Scott T. Tagawa, MD, FACP

 As far as advice for the average clinician who has prostate cancer as part of their practice, No. 1 is you’re not alone. Reach out to colleagues or friends. That may be someone within your practice who you may have trained with, or it may be someone at your local academic center, or across the world. Now that we’re so connected, whether that’s phone, email, or other, it’s important. Generally speaking, sometimes these curbside consultations are difficult on either end. I’m sure it’s happened to all of us. But sometimes it’s a simple question, and sometimes we’re able to do formal evaluations of individual patients. That’s one important fact to learn.

Another is that we have a number of different drugs. Some of them are similar. But we don’t have a lot of head-to-head comparative data. For instance, an AR [androgen receptor] signaling inhibitor or a PARP inhibitor will have different labels, but some of them are overlapping. Learn to use at least one of them well. The PARP inhibitors may be used in other cancers, so maybe there’s expertise already. As long as the data are reasonable, using that one as preferred to others is absolutely fine because it’s probably better to use a drug correctly with some data than use another one incorrectly that may have a higher level of data. That’s important, and a factor.

Also, keep up. I’m not saying keep up on the overall data, but at least looking at buckets; these may come from guidelines, review articles, or CME [continuing medical education]-type discussions. I’ll give you 1 specific example. Since the December 2013 press release, and 2014 ASCO [American Society of Clinical Oncology annual meeting] and beyond, we know that we can make a major improvement in overall survival by adding one of these drugs. I don’t believe chemotherapy is crummy, but as a naysayer, chemotherapy, docetaxel, doesn’t do so much for metastatic CRPC [castration-resistant prostate cancer]. That same drug with a few cycles has a major benefit for metastatic castration-sensitive, or noncastrate disease. There are now a lot of drugs that do that.

I’m not even going to mention doublets vs triplets, in part because through at least 2019, we know from data sets that a lot of patients are still getting old-fashioned therapy such as ADT [androgen deprivation therapy] alone or ADT plus a nonsteroidal or old-fashioned antiandrogen. This shouldn’t never happen, but it should happen in a very small minority. We want to make sure at least in principle that patients are getting the right therapy. There’s no way any specific doctor, including myself, can know all of the data. But as a patient is sitting in front of you, at least look up guidelines, phone a friend, or say something like, “This is your situation, and these are the general options that I see. I’m going to look into them a little more and then we’ll call you,” if it can’t be done in real time.

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Scott T. Tagawa, MD, FACP, shares clinical pearls and advice for the management of mCRPC.

Clinical Pearls for the Management of mCRPC

 Fortunately, we’ve already had a number of different agents approved over the last 10 years and going back further, and those are in prime time, already in use. Those same drugs have been or are being studied in earlier lines of therapy where we’ve seen—particularly moving from castration-resistant prostate cancer to noncastrate, or hormone-sensitive castration-sensitive disease—where their hazard ratio for overall survival is even bigger. We’re moving earlier.

Then we have combinations. We had rationale for instance to combine a PARP inhibitor and AR [androgen receptor] pathway inhibitor. We had a randomized phase 2 trial that was positive, and we just had a press release showing that combination is positive, importantly, for PARP inhibitors in an unselected patient population in terms of genomics. We don’t know the data, so I’m not ready to use that today, but that’s an example of something that has some scientific rationale, and then is being tested with initial safety studies followed by randomized phase 2, followed by randomized phase 3. That may become a standard of care. That’s one set of trials that we have excitement over in terms of maximizing our use of the current drugs.

There are a number of other drugs out there. We know that the AR pathway is the dominant pathway throughout the lifecycle of most patients and tumors, and we know that there are resistance pathways. Subverting resistance with bypass pathways, such as AKT, we know that actually works, thanks to a positive trial. However, that trial with an AKT inhibitor has some issues with tolerability, but in principle, we’re finding ways to get around some bypass pathways or to prevent lineage plasticity. For instance, with an EZH2 inhibitor, or some other epigenetic modifier to prevent lineage plasticity and transformation to neuroendrocrine small cell prostate cancer. There are other—I don’t necessarily want to say better or more potent, just because that may be true in cells—different types of AR pathway inhibitors, such as those targeting internal domain or AR degraders. Those have made their way from preclinical studies into the clinical realm.

