Bobby Liaw, MD

 A lot is changing in the field of prostate cancer. Here are a couple of my thoughts on future directions and unmet needs. In terms of unmet needs, there still needs to be a little more focus on how we optimally sequence and combine the multiple drugs that we already have for prostate cancer. We’re already starting to see studies coming out for combination use. PEACE-1 data just started to come out and are showing that there may be a significant benefit to the combination of abiraterone and docetaxel in the upfront metastatic CSPC [castration-sensitive prostate cancer] setting. But we’re still waiting on data that will be coming out relatively soon from the ARASENS study, which is combining docetaxel with darolutamide, another oral AR [androgen receptor]-targeted drug. The data there are still pending, but that study is examining using a triplet regimen for upfront treatment of hormone-sensitive prostate cancer.

Outside of combinations, we’re also starting to see some of our “advanced drugs” that we used to reserve for castration-resistant prostate cancer make their way into localized disease. The recent STAMPEDE study is also showing improvement in outcomes when we combine abiraterone with hormone therapy, along with definitive curative-intent radiation therapy. We need to also expand our arsenal for people in the neoadjuvant and adjuvant settings, things that will perhaps intensify therapy to improve outcomes in patients undergoing definitive therapy. Certainly, more needs to be done in the metastatic setting.

PSMA [prostate-specific membrane antigen]-directed therapy is going to be very big. There’s going to be a very big push in developing more PSMA-directed therapy. We’re already anticipating the approval of Lutetium-177–PSMA-617, which is most likely to be approved in the castration-resistant prostate cancer setting, but there are ongoing studies to evaluate its use in the hormone-sensitive prostate cancer setting. We’re also engaging more in immunotherapy. PSMA-directed bispecific T-cell engagers are a very hot topic. We’re hoping that will add to our arsenal for people who have metastatic prostate cancer. And while there’s been a lot of movement in genomic sequencing of prostate cancer, trying to identify new genomic targets, as of right now, as part of standard options, we have PARP inhibitors for the group of patients who have homologous recombination repair deficiencies, but more needs to be done. Hopefully we’ll start to see more treatment options for all the other genomic abnormalities that we’re starting to find for prostate cancer.

There are a lot of key takeaways and clinical pearls. The prostate cancer landscape is constantly changing. As far as it’s come for metastatic hormone-sensitive prostate cancer, I’d say that combination therapy is now a standard of care. It’s really nice that we have many different options to choose from so that we can individualize the selection based on patient preference as well as disease presentation.

One thing that I’ll leave my colleagues with is that as we see many more of our therapeutic agents that were traditionally reserved for castration-resistant prostate cancer moving into hormone-sensitive and localized disease, it’s safe to say that’s a trend that’s here to stay. It’s going to be more important than ever for us to have a multidisciplinary approach to the treatment of our patients with prostate cancer. We may need to become more used to seeing patients who have much more localized disease, or even at the very beginning, when they’re starting to have biochemical recurrence, we’re starting to see that by being a little more thoughtful and a little more aggressive with our treatment therapy up front, we can really move the needle and improve patient disease control as well as disease outcomes in the long term.

A 73-Year-Old Man With Biochemical Recurrence of Prostate Cancer and Metastatic Castration-sensitive High-volume Disease

A 73-year-old man presents with urinary retention, fatigue and decreased appetite

Patient History, Lifestyle and Clinical workup

History of mild alcoholic liver cirrhosis

Patient is active and is very involved in his grandchildren’s activities

TRUS and biopsy revealed adenocarcinoma of the prostate gland, Gleason score 8 [4+4] with disease in 10/12 cores.

Patient is diagnosed with localized prostate cancer

He undergoes robotic radical prostatectomy with subsequent PSA decrease (12 ng/mL)

CT and bone scans showed no residual disease

Patient complains of right hip pain and abdominal pain

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

Liver function tests continue to be abnormal

Patient is diagnosed with biochemical recurrence of prostate cancer with high-volume castration-sensitive metastatic disease

Patient wishes to receive oral treatment with good quality of life so he can continue to be involved in his grandchildren’s activities

Due to his abnormal liver function tests and desire to receive oral treatment, he is started on ADT + apalutamide

At his 1-year follow-up, the patient’s PSA remains undetectable

Follow-up imaging shows stable disease, and he continues to report a good quality of life

Videos

Dr. Bobby Liaw looks to the future of metastatic castration-sensitive prostate cancer treatment and provides some advice and clinical pearls.

