Alicia Morgans, MD, MPH


Androgen deprivation therapy (ADT) has long been the primary systemic therapy given for advanced prostate cancer (aPC). However, ADT alone may not prevent the rise of prostate specific–antigen (PSA) levels, tumor growth, or metastasis. Fortunately, a greater understanding of how ADT can be used in combination with secondary hormonal therapies, chemotherapy, immunotherapy, and targeted therapy has improved patient outcomes.

The success of ADT combinations has grown along with advances in genetic testing, biomarkers, and nuclear imaging for prostate cancer. These are explored in “

The role of imaging and genomic testing in prostate cancer therapy

New horizons in nuclear medicine for prostate cancer

New Precision Medicine Approaches in Prostate Cancer

These advances—including the recent success of lutetium Lu 177 PSMA-617 (LuPSMA), a PSMA-targeting theranostic—provide promising and exciting possibilities for ADT combinations. However, the novelty and number of these advances also complicate selection of the right treatment for patients given a diagnosis of aPC.

In the third interview of the series, Alicia Morgans, MD, MPH, medical director of survivorship at Dana-Farber Cancer Center, explains the role of ADT, second-line options in the treatment of aPC, and methods of selecting appropriate treatment.

: What are some of the most significant challenges when it comes to treating patients with advanced prostate cancer?

These days, one of the biggest challenges in treating advanced prostate cancer is also a blessing: we have several treatment options. On account of this, it's important that we clinicians find the right treatment for each patient. Sometimes, longer conversations with the patient over time ultimately identify the best path. These conversations give us an opportunity to know our patients and to personalize therapy even when we aren't using specific targeted therapies.

: ADT is administered as primary systemic therapy for aPC. In light of the increasing options that we're seeing, what is the role of ADT?

ADT is really the backbone of systemic therapy for advanced prostate cancer, and it has been for decades. Importantly, we now know that in many situations of advanced prostate cancer, it's ADT intensification or ADT combinations that are really now standard of care. So as we move with patients through their journeys, we typically add layers of hormonal suppression or chemotherapies—or, sometimes, immunotherapies, targeted therapies, or radiopharmaceutical treatments—on top of ADT. This allows us to capitalize on the benefits that ADT and those additional agents have to offer. We're finding more and more that ADT combinations with other agents—even when administered at some of the earliest stages of disease—are what most improve our patients’ quality of life and length of life.

: How do you choose whether to use ADT or ADT in combination with another agent?

We choose different combinations of ADT or ADT-intensified therapy based on factors related to the patient and the disease state. The first place to start is always our guidelines. What do we know can improve survival and quality of life at this stage of prostate cancer?

Once we understand our options, we can work with the patient, and we often come to a shared decision that accounts for the patient's preferences. One patient may prefer an intravenous therapy, an oral therapy, or a therapy that can avoid certain complications, like hair loss or fatigue. Another patient may prefer to take on some of the more difficult complications and toxicities, because he wants to be more aggressive against the cancer. Specific patient preferences can help guide us.

We also have to think about where the cancer is located and about the cancer’s clinical characteristics. Is it in the bone, lymph nodes, or liver? Is it moving along at a rapid pace, spreading and causing severe pain and other complications, or is it something that's a little bit more indolent?

All of these factors come into play as we're choosing ADT's intensification partner. In most cases, we're not using ADT alone anymore; that's why I have continued to emphasize those combinations. In certain situations—particularly when we have high-risk, localized prostate cancer that's being treated with radiation—we do use ADT alone, because we don't 

have evidence that additional agents will benefit the patient. However, that evidence changes every day; we have meetings in the coming weeks and months that may change that.

: When the combination therapy or ADT alone is starting to fail, how do you move on to the next treatment?