We all want to get immunotherapy to work better. We have, at least in the United States, sipuleucel-T, which at least in older studies led to a significant overall survival advantage. There’s a subset for on-label use of immune checkpoint inhibitors. That subset is small, about 1 in 20 to 25. Importantly, it’s 0 out of 25 if you never check, so it’s important to check. But how can we come up with different immunotherapeutics or make the existing ones work better? I mentioned radiation, for instance, more specifically PSMA [prostate-specific membrane antigen]-targeted radiation in combination. But there are a number of phase 3 trials that we expect to read out in the next few years that may lead to combinations that improve or expand the population who may benefit from an immune checkpoint inhibitor, at least as defined by anti–PD-1 or PD-L1.

PSMA is probably the leading, but not the only, cell surface target for immunotherapy right now, including for CAR [chimeric antigen receptor] T cells, which are very important and may lead to some major improvements, but it’s slow. We’re proceeding cautiously in terms of safety with those.

What’s happening more quickly are the bispecific antibodies—most common would be a cell surface target such as PSMA with CD3, but there are other things that might be on the other end of the molecule. We know that paradigm works against CD19, for instance. In preliminary presentations, it can be safe, at least in the right hands, and there can be responses. These are moving fairly rapidly from phase 1 to phase 3, at least with one agent. That’s interesting. Staying on the theme of cell surface targeting, there are antibody-drug conjugates. So using some of the same types of cell surface targets such as, and I don’t mean to sound like a broken record, PSMA. There are other important cell surface targets such as CYP1. DLL3 is a very interesting cell surface target. They’re maybe in general adenocarcinoma castration-resistant disease at a low level, but more commonly to a higher level in small cell neuroendrocrine. There may be other targets such as B7H3 and others that are with drugs in development.

An expert in prostate cancer comments on emerging agents and combinations in the pipeline for the treatment of mCRPC.

Future Treatment Landscape of mCRPC

 There are a number of different questions that remain for PSMA [prostate-specific membrane antigen]-targeted radionuclide therapy in general, but I’ll narrow it to lutetium-PSMA-617, which probably applies to the other lutetium-PSMA–targeted small molecules. One is patient selection. I may argue that in someone who’s received every known therapy, who doesn’t have a clinical trial available or other therapies available, and has good performance status, that maybe I don’t need a PSMA-PET [positron emission tomography] to treat them, in part because 95% of patients in the VISION study had a positive PET, at least defined by at least 1 lesion lit up brighter than liver. Even with discrepancies that are another small group, an overall patient population would probably still benefit. That’s one question in my mind.

There are a lot of other questions that are in the setting of choices. There are now 4 phase 3 trials that I know of looking at lutetium-PSMA–targeted beta in early lines of therapy: 3 in chemotherapy-naive metastatic CRPC [castration-resistant prostate cancer], and 1 in conjunction with AR [androgen receptor] pathway inhibitors and ADT [androgen deprivation therapy] for noncastrates, ie, castration-sensitive hormone-sensitive metastatic disease. So earlier lines of therapy make sense. There‘s less likely to be PSMA-negative disease. As I mentioned in one of the first segments of this, those who are more heavily pretreated with AR-targeted therapy are more likely to lose AR pathway and PSMA. It’s less likely in those earlier disease settings. Radiation resistance pathways or alterations such as 

 are less likely in earlier lines of therapy. They’re more likely to benefit from an agent such as lutetium-PSMA-617. Does this work in earlier lines of therapy? We don’t know, but we’ll test those.

The other major part is combinations; we certainly are already testing these with-AR targeted therapy. In the VISION trial, a big proportion of the patients received AR-targeted therapy as standard of care and had lutetium-PSMA-617 added to that. But other types of therapy warrant additional study. We have some safety data and early efficacy data in combination with immune checkpoint inhibitors and PARP inhibitors. There’s at least 1 trial with concurrent lutetium-PSMA antibody and concurrent docetaxel. Those all make sense to me, besides assessing different lines of therapy. And then going back to one of the things I started with, in terms of patient selection, it’s not just imaging. Imaging is one thing. There’s the theragnostic paradigm: see what you treat. It makes sense; is the target there? But there are factors that are beyond that, including patient factors as well as likely tumor factors, such as genomics, that may play a role.

Scott T. Tagawa, MD, FACP, shares his thoughts on remaining questions for imaging and PSMA-targeted therapy for mCRPC.

