first-line mCRPC [metastatic castration-resistant prostate cancer] setting. These patients have an improved survival rate with these potent AR inhibitors, such as abiraterone, enzalutamide, darolutamide, and apalutamide. However, over either months or years, patients will inevitably progress, despite this very potent hormonal therapy, and face this daunting prospect of chemotherapy. They will have to take docetaxel, cabazitaxel, or bone-targeting radiotherapeutics, such as radium 223. Most of these patients, when you do a PSMA [Prostate-specific membrane antigen] PET [positron emission tomography] scan, will have positive disease. About 87% of patients, for example, in the VISION study that we will be talking about, had positive PSMA PET scans that qualified them for the PSMA lutetium study. That means most patients are PSMA-positive. The unmet needs of these patients are really the unmet needs of almost all of our patients. We need to have a therapy that improves their survival, maintains good quality of life, and can put tumors into remission—ideally durably—without undue toxicities.

Precision medicine is really something that is taking the field of prostate cancer by storm. Just last year, for example, we had our first precision medicine therapies approved by the FDA [Food and Drug Administration] for patients with mCRPC, who had DNA [deoxyribonucleic acid]-homologous repair deficiencies. These were olaparib and rucaparib, for example. Again, most of these patients will also be PSMA-positive. This is illustrating the fact that these PARP [Poly (ADP-ribose) polymerase inhibitors] can improve survival in a selected, precise subgroup of patients that have DNA repair defects, particularly men with 

 deficiencies. This further demonstrates the value of precision medicine in doing genetic—both germline and somatic—sequencing. PSMA is another form of precision medicine, where PSMA is a target that is expressed at the protein level and at the cell surface of the vast majority of men with prostate cancer. Unlike DNA repair defects, PSMA expression is much more broadly expressed in a cohort of men with advanced prostate cancer. Again, more than 75% of patients will have very bright PSMA expression. This is not something that can be detected with a foundation or a liquid biopsy test at this point, but rather is measured based on image or tumor expression of this marker, by protein criteria. A PSMA PET scan is 1 method to detect PSMA expression, which is the target of our PSMA-directed therapies, such as PSMA lutetium.

Andrew J. Armstrong, MD, MSc, provides insight on unmet needs and the use of androgen receptor inhibitors for patients with progressive PSMA-positive metastatic castration-resistant prostate cancer.

Andrew J. Armstrong, MD, MSc | Authors

Articles

Safety Profile of LuPSMA Therapy in mCRPC

Patient Selection of LuPSMA Therapy in mCRPC

Phase 3 VISION Trial in PSMA-Positive mCRPC

Response to LuPSMA Therapy in mCRPC

Standard of Care for PSMA-Positive mCRPC