[W]hen ADT or a combination therapy starts to fail the patient, and the PSA is rising, and the disease looks like it may be spreading or growing on scans, we absolutely need to think about next steps. And, in most cases, I try to think about next steps in our treatment journey before we get to that point, just to make sure I understand what our options are so that I'm ready to move forward, especially if it's an emergent situation. Some of that preplanning, of course, requires that we do additional testing. And particularly for things like PARP inhibitors, where we need to do genetic germline or somatic testing, that is going to need to happen in advance of when we need that treatment.

Understanding where we are and where we can go is part of the process. When things start to progress, we need to consider patient factors, clinical factors, disease factors, and treatment options to choose the next treatment combination.

: When ADT fails in PC, a provider might turn to secondary hormonal therapies, chemotherapy, immunotherapy, or targeted therapy (including use of PARP inhibitors). However, the National Comprehensive Cancer Network (NCCN) acknowledges that there isn’t much data to inform the optimal sequence for delivery of second- and subsequent-line treatments for men with metastatic, castrate-resistant prostate cancer. How do you prepare to treat these patients?

[I]t's a great thing that the NCCN … continues to meet and update its prostate cancer guidelines continuously, as it does with all of its cancer guidelines. And 1 of the updates that has been made within the last year or 2 has been to really solidly recommend that as soon as a patient has metastatic prostate cancer or high-risk or very high–risk localized prostate cancer, that patient is eligible for—and, in fact, recommended to undergo—germline genetic testing. And the reason that the guidelines suggest this is because the earlier we can get that testing done in a population that is at high-enough risk (where we will see mutations, so that it's worth doing the testing) … the earlier we can have that information … at our disposal should we need it in the future.

All patients with high-risk localized, very high–risk localized, or metastatic prostate cancer—regardless of age and regardless of family history of cancer—are recommended to get germline genetic testing. Patients who have a family history that is consistent with a cancer syndrome should also get that genetic testing as soon as that family history is identified. The guidelines encourage us to do this testing early to avoid waiting 3 or 4 weeks for information relevant to our current decision-making.

The guidelines also recommend somatic testing for patients who have metastatic disease, and especially for those who have metastatic, castration-resistant disease. Some argue that this is not necessary if we're doing germline testing. But really, about half of the DNA repair–defect mutations that we're looking for will only appear in somatic test results. The guidelines also recommend doing somatic testing early. With somatic testing, we should also look for [microsatellite instability] –high status and for those genes that can predispose to high tumor mutational burden or Lynch syndrome: the 

 genes. Somatic testing can also make patients eligible for things like pembrolizumab.

The guidelines recommend that we perform both germline and somatic testing quite early on. Closely following that recommendation—and the rest of the guidelines—gives us and our patient options when we need them.

: Testing and targeted therapy are clearly expanding for aPC. How should we think about this growth?

There are 2 things to remember as we evolve to testing more and more patients and to using more targeted therapy. One is that the more we test, the more we'll find, and the more opportunities we'll have to use these agents. And these agents, particularly pembrolizumab and other [immune] checkpoint inhibitors, as well as PARP inhibitors, are being tested in earlier and earlier stages of prostate cancer. And so we may find that we're using these agents even in localized disease at some point in time and certainly early enough [in the] hormone-sensitive metastatic setting, as well. So the more we test, the more we find.

The second thing to remember is that germline mutation tests also inform the patient’s family about heritable cancer syndromes. The tests give family members the opportunity to have earlier cancer screening, earlier diagnosis, and, potentially, cures for cancers that have just begun.

In the end, more testing has pronounced benefits for both the patient and his family members.

: What is on the horizon for aPC treatment?

I think that the next few years are going to be incredibly rich when it comes to prostate cancer clinical trials, and the advances are going to be coming fast and furious. It's been only 6 months or even less since we learned the results of the VISION trial. We had a press release that suggested that lutetium PSMA prolonged both radiographic progression-free survival and overall survival. I expect that there will be an FDA approval that makes that drug available to patients—certainly here in the United States and, ultimately, to patients worldwide.