Advice for Community Oncologists Treating Metastatic Castration-Resistant Prostate Cancer

 The TITAN study was an international multicenter, double-blind, placebo-controlled phase 3 clinical trial where they randomized 525 men with metastatic castration-sensitive prostate cancer 1:1 to receive either ADT [androgen deprivation therapy] plus apalutamide or ADT plus placebo. The primary end points of this particular study were radiographic progression-free survival as well as overall survival. Secondary end points included time to cytotoxic chemotherapy, time to pain progression, time to chronic opiate use, and time to skeletal-related events. They also had a couple of exploratory end points, including time to PSA [prostate-specific antigen] progression, second progression-free survival, and time to symptomatic local progression.

I’ll highlight a couple of notable inclusion/exclusion criteria for this study. Patients were allowed to receive previous docetaxel—up to 6 cycles—as part of their metastatic castration-sensitive prostate cancer treatment per the CHAARTED study data that had come out around that time. In fact, about 10.7% of patients had received prior docetaxel on this study. The study also allowed patients with metachronous recurrence of metastatic disease to enroll. This differs a little from some of the studies, such as CHAARTED and LATITUDE, that required patients to be de novo metastatic. In fact, 16.4% of patients on TITAN had undergone prior prostatectomy or radiation therapy for localized disease.

At the time of the first interim analysis, which was shared with us back in 2019, there was a significant improvement in radiographic progression-free survival in patients who received apalutamide. The radiographic progression-free survival at 24 months, at the initial analysis, was 68.2% vs 47.5%, with a very clinically significant hazard ratio of 0.48. We were already seeing a very significant overall survival benefit at 24 months in favor of apalutamide, with a hazard ratio at that point of 0.67.

The final analysis of the TITAN study was shared with us in early 2021. Following unblinding of the arms, patients on the placebo arm were allowed to cross over to receive apalutamide. This ended up being 39.5% of the placebo arm that crossed over. And even with the crossover, in the final analysis, apalutamide retains a significant overall survival advantage, with a hazard ratio of 0.65, reducing risk of death by 35%. The treatment effect on overall survival was favorably consistent across multiple prespecified subgroups. This includes that all-important high-volume vs low-volume disease. We’re seeing a consistent effect across high-volume and low-volume disease.

I’ll also bring up that interestingly, when we look at one of their exploratory end points, apalutamide actually prolonged their secondary progression-free survival significantly. It significantly reduced the risk of death from second progression by 38% when compared with placebo. This isn’t a standard end point, of course. It’s defined as time between initiating the first subsequent therapy and the progression on that first subsequent therapy. But it really goes to reflect and highlight the clinical advantages of early treatment with a drug such as apalutamide off the bat when we’re facing metastatic castration-sensitive prostate cancer.

As part of prespecified exploratory endpoints on the TITAN study, patient-reported outcomes were collected using a variety of different patient surveys, including the Brief Pain Inventory—Short Form, the Brief Fatigue Inventory, the FACT-P [Functional Assessment of Cancer Therapy-Prostate], and the EuroQol Quality of Life 5D questionnaire. Most of these patients came onto the study pretty asymptomatic at baseline.

It’s uplifting to see that patients on the study who experienced pain and fatigue, we’re talking about intensity, it didn’t differ significantly between the groups, between people who got apalutamide and didn’t get apalutamide, and that actually holds for the duration of treatment. The FACT-P survey as well as the EuroQol data showed that there was good preservation of health-related quality of life in both groups. It’s important to highlight that this maintaining of quality of life was despite the addition of an androgen blockade. Taking into context that this is a very active drug that improved survival for patients with metastatic hormone-sensitive prostate cancer, this is a drug that people will end up staying on for a significant amount of time.

