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

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” and “New horizons in nuclear medicine for prostate cancer,” the first 2 articles of the New Precision Medicine Approaches in Prostate Cancer series of Targeted Oncology™.

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.

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

MORGANS: 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.

TARGETED ONCOLOGY™: 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?

MORGANS: 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.

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

MORGANS: 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 currently 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.

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

MORGANS: [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.

TARGETED ONCOLOGY™: 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?

MORGANS: [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 MLH and MSH 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.

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

MORGANS: 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.

TARGETED ONCOLOGY™: What is on the horizon for aPC treatment?

MORGANS: 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.