Tomasz M. Beer, MD, FACP

The question is what are the unmet needs in metastatic CRPC [Castration-resistant prostate cancer]? I would say that there are a lot of them. When I think about unmet needs, my mind first goes to those heavily pretreated patients who are running out of treatment options altogether. That’s obviously the most pressing unmet need. But when we think about it, we should be aiming higher than sequential single-agent therapies that produce disease control for a period of time, and then the disease emerges with resistance. There is a need for much more effective therapies earlier on, that control the disease long term, and ultimately that produce durable disease-free status for our patients. While there’s an unmet need for late-stage therapeutics, I’d like the field to think hard about innovative combination therapies and aim high and aspire to produce, reliably produce complete remissions that are durable.

Are there other ongoing trials that are likely to change the treatment landscape? There are so many interesting studies out there, it’s almost hard to offer a list without worrying that I’ll forget something that is important to mention. But let me talk a little bit about several classes of agents and think about which ones might be most interesting. One area that I would think about is other targeted agents. We saw the initial results with ipatasertib and I’m very interested in seeing longer-term follow-up and more data on drugs like that that target specific genomic alterations in tumors. I’d like to see a situation where when we do a molecular analysis of a tumor, it’s not just for whether they qualify for PARP [poly ADP-ribose polymerase] inhibitors, but to access a pharmacopeia of targeted drugs that are individualized. I’m looking for those.

We’re seeing an awful lot of activity with PARP inhibitors in a variety of combinations. Time will tell where those go, but certainly something to pay attention to.

We’re seeing a lot of activity in a variety of immunotherapeutic areas, and here I would highlight some innovative technologies like bispecific antibodies that target prostate cancer cells through a cell surface antigen and T-cells and bring those physically together to activate an immune response. The first generation of those is going to target PSMA, [Prostate-specific antigen] but there are other antigens on the surface of cells that are also likely to be exploited with that technology.

A different approach that’s interesting in this area is antibody-drug conjugates. These are, at this point, early-stage phase 1/phase 2 studies, but we’re seeing more and more such agents to a variety of cell surface antigens, some prostate-cancer specific and some that are relevant to multiple cancers, where an antibody is used to deliver a pharmaceutical payload that is internalized by the cancer cell and delivered locally. That class of drugs is certainly of great interest.

Finally, one of the big trends in the field has been the movement of next-generation hormonal agents into earlier stages of disease. That is probably the most important development in terms of making a difference for patients. We’ve seen drugs like abiraterone, enzalutamide, apalutamide move from advanced metastatic castration-resistant prostate cancer to newly-diagnosed disease, and in the case of enzalutamide and apalutamide, into non-metastatic CRPC. We’ve seen darolutamide start directly in non-metastatic CRPC, and now being evaluated for newly-diagnosed metastatic disease. There are some additional studies in that space that are looking at multi-drug combinations for newly-diagnosed high-risk localized disease and for initial biochemical recurrence, PSA [Prostate-specific antigen] rises in a hormone-naïve setting. I would anticipate that we’re going to continue to see the trend towards earlier use of multi-drug hormonal combinations. That’s had a big impact on progression-free survival and overall survival on the disease, and although it is more of a learning how to use a set of drugs than developing completely new drugs, in terms of impact it’s a very important area to keep an eye on.

Key takeaways for metastatic CRPC is that field is evolving fast. The key nowadays is an individualized approach to patients based on their prior treatment experience, based on their comorbidities, and based on their tumor genotype. That’s the triad of things that we consider strongly in selecting therapies for individuals with metastatic CRPC. Then I guess the last pearl would be keep an eye out for new drug approvals because there’s a lot going on in the field, and I genuinely expect that every year or so the standard of care will evolve as we get new tools and learn new things. It’s a very dynamic field.

A 62-Year-Old Man with Metastatic Castration-Resistant Prostate Cancer

A 62-year-old man is found to have a firm prostate nodule of 1.5 mm on his routine physical exam

Digital rectal exam and transrectal ultrasound (TRUS) of the prostate confirm advanced adenocarcinoma of the prostate and Gleason score of 7 (3 + 4)

MRI shows lack of metastasis and node involvement (cT2bN0M0)

In Feb. 2017, patient was treated with radical prostatectomy (RP) with nerve sparing surgery and there were no complications.

PSA levels go down to 0.3 ng/ml post-operatively but rise to 1.5 ng/ml within 3 months.

Patient receives local salvage radiation therapy and PSA goes down to 0.1 ng/ml.

PSA doubling time increased between 2 last check-ups and now PSA is 3.5 ng/ml.

Patient undergoes CT and bone scans and is found to 1 metastatic bone lesion.