Remaining Questions for LuPSMA Therapy in mCRPC

 As with all of our therapies, there are a number of adverse events that are associated with treatment. There are 2 randomized trials of lutetium-PSMA [prostate-specific membrane antigen]-617. We have the VISION trial, which includes lutetium-PSMA-617 in addition to standard of care vs standard of care alone, as well as some head-to-head data against cabazitaxel chemotherapy. What’s important to know is that both of these trials were positive. The duration of exposure and duration of looking closely at adverse events was much longer in those getting lutetium-PSMA-617 compared with the control arms. That being said, there are some somewhat generic adverse events that might occur. Then there are some that are specific to the agent.

The important ones are those that are specific to agents, because I suspect there are a number of clinicians out there, whether it’s a physician extender, a nurse, a patient, or the family members, who we need to understand that there’s some gamma emission. This isn’t true of all radionuclides, but it is true of lutetium-PSMA-617. Gamma emission can be dangerous to those around. It’s a low level overall, but it’s something we need to think about. The patient receives therapy, walks out the door, and is emitting to the public, but generally not enough to be dangerous. But for someone who’s in close proximity for a prolonged duration of time, it’s something to think about. That’s not part of general presentations or publications.

In terms of the adverse events commonly associated with lutetium-PSMA-617, there are some constitutional symptoms, such as fatigue. There’s fatigue with any type of generic administration of radiation, whether it’s localized or systemic. There was more fatigue in the VISION study with lutetium-PSMA-617 compared with standard of care. Generally speaking, it was low-grade fatigue, but high-grade was also more common than standard of care alone. There are some hematologic issues. All of the counts can be decreased. Thrombocytopenia stands out, not only from the VISION study, but because that was the cell type that was worse compared with cabazitaxel chemotherapy in the TheraP study. These generally aren’t high grade, but they can be. With any type of radiation that’s affecting the bone marrow, at least in theory, these could be of long duration or theoretically even permanent. That hasn’t been seen very often, but we’re mostly administering this in metastatic CRPC [castration-resistant prostate cancer], where not many people make it to 10 years, unfortunately. Hopefully that will change in the future.

There are certain areas that are on target in terms of PSMA-positive areas in the body, but off-tumor. For instance, the salivary glands as well as the lacrimal gland. We’re talking about the head and neck. In my personal experience, dry eye is not that common, but it can happen. Dry mouth is common, however, and possibly even underreported in the VISION study because in other studies with a lot of PSMA-specific investigators, they’re asking the questions on a daily or weekly basis. It’s a higher percentage who are affected. That being said, generally speaking, the average patient would have that for a defined duration of time, days or weeks, at a low grade.

There’s some nonspecific nausea that may occur, but there’s also some specific nausea with uptake into PSMA in the small bowel. Nausea stands out as more common with lutetium-PSMA-617, along with the other small molecules. We luckily haven’t seen a significant kidney toxicity signal, ie, in terms of renal failure. That being said, that may be a late effect, so it’s certainly something to keep in mind. When I put all of those together, like with any other treatment, I counsel my patients prior to the treatment, generally in the visit or visits that happen prior to the administration, and then usually I’ll quiz them and then remind them on the day of administration. We can do certain things, like having them hydrate well orally. This can also happen intravenously. That’s happened in some drug developments, particularly for alpha PSMA-targeted radionuclide therapy. But for someone who feels dehydrated, that can help. We have them drink more than usual for days or weeks following therapy. That might help protect the kidney, and may also combat dry mouth.

We also may administer prophylactic antiemetics. That was recommended in the VISION study, although not absolutely mandatory. Just like with chemotherapy, we have some patients who have very severe nausea. We have some who have absolutely none. But it’s one of the more common toxicities to occur. You can give a prophylactic administration of a 5-HT3 [receptor antagonist] with therapy, as well as making sure they have antiemetics at home for as needed use. I will generally follow up with them after therapy, certainly within 2 weeks. The VISION study had weekly follow-up. That doesn’t necessarily have to be in person. Whether that’s a phone follow-up or a telemedicine video visit, it depends on the individual practice. This isn’t so different from other drugs.

At the beginning, cycle 1, I’m more conscious and cognizant of what might happen because everyone is different. I’ll make sure I see them within 2 weeks, and often within 1 week. With subsequent cycles, that may be relaxed a bit as long as there’s counseling, “You need to call us if something happens.” Usually I’ll talk to their family or support system as well, just to have them give me a call if there are any issues that arise.