But that's just the beginning in terms of that drug. I do expect that the ongoing trials investigating [LuPSMA] are going to probably move it forward, and we will be able to see its benefits be even more pronounced as we move it earlier in the disease spectrum.

Beyond that, we're going to see combinations of drugs that we already have and new drugs come into play, I think, that are going to further prolong life expectancy and also maintain or improve quality of life because of better disease control and good tolerability of these drugs. Just a few weeks ago we learned that combining ADT, docetaxel, and abiraterone in men with high volume, de novo, metastatic hormone sensitive prostate cancer is associated with prolonged overall survival as compared with ADT and docetaxel alone in the PEACE-1 trial. We are waiting to see the data from ENZAMET, which is looking at ADT, docetaxel, and enzalutamide in the same setting. We're also waiting for multiple, industry-sponsored, phase 3 trials that are looking at androgen receptor–targeted agents, immunotherapies, PARP inhibitors, and radiopharmaceuticals.

The combinations really are pretty endless, but the good thing is that this is all in [the] interest [of] trying to find new treatments, new combinations, and new ways to help people live longer and feel better. So I'm really heartened that it's going to be a whirlwind, but it's also going to be a really, really hopeful one, and I look forward to seeing where this journey takes us.

Articles

In this companion article, Alicia K. Morgans, MD, MPH, explains the role of androgen deprivation therapy, second-line options in the treatment of advanced prostate cancer, and methods of selecting appropriate treatment.

EP. 3B: Expert Perspective on the Changing Treatment Spectrum for Advanced Prostate Cancer



[Androgen deprivation therapy] (ADT) is really the backbone of systemic therapy for advanced prostate cancer, and it has been for decades. Importantly, we now know that in many situations of advanced prostate cancer, it's ADT intensification or ADT combinations that are really now standard of care.

When ADT or a combination therapy starts to fail the patient, and the [prostate–specific antigen] (PSA) is rising, and the disease looks like it may be spreading or growing on scans, we absolutely need to think about next steps. And, in most cases, I try to think about next steps in our treatment journey before we get to that point, just to make sure I understand what our options are so that I'm ready to move forward, especially if it's an emergent situation. Some of that preplanning, of course, requires that we do additional testing. And particularly for things like PARP inhibitors, where we need to do genetic germline or somatic testing, that is going to need to happen in advance of when we need that treatment.

The more we test, the more we'll find, and the more opportunities we'll have to use these agents. And these agents, particularly pembrolizumab and other [immune] checkpoint inhibitors, as well as PARP inhibitors, are being tested in earlier and earlier stages of prostate cancer. And so we may find that we're using these agents even in localized disease at some point in time and certainly early enough [in the] hormone-sensitive metastatic setting, as well. So the more we test, the more we find.

It's a great thing that the NCCN … continues to meet and update its prostate cancer guidelines continuously, as it does with all of its cancer guidelines. And 1 of the updates that has been made within the last year or 2 has been to really solidly recommend that as soon as a patient has metastatic prostate cancer or high-risk or very high–risk localized prostate cancer, that patient is eligible for—and, in fact, recommended to undergo—germline genetic testing. And the reason that the guidelines suggest this is because the earlier we can get that testing done in a population that is at high-enough risk (where we will see mutations, so that it's worth doing the testing) … the earlier we can have that information … at our disposal should we need it in the future.

I think that the next few years are going to be incredibly rich when it comes to prostate cancer clinical trials, and the advances are going to be coming fast and furious. It's been only 6 months or even less since we learned the results of the VISION trial. I do expect that the ongoing trials investigating lutetium [Lu 177] PSMA[-617] are going to probably move it forward, and we will be able to see its benefits be even more pronounced as we move it earlier in the disease spectrum.