Patient is treated with androgen deprivation therapy (ADT), leuprolide

 as continuous treatment and PSA levels go down to 0.2 ng/ml.

PSA levels rise to 5 ng/ml, but patient is asymptomatic and has adequate organ and bone marrow function.

Patient meets the inclusion criteria for the ODENZA trial and is enrolled in it.

Patient is treated with darolutamide(1200 mg/day) for 12 weeks, followed by enzalutamide (160 mg/day) for 12 weeks, in addition to continuing on ADT

Patient is currently in the extension phase of the study and is being treated with darolutamide.

Videos

Tomasz M. Beer, MD, FACP, shares unmet needs and clinical pearls for the management of patients with mCRPC.

Future Directions for the Treatment of mCRPC

The question is about the broad range of options of metastatic castration-resistant prostate cancer in terms of systemic therapy. Here, we have a series of drugs that have been FDA approved based on an overall survival advantage. In terms of drugs that are molecularly unselected, I think about sipuleucel-T immunotherapy, enzalutamide and abiraterone for metastatic disease, docetaxel, cabazitaxel, and radium-223 dichloride. We’ve got 6 agents that are FDA approved for metastatic CRPC [castration-resistant prostate cancer]. We also have pembrolizumab, which has a general approval for microsatellite unstable tumors, and that’s across histologies; it includes prostate cancer. That’s a rare situation in prostate cancer, but 2% or 3% of patients might qualify for that. Then we have olaparib and rucaparib approvals based on mutational status in metastatic CRPC after at least an androgen signaling inhibitor and, in the case of rucaparib, chemotherapy as well.

We have a host of options, and choosing between them ends up being an extraordinarily individualized exercise. The first thing we think about is the patient’s prior treatment history: what have they been exposed to so far, how they fared on that treatment, comorbidities, and which regimens they can tolerate and benefit from. That often narrows the choices. A lot of folks are treated for their initial disease, metastatic disease, with a 2-drug combination. A lot of folks present with nonmetastatic CRPC and end up on a next-generation androgen signaling inhibitor. By the time they get to metastatic CRPC, we may not have the abiraterone and enzalutamide treatment options available. In that context, we would choose a taxane chemotherapy, typically docetaxel first line. We would assess the patient tumor genotype and consider whether they might qualify for PARP inhibitors and, less commonly, pembrolizumab. We would typically use 2 lines of chemotherapy as necessary and radium-223 dichloride for bone-predominant disease in our practice after chemotherapy. That’s the general approach.

The field has seen a positive result out of the VISION phase 3 randomized clinical trial, which examined 177Lu-PSMA-617. It was the first targeted radiopharmaceutical in prostate cancer to produce a high response rate, a progression-free survival advantage, and an overall survival advantage in metastatic CRPC. The study was conducted in patients who had been relatively heavily pretreated and received at least 1 prior next-generation androgen signaling inhibitor and at least 1 taxane chemotherapeutic. It’s not FDA approved, but we’re certainly anticipating the likely possibility of FDA approval of 177Lu-PSMA-617 therapy. I see that as the most likely next addition to our armamentarium in this disease.

An expert in prostate cancer comments on selecting the optimal systemic therapy for metastatic castration-resistant prostate cancer (mCRPC) treatment.

Approaching Systemic Therapy for mCRPC

 My personal experience with darolutamide is in line with the data that are available in the label and primarily in the ARAMIS study. I’ve found darolutamide to be a relatively straightforward drug to prescribe, and I’ve seen the expected adverse effects of a second-generation androgen signaling inhibitor. I haven’t seen cognitive dysfunction, which is in line with what’s been reported with ARAMIS. It’s important to recognize that these patients are also on primary hormonal therapy and some degree of fatigue is expected, some of the complaints that we’re talking about are often present even before prescribing enzalutamide, apalutamide, or darolutamide. But typically, I haven’t seen worsening in those complaints in the patients I’ve prescribed darolutamide to.

To be candid, how do we manage adverse effects? I haven’t encountered a lot of important adverse effects that require management, and that’s true across the board to some extent. Certainly, we see some adverse effects with the other agents out there, and we see some fatigue with enzalutamide where we dose-reduce folks. But these androgen receptor antagonists are generally quite well tolerated, and darolutamide is no exception. I haven’t had a lot of challenges with adverse effects over and above what my patients are already experiencing with the underlying hormonal therapy.