One thing I’ll mention that’s relatively new and not yet peer-reviewed, is that despite the higher incidence of adverse events in the lutetium-PSMA arm of VISION compared with standard of care alone, that didn’t translate into a major problem in terms of patient-reported outcomes. Karim Fizazi, [MD, PhD,] reported the secondary end points of patient-reported outcomes at ESMO [European Society for Medical Oncology Congress] 2021, and there was a significant improvement in time to deterioration of global quality of life as measured by FACT-P [Functional Assessment of Cancer Therapy–Prostate], time to deterioration of pain as measured by the Brief Pain Inventory, and time to first symptomatic skeletal event. This is despite the fact that there were more adverse events, partly because of longer follow-up. There are real toxicities that may happen with that. Despite that, likely because of a combination of not so severe and long-lasting, plus the impact on prostate cancer, these did translate into improvements in patient-reported outcomes.

Dr Scott T. Tagawa discusses common adverse events associated with 177Lu-PSMA-617 in patients with mCRPC and how to appropriately manage them.

LuPSMA Therapy in mCRPC: Managing Adverse Events

 I believe that the VISION results, particularly in the context of all of the other studies—particular prospective studies that might’ve been single arm, plus the TheraP study, which was a patient population highly selected by imaging head-to-head against cabazitaxel—lutetium-PSMA [prostate-specific membrane antigen]-617 improved outcomes. In that context for patients with metastatic castration-resistant prostate cancer [CRPC], arguably for at least those who have some PSMA positivity, this represents a new standard of care.

That new standard of care isn’t yet available, at least not in the United States, outside of clinical trials. But I believe that this is coming. I’m guessing sometime in 2022, this is going to be an agent that will be implemented across the board. Centers will learn to have to use PSMA-PET [positron emission tomography] imaging as well as handle radionuclide therapy. Because different types of PET have been incorporated across oncology, including prostate cancer, and PSMA-PET is starting to come across the country, particularly for those with high-risk localized disease, or even more so with biochemically recurrent disease, this will be more embedded into what our practices have. Most centers will have access to this. This is certainly not going to be all.

There are some logistical issues. This is for treatment, too, as these are all radionuclides. They all have half-lives. For instance, the half-life of F-18 [fluorine-18] is approximately 110 minutes. We can make a lot and ship it, but we can’t have it sitting on a shelf and use it in a couple days. There are some practicalities. That’s also true of the therapy, with lutetium-177 having a half-life of approximately a week. As long as there are adequate safety protocols in place with a radiation safety officer, we can receive it one day and use it the next day or the following day. These are generally stable for 4 days. We have to calculate that a seventh of it is being decayed each day, so if we’re not going to use it the day of receipt, we need to receive more than we intend to use.

There are a number of practicalities there. One additional practicality is that even though this has been at least somewhat incorporated into the recent NCCN [National Comprehensive Cancer Network] guidelines, the FDA-approved labels for PSMA-PET at this point don’t include treatment selection for metastatic CRPC. I suspect that it’s going to be part of the label for lutetium-PSMA-617. Novartis may have their own companion diagnostic. If there’s a bundled type of scenario where there’s a PSMA-PET built into the cost of lutetium-PSMA-617, and it’s paid for even if it’s negative, that’s one way until we can get more ubiquitous use of PSMA-PET. That will be a logistical issue at the beginning.

A prostate cancer expert considers clinical implications from the phase 3 VISION study, including the potential role of 177Lu-PSMA-617 therapy for patients with mCRPC.

Clinical Implications From the VISION Trial in mCRPC

 PSMA [prostate-specific membrane antigen]-targeted radionuclide therapy means directing a radionuclide, which is either generally a beta or alpha emitter. People are familiar with alpha emitters, as in the approved radium-223, and may remember some beta emitters. Certainly, everyone’s familiar with iodine-131 for thyroid cancer. But in the older days, we used strontium and samarium to palliate painful bone metastasis. Lutetium-177 is an approved agent targeting somatostatin for GI [gastrointestinal] neuroendocrine tumors, and is one of the leading agents in a number of tumor types, including prostate cancer. We can target or aim these radionuclides against PSMA using either small molecules or antibodies. I’m not going to go into great details about these other than to say that they have different properties and kinetics. Both are given intravenously or systemically and wind up in the tumor. The small molecules wind up in some other PSMA-positive areas, and I do think that’s important to know in terms of the toxicity or adverse event profile.