Beyond that, we're going to see combinations of drugs that we already have and new drugs come into play, I think, that are going to further prolong life expectancy and also maintain or improve quality of life because of better disease control and good tolerability of these drugs. The combinations really are pretty endless, but the good thing is that this is all [the] interest [of] trying to find new treatments, new combinations, and new ways to help people live longer and feel better. So I'm really heartened that it's going to be a whirlwind, but it's also going to be a really, really hopeful one, and I look forward to seeing where this journey takes us.

Videos

In the third video of the series, Alicia K. Morgans, MD, MPH, of the Dana-Farber Cancer Institute sheds light on the rapidly developing treatment landscape for advanced prostate cancer.

EP. 3A: Androgen Deprivation Therapy Failure and Second-Line Options in Advanced Prostate Cancer

Until we cure patients of prostate cancer, including metastatic CRPC [castration-resistant prostate cancer], there will always be an unmet need in this disease space and for these men. Combinations of therapies, including 177Lutetium or not, will hopefully get us over the goal line at some point and give us the opportunity to say—even for men with disease that we can’t cure—they’re cured. There are many exciting combination studies being done with radiopharmaceuticals, PARP inhibitors with AR [androgen receptor]–directed therapies, immunotherapies, and other things that we don’t know exist but are in early phase 1 or first-in-human trials and are moving into our field. It’s an incredibly exciting time in prostate cancer, and I look forward to seeing our opportunities for treatment grow; the sky is the limit. With a partnership between patients who want to engage in clinical trials and physicians who can open and run these safely and effectively for our patients, we can make quite a difference over time.

One piece of advice that I would offer is to continue to engage as multidisciplinary care teams that includes urologists and medical oncologists but now will increasingly also include nuclear medicine physicians and others who feel comfortable and are skilled to give our radiopharmaceuticals. We’re also recognizing that supportive care of bone health and protecting the cardiovascular health of our patients is critical. Engaging with our colleagues who can help support patients in these areas, and learning those skills on our own and incorporating them into our clinics, is critical in treating the whole patient.

A 70-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

A 70-year-old man presents with nocturia and decreased appetite

TRUS and biopsy revealed adenocarcinoma of the prostate gland, Gleason score 9 [5+4]

Patient started on ADT with initial PSA response 12 ng/mL

Patient complained of right hip pain and abdomen pain

Imaging with CT and bone scan showed 2 metastatic bone lesions in the pelvis and diffuse liver lesions

Patient started on docetaxel, 6 cycles completed

Routine imaging shows new metastatic bone lesions in the pelvis

Patient started on abiraterone and prednisone, after 6 months he has a restaging scan which shows continued progression of disease

Patient had a 68Ga-PSMA-11 scan when screening for the VISION trial which shows several positive metastatic lesions in the pelvis and liver metastases

He qualified on screening and enrolled in a clinical trial and treated with 177Lu-PSMA-617 as per the VISION protocol (7.4 Gbq [100 mCi] every 6 weeks for 4-6 cycles)

Dr. Morgans discusses unmet needs and importance of including multidisciplinary teams when treating patients with mCRPC.

Future Directions and Unmet Needs

The VISION trial was an international multi-institutional phase 3 trial that recently completed and demonstrated that treatment with 177Lu-PSMA-617 was associated with a prolonged radiographic progression-free survival and overall survival compared with best supportive care. This trial included patients with metastatic CRPC [castration-resistant prostate cancer] who had been exposed to treatment with an AR [androgen receptor]–directed therapy as well as docetaxel chemotherapy at a minimum. Patients may have had multiple therapies in addition to that.

Patients who were enrolled were randomized to best standard-of-care treatment, which could have been the alternate AR-targeted agent, pain medications, or even steroids vs that best standard of care plus 177Lutetium for 4 to 6 cycles. They were followed for radiographic progression-free survival [rPFS] and overall survival composite end point. We received a press release, a subsequent presentation, and a 

 publication that explained that 177Lutetium plus best standard of care was associated with an improvement in rPFS and OS [overall survival] in this heavily pretreated population. Safety information from the 

 publication and presentations demonstrated that 177Lutetium was generally well tolerated, and there were no new safety signals identified.