When we look at the study, the median treatment duration for someone in the apalutamide arm was something on the order of 39 months. That’s a little more than 3 years. For a drug like apalutamide, which we know can potentially have some adverse effects, to maintain its quality-of-life metrics compared with placebo over the long haul while having a very acceptable safety profile, this demonstrates that we need to heavily consider the use of combination therapy with our men with metastatic hormone-sensitive prostate cancer.

A key opinion leader reviews how findings from the TITAN study affect treatment of metastatic castration-sensitive prostate cancer.

Metastatic Castration-Sensitive Prostate Cancer: the TITAN Study

 If this patient had recurred with his Gleason score 8 prostate cancer with low-volume disease, then off the bat, I’d say that chemotherapy would be a much less considered option, only because the data for docetaxel use in low-volume metastatic castration-sensitive disease aren’t as appealing as for high-volume disease. When you think about apalutamide and enzalutamide, both of these studies included patients with low-volume disease. About a third of cases were considered low-volume disease by CHAARTED trial criteria. And looking at the subgroup analysis, both drugs—apalutamide and enzalutamide—retained good consistency in terms of disease control and survival advantage in the low-volume patients. Certainly, in low-volume disease, I wouldn’t consider chemotherapy, but apalutamide remains a good option with good data to support its use.

In an alternate situation where there are no signs of radiographic disease on scans, oftentimes after prostatectomy, we have the consideration for whether they’d be a good candidate for salvage therapy. By salvage therapy, I’m usually talking about salvage radiation combined with hormone therapy. It could be argued that for anyone who still has a PSA [prostate-specific antigen] that’s as elevated as 12 ng/mL following a prostatectomy, salvage radiation is unlikely to give you a second chance at a cure. But usually, that would be one of the things that we’d at least first consider and discuss with radiation oncology about.

Outside of the prospect of salvage radiation, for someone who has a rising PSA after prostatectomy, this patient just had monitoring of his PSA levels. The other tactic that we’ll often utilize in biochemical recurrence is hormone therapy. But more specifically, we’d consider a patient for intermittent use of hormone therapy. For patients with biochemically recurrent disease, there have been studies looking at intermittent vs continuous use of hormone therapy, for which intermittent use was shown to be noninferior to continuous use and noted to have some potential improvements in quality of life. The more time that we can give people off of hormone therapy to have normalized testosterone levels goes a long way to making men feel generally physically better. I would’ve considered intermittent hormone therapy for this patient outside of just monitoring.

Bobby Liaw, MD, explains the potential treatment strategy for a prostate cancer case with low-volume metastatic disease.

Treating Prostate Cancer with Low-Volume Metastatic Disease

 Circling back on our case and thinking a little about some of the treatment decisions that were made following the surgery, for a patient to still have a PSA [prostate-specific antigen] that’s elevated to about 12 ng/mL after a curative intent prostatectomy, even though bone and CT scans at the time didn’t necessarily show anything, I personally would’ve tried to get him some more advanced imaging. Like I mentioned before, it’s not always the easiest thing to obtain, depending on where you are, but an Axumin PET [positron emission tomography] scan or a PSMA [prostate-specific membrane antigen] PET scan are both going to be much more specific and sensitive for picking up stray residual, perhaps even more microscopic-size disease that the CT and bone scans will not pick up. I bring this up only because if we were able to capture the disease at an earlier point, perhaps we would’ve tried to start him on at the very least ADT [androgen deprivation therapy] alone first.

But going with what we have once the disease is shown to be metastatic, now that we know that it’s in bone and liver, and taking into consideration some of the patient’s personal priorities—he wanted to make sure he was going to be able to remain active and involved in his family life—and also some of his personal history of baseline LFT [liver function test] abnormalities due to his alcoholic cirrhosis, it was a pretty good idea to go with apalutamide. The reasoning is that chemotherapy can be difficult for some patients to tolerate.