One of the specific agents, lutetium-PSMA-617, has been initially used anecdotally as part of expanded access programs, and then more recently in prospective single-arm trials. There are now 2 completed and published randomized clinical trials. The potentially registration phase 3 trial is called VISION. This was a trial that was designed to enroll men with castration-resistant prostate cancer who had no other options. They were supposed to receive all the hormonal therapy, targeted therapy, and chemotherapy that was appropriate for them. They were required to have at least 1 prior modern AR [androgen receptor] pathway inhibitor and at least 1 prior taxane. But if they were appropriate for radium, a PARP inhibitor, and a second taxane, they should have received that first. That was the overall intent of the study design.

For the treatments among that population of men, there was another selection besides the general selection criteria that we use for clinical trials, such as intact performance status and organ function: PSMA positivity. This was defined for the protocol, and for those who are interested in the details, most protocols are not the same. The other randomized trial is called TheraP. It has much different PSMA imaging inclusion criteria than the VISION study. Basically, the VISION study said that all of the soft tissue lesions needed to be PSMA-positive. None of them that were evident on CT—at least defined by the study—could be negative, with negative designed by uptake less than liver.

These patients were enrolled and started on whatever the most appropriate standard of care per the protocol allowed. Then they were randomized 2:1 with or without lutetium-PSMA-617. Because of the way the study was designed, that they were supposed to receive all the drugs before, and with the limited amount of safety information for combinations, there were 2 main types of drugs that were excluded in terms of standard of care: chemotherapy and radium. Those were supposed to be given prior to the study. Patients were enrolled on this standard of care alone or standard of care plus lutetium-PSMA-617 with an alternative primary end point of radiographic progression-free survival. Those of you who have seen prostate cancer clinical trials understand what that is. It also looked at overall survival. Alternative primary end points means that if only one of those is positive and the other one’s negative, then the study is seen as positive overall.

These men were enrolled at a number of different centers across the world. The type of the standard-of-care agent was declared up front. That was a stratification factor, specifically modern-day AR pathway inhibitor or not. They had PSMA-PET [positron emission tomography] scans and then were treated. On PSMA-PET imaging, approximately 95% were PSMA-positive as defined by having at least 1 PSMA-positive lesion. But then an overlapping 8.7%, which equals about 13% overall, weren’t included. Overall, 87% were included by the study definition of PSMA positivity.

Patients were treated, and as all of you know from the ASCO [American Society of Clinical Oncology] plenary presentation followed by the 

 publication, both primary alternative end points were positive. There was a nearly 40% improvement in overall survival. The hazard ratio was 0.62 with confidence intervals that didn’t come close to 1. The radiographic progression-free survival was even bigger, with a hazard ratio of 0.4, or a 60% improvement in radiographic progression-free survival. Generally speaking, both of these were positive across all individual subgroups. The secondary end points were also generally positive, while some analysis is ongoing for some of them. That included PSA [prostate-specific antigen] declines as well as objective RECIST responses in measurable disease.

The patients who were included in the VISION trial were fairly typical of those who have received a number of different therapies. It may not be exactly the same thing as the “real world” because they have to qualify for a clinical trial and be at a center for the clinical trial, so clinical trial data aren’t always the same as real-world data. That being said, as we’d expect for someone with 1 to 2 lines of potent AR pathway inhibitors and 1 to 2 lines of chemotherapy plus others, most had bone metastasis and a lot had soft tissue disease, including both nodal and visceral disease, with visceral disease including both lung and liver. All had to have an intact performance status enough to qualify for a clinical trial, as well as organ function, such as laboratory tests and blood count enough for clinical trial. But that’s not so different than we’d expect for most clinical trials.

Scott T. Tagawa, MD, FACP, reviews the phase 3 VISION trial evaluating the use of 177Lu-PSMA-617 therapy in patients with mCRPC.

Scott T. Tagawa, MD, FACP | Authors

Articles

Clinical Pearls for the Management of mCRPC

Future Treatment Landscape of mCRPC

Remaining Questions for LuPSMA Therapy in mCRPC

LuPSMA Therapy in mCRPC: Managing Adverse Events

Clinical Implications From the VISION Trial in mCRPC

Phase 3 VISION Trial in mCRPC