In this case, it was a wonderful idea to enroll the patient in the VISION clinical trial and give him the opportunity to undergo this treatment. I recall that it was very difficult to get a spot on that trial as patients were flocking to the centers because there had been such excitement regarding this therapy. To have the opportunity to go on the trial and then also receive 177Lutetium was great for this patient. If he had done standard of care, he could have considered things like cabazitaxel. He likely considered that, but he was probably deemed ineligible, which is why he became eligible to enroll in the VISION trial. The trial excluded patients who could receive cabazitaxel or radium as they could not be safely combined with 177Lu-PSMA-617 at the time. This option was great for this patient because presumably he didn’t have options like radium or cabazitaxel to use safely.

In my experience treating patients on the VISION trial, 177Lu-PSMA-617 was relatively easy to manage in terms of monitoring and safety. We kept an eye on patients’ bone marrow and watched for the development of cytopenias, because this is possible during treatment with 177Lutetium. We talked to our patients about xerostomia, or dry mouth, to ensure they were not developing severe dry mouth that could cause problems in terms of dental health or simply discomfort. In general, patients seemed slightly fatigued for a day or so after their treatment, but it was not extreme fatigue, and they felt there was minimal limitation. Otherwise, some patients were relatively symptomatic when they underwent treatment with 177Lutetium. Under my care and within a short period of time, some of their symptoms—including pain and fatigue—improved during treatment, and we were very happy to have the opportunity to enroll patients on the trial. Giving treatment with 177Lutetium was not more challenging than giving treatment with other radiopharmaceutical options like radium or chemotherapy, from my perspective.

In our experience with prostate cancer, we as a field have seen that most of our agents, when moved earlier in lines of therapy, are more effective. There’s a phase 3 clinical trial that’s being launched for men with metastatic hormone-sensitive disease looking at 177Lutetium in that patient population, and it will be interesting to see how patients tolerate the drug and how well it works in that setting. That’s still to be determined and why we’re doing the trial. There are other trials that are looking at 177Lutetium in even earlier patient populations to determine whether it can be helpful in an adjuvant or neoadjuvant setting and elsewhere. It’s important as a field that we give the opportunity of every drug that seems effective to be studied in different patient populations, so that we understand where it is most useful and how we can get the most out of it for the patients we see. Men come into our care at different states in their disease, and having many opportunities to use effective agents in those patients is always a good thing.

A review of the data from phase 3 randomized Phase 3 Study of 177Lu-PSMA-617 or best supportive/standard of care, VISION, in the treatment of patients with progressive PSMA-positive mCRPC and Dr. Morgans’ experience with 177Lu-PSMA-617.

VISION Study

Treatment for metastatic CRPC [castration-resistant prostate cancer] in the second- and third-line settings and beyond is very similar to the way that we treat metastatic CRPC in the first line. What I mean by that is, we must think about what the patient has had in the past as we’re trying to make decisions for that patient’s current and future treatment. As a team, we need to consider the patient’s preferences, the patient’s clinical status, and of course whether the patient has had exposure to AR [androgen receptor]–targeted agents, chemotherapy, radium, or other things that make it less likely they’ll respond to future agents like an AR-targeted agent followed by an AR-targeted agent—that’s unlikely to be effective—or that may have changes in their bone marrow or their tolerability to get other treatments.

If the patient has had chemotherapy and has an anemia due to marrow suppression related to chemotherapy exposure, radium may be a more challenging treatment to give. Ultimately, it’s a combination of our patient’s clinical factors, the disease characteristics in terms of where the metastatic disease is, the patient’s preferences, and prior treatments that come together to help us choose treatment options for our patient going forward.