Certainly, whenever I offer chemotherapy to any of my patients, they always understand that docetaxel is generally pretty well tolerated, and because we have so much experience in using it, we feel pretty confident that we should be able to support them through some of the potentially mild or difficult adverse effects they might come across. But there’s going to be something, such as the LFT abnormalities, that we don’t have as much control over. Knowing that we run into LFT abnormalities at times with abiraterone, it requires more frequent laboratory testing to make sure we don’t run into electrolyte abnormalities or LFT abnormalities. For someone who really wants to prioritize their home life and not always be tied to the office for follow-up and laboratory tests, apalutamide is a very good drug to select in this type of a context.

I’ll also mention that when we look at his particular case, liver metastases aren’t the most typical presentation for prostate cancer recurrence. You can make the argument that for a Gleason score of 8, these are more high risk, you might be at a higher likelihood of having visceral metastases. But whenever I see visceral metastases, we know that these typically portend a worse overall prognosis. I usually will find a way to be a little more aggressive and try to find ways to offer chemotherapy in this type of a context, as I feel like that’s something that’s possibly pretty valuable in terms of this patient’s long-term treatment. That’s not to say that there weren’t patients with hepatic metastases on the TITAN study, which was the phase 3 study that got apalutamide its FDA indication. But the number of cases of patients with hepatic metastases in the TITAN study was relatively low.

We do see that in the subgroup analyses of people with visceral metastases, apalutamide still performed very well. But at the same time, knowing that this is perhaps something that’s going to be a little more on the poor prognostic side of things, I generally try to take a much more aggressive stance on it. But as always, individualizing treatment decisions to patient characteristics, disease characteristics, but also according to the patient’s preference, also need to be considered. All in all, I still think it’s a very solid and reasonable decision to go with apalutamide.

A prostate cancer expert reviews the treatment approach in the presented case of biochemical recurrence of prostate cancer with high-volume castration-sensitive metastatic disease.

Treating Biochemical Recurrence of Prostate Cancer with High-Volume Castration-Sensitive Metastatic Disease

 All 4 of these drugs are excellent options for someone who’s coming in with a new diagnosis of metastatic castration-sensitive prostate cancer. Unfortunately, none of the studies compared one drug to another. They were all compared to placebo, which is reasonable because that was the standard of care at the time that all these studies were designed. But that puts us in a difficult position. You have a lot of different drugs that all have excellent data to support their use, with docetaxel being the one that’s a little different in that it’s chemotherapy, where we know that volume of disease matters. That tends to be the main reason we may or may not choose chemotherapy.

Although in my own personal practice, for people with very symptomatic disease, when you want to try to effectively improve upon symptomatology as quickly as possible, I find that docetaxel may be a good solution in that type of a situation. Of course, we need to consider some individual characteristics of the patients being selected for treatment. For people who are much older, for whom we might anticipate difficulty in tolerance with chemotherapy, we may want to select one of the oral agents instead.

As far as abiraterone vs apalutamide vs enzalutamide, it becomes a little more difficult to choose sometimes. Abiraterone requires the concurrent use of a steroid on a daily basis to combat some of its adverse effects. Additionally, for abiraterone, we need to consider that there needs to be some regular maintenance laboratory tests performed in order to make sure there aren’t going to be any issues with LFT [liver function test] derangements as well as electrolyte derangements, because these are adverse effects of the medications that need to be monitored closely.

Drugs like apalutamide and enzalutamide don’t require as many of these maintenance laboratory tests. For patients who are perhaps a little less willing to come for frequent laboratory checks, these may be better drugs to select in those situations. I tend to favor abiraterone whenever I choose one of these, but for the right patients, for people who I know will run into difficulties with the steroid use, such as if they have diabetes or they already have pretty brittle bones, if we already have issues with metabolic disorders where I want to avoid the steroid use, I often will choose either apalutamide or enzalutamide.

One additional thought that needs to be considered going forward is whether we should be thinking about triplet therapy. Recently presented at ESMO [European Society for Medical Oncology Congress] in 2021 were some of the early findings from the PEACE-1 study, where there was an experience in using ADT [androgen deprivation therapy] plus docetaxel plus abiraterone. What we’re seeing in early analysis is that using the 3-drug combination up front actually led to better outcomes than in men who use just 2 drugs in de novo metastatic hormone-sensitive prostate cancer. A lot of the early data show that when abiraterone was added to ADT and docetaxel, there was a significant improvement in overall survival, with a hazard ratio of 0.75, meaning that men experience an additional 25% reduction in risk of death compared with ADT and docetaxel alone.

There needs to be some additional follow-up on these study data before we get a better sense of how tumor burden, volume of disease, affects survival in these 2 different groups. But so far, it seems that the triplet regimen is significant in providing additional years of disease control without progression in men with high-burden disease. It’s more about whether we’ll see the same benefit bear out on patients with low-burden disease. It’s a significant consideration. At this moment, when it comes to people with high-risk disease, someone for whom you’re hoping to be able to optimally control the disease immediately and better control their disease in the long term, especially patients who are younger who can tolerate some of the additional mild adverse effects that come with the addition of abiraterone to docetaxel, the triplet regimen is something that is increasingly crossing my mind to offer to some of my patients.

Dr. Bobby Liaw compares the available first-line therapy options for metastatic castration-sensitive prostate cancer and explains how to decide on a therapy.

Metastatic Castration-Sensitive Prostate Cancer: Comparing First-Line Therapy Options

 The therapeutic landscape for first-line therapy for metastatic castration-sensitive prostate cancer has changed dramatically in recent years, as data for drugs such as docetaxel, abiraterone, apalutamide, and enzalutamide have been shown in their own individual randomized phase 3 studies to improve overall survival when used in people with metastatic castration-sensitive prostate cancer. A lot of the data started with the CHAARTED study, where it showed that the inclusion of 6 cycles of docetaxel in combination with ADT [androgen deprivation therapy] showed a significant improvement in overall survival for men with newly diagnosed de novo metastatic castration-sensitive prostate cancer.

With docetaxel, we need to consider disease volume while trying to figure out who would be a good candidate and who wouldn’t. That’s because as part of this study, we saw that patients with a high volume of disease are the ones who had the overall survival advantage with the addition of 6 cycles vs those who had low-volume disease didn’t seem to meet that mark. In regard to the definition of high-volume disease, the CHAARTED criteria considered the number of bone metastases—meaning 4 or more sites of bone disease, one being extra-axial—or the presence of visceral metastasis.

In looking at people who might not be a good candidate for chemotherapy, whether it’s anticipating difficulties tolerating it, or if we’re running into a patient preference where they don’t want to consider chemotherapy, we have 3 other drugs that fall within this androgen receptor pathway inhibitor that have also been very instrumental in showing overall survival advantage. Abiraterone, apalutamide, and enzalutamide all work in slightly different ways, although they all work on the androgen pathway axis.

Abiraterone showed its benefits in the LATITUDE study. In that particular study, they were looking at patients with high-risk disease, defined as a Gleason score of 8 or above, the presence of 3 or more sites of bone metastasis, or presence of visceral metastasis. Meanwhile, apalutamide and enzalutamide were both tested in a very broad selection of patients with metastatic prostate cancer, inclusive of both low-volume disease and high-volume disease. All 3 of these drugs—abiraterone, apalutamide, and enzalutamide—have met overall survival advantage in long-term follow-up and analysis.

Case: A 73-Year-Old Man With Biochemical Recurrence of Prostate Cancer and Metastatic Castration-sensitive High-volume Disease

An oncologist details the first-line therapy options for metastatic castration-sensitive prostate cancer.

Bobby Liaw, MD | Authors

Articles

Advice for Community Oncologists Treating Metastatic Castration-Resistant Prostate Cancer

Metastatic Castration-Sensitive Prostate Cancer: the TITAN Study

Treating Prostate Cancer with Low-Volume Metastatic Disease

Treating Biochemical Recurrence of Prostate Cancer with High-Volume Castration-Sensitive Metastatic Disease

Metastatic Castration-Sensitive Prostate Cancer: Comparing First-Line Therapy Options

First-Line Therapy Options for Metastatic Castration-Sensitive Prostate Cancer