Alternative second-line mCRPC for this patient might include cabazitaxel, which is a chemotherapy that can be used after disease has progressed on docetaxel and an AR-targeted agent. It’s a good option, as we’ve seen in the CARD trial for controlling prostate cancer, particularly if there are liver metastases as in this case. 177Lu-PSMA-617 may be an option for us to use in the future because that’s what this patient got in a clinical trial. There’s a phase 2 trial that attempts to compare tolerability, PSA [prostate-specific antigen] response, and radiographic progression-free survival between cabazitaxel and lutetium. That trial is the TheraP trial, which was performed by a team of oncologists, nuclear medicine doctors, and urologists in New Zealand and Australia and was presented about a year ago. In that trial we noticed that cabazitaxel, which is known to be quite effective in this third-line setting, did not have as strong of a PSA-suppressive response or as long of a radiographic progression-free survival as lutetium. However, it should be noted that this is a phase 2 trial and isn’t substantial enough to change treatment, particularly because lutetium is not approved for the treatment of metastatic CRPC. This certainly adds to our clinical decision-making and may be important for patients and clinicians, should Lutetium177 be approved, because they’re deciding between those 2 agents in the third-line setting.

When choosing any line of therapy, particularly as we get to third line and beyond, it’s very important that we ensure we understand all options of treatment available to our patient. We must remember radiopharmaceuticals that have already been approved, like radium. We must remember to do germline and somatic sequencing to see if our patient is eligible for treatment with a PARP inhibitor. Somatic sequencing gives us the opportunity to identify MSI [microsatellite instability]–high status, which allows the patient the opportunity to be treated with pembrolizumab. Understanding all the options, including whether a patient has the opportunity to enroll in a clinical trial, can help us ensure that our patient is given every opportunity to have the disease controlled, to feel better, and to optimize their time.

Dr. Morgans talks about available second-line treatment options for patients with mCRPC and considerations when choosing second and subsequent-line treatment options.

Second-line and Beyond: Treatment of mCRPC

Patients with metastatic CRPC [castration-resistant prostate cancer] are followed in many schemata in our clinical practices. At present, there is no specified idealized way for us to follow these patients. I see the majority of my patients with mCRPC [metastatic CRPC] every 4 to 6 weeks. Typically, that’s because I want to make sure their LFTs [liver function tests] are within normal limits, they’re not having a rising PSA [prostate-specific antigen], their testosterone is adequately suppressed, and they’re clinically doing well. For patients who are on ADT [androgen deprivation therapy] plus an AR [androgen receptor]–targeted agent and who have a relatively low burden of disease, they can go longer; some of those patients don’t come in except possibly every 12 weeks if they’re stable on their combination therapy.

The duration of time between follow-up visits is dictated by the burden of disease, the symptomatology of the patient, and the location of metastatic sites. For example, if a patient has liver metastases, I’ll see them more frequently than a patient who has some pelvic nodal metastases. For patients who have a lot of pain associated with their mCRPC, I’ll likely see them more frequently to make sure their pain control remains adequate and to follow them closely for signs of clinical progression.

PSA is something we follow when we’re monitoring patients who have metastatic CRPC, but in most cases I don’t change therapy based on a rise in PSA alone. I think of PSA as being a canary in a coalmine, something that changes and signals that something ominous could be happening and alerts me to get imaging in those cases. I also consider PSA in combination with the patient’s clinical status. If a patient has a rising PSA and is also developing a change in taste or is losing weight without trying, I consider that combination particularly concerning for progression of disease and will immediately get imaging to back me up, but I’m thinking about where we need to go next in terms of treatment.

If a PSA is only slightly increasing and the patient feels quite well, there’s a good chance that imaging will demonstrate that there’s relatively little to no change and we don’t need to change treatment. These are ways that we can be signaled that something could be happening, but PSA alone in most cases isn’t sufficient for me to change treatment, at this time at least.

An overview of how patients with mCRPC are monitored and followed-up in practice and the triggers to reevaluate the treatment patient is receiving.