I’m being asked to speculate about which patient types I might prescribe darolutamide to in a metastatic setting, and I find that a very challenging question to answer because the field is complicated. The most likely scenario that I anticipate is if the current randomized trial is successful, then we would see an indication in newly diagnosed metastatic disease in combination with primary hormonal therapy as well as docetaxel chemotherapy. If that trial is successful, that would reinforce what we’re seeing from PEACE1 with abiraterone and docetaxel and would convince me that a triplet combination is the way to go. I see myself embracing that approach with abiraterone in some patients and darolutamide in others. That’s the most likely scenario where I would see indications for darolutamide in the metastatic setting.

The question is, do I agree with the patient participating in the ODENZA trial with darolutamide and enzalutamide and then back on darolutamide. The long and short of it is absolutely. This is an excellent clinical trial that’s asking an important question, and it’s offering appropriate therapy for a patient who has newly diagnosed metastatic disease and has not previously been treated with a next-generation androgen signaling inhibitor. Enzalutamide is FDA approved in this setting, and darolutamide has an ample level of evidence for safety and activity based on other studies that have been done, particularly in nonmetastatic CRPC [castration-resistant prostate cancer]. That’s certainly appropriate in the context of a clinical trial to evaluate it in low-volume metastatic castration-resistant disease.

The 1 thing I would have perhaps done differently in this case is start the 2-drug therapy sooner, at the beginning of hormonal therapy, which then might have made this patient ineligible for ODENZA. But given his course of treatment, and the fact that he was treated with leuprolide alone initially, this made him an excellent candidate for the ODENZA study.

Tomasz M. Beer, MD, FACP, shares his personal experience using darolutamide for patients with CRPC and discusses his approach to patient selection of the drug in the metastatic setting.

Using Darolutamide in Clinical Practice for mCRPC

Darolutamide is a potent androgen receptor inhibitor. It’s the third approved next-generation drug in this space, with enzalutamide and apalutamide preceding it. Darolutamide has a distinct chemical structure, and it’s thought to be less capable of penetrating the blood-brain barrier. As a consequence, it’s thought to have much lower concentrations in the central nervous system than the other 2 drugs. The 3 drugs haven’t been compared head-to-head until the ODENZA study—we’ll talk about that in a minute—but they’ve all been studied in nonmetastatic castration-resistant prostate cancer. That’s a situation where a patient has a rising PSA [prostate-specific antigen] on primary hormonal therapy, leuprolide or equivalent and doesn’t have visible metastases on imaging. In that setting we’ve seen 3 randomized studies conducted, SPARTAN, PROSPER, and ARAMIS, evaluating apalutamide, enzalutamide, and darolutamide, respectively.

It’s certainly not appropriate for us to compare across studies, and it’s challenging to do so because when we look at specific adverse effects, it’s important to recognize that studies are done at different sites, so the way investigators collect adverse-effect data may differ. There are differences across studies that we must be careful about. Having said that, the observations from ARAMIS were quite thought-provoking. What we saw was no increase in falls relative to placebo, no increase in dizziness relative to placebo, no increase in patient-reported mental impairment relative to placebo, and a modest increase in fatigue. But when corrected for duration of exposure of the drug relative to placebo, there was no clear increase in fatigue either. All those findings support the hypothesis that perhaps darolutamide is less capable of entering the central nervous system and less capable of causing the kinds of adverse effects that you’d expect from the central nervous system.

With those thoughts in mind, several studies are underway. One is a study that I’m personally involved with, called DaroAcT, which is carefully looking at both physical and cognitive function and comparing darolutamide and enzalutamide. Another study is ODENZA, which is a randomized crossover study with a planned enrollment of about 250 participants, with the primary end point being patient preference. In the ODENZA study, participants are treated with either enzalutamide or darolutamide for 12 weeks, and then they cross over to the other drug, and they’re queried about which drug they prefer—they’ve experienced both. Some secondary end points focus on cognitive assessment. Preliminary results of those cognitive assessment tests were reported at the recent ESMO [European Society for Medical Oncology Congress], and there are some findings that suggest an advantage for darolutamide. But at this point, it’s quite preliminary. I’ll be looking forward to a peer-reviewed complete publication of those results.

Dr Tomasz M. Beer reviews the use of darolutamide for nonmetastatic CRPC as seen in the ARAMIS trial and metastatic CRPC as seen in the ODENZA trial.

ARAMIS and ODENZA Trials in CRPC

 The question about molecular or biomarker testing is a wonderful question. NCCN [National Comprehensive Cancer Network] Guidelines nowadays endorse recommending germline genomic testing for patients with metastatic prostate cancer and with high-risk locoregional disease as well. We would expect to find a mutational genetic predisposition to cancer in 10% to 12% of patients in that situation. Certainly germline testing would have been appropriate.

The other type of testing is somatic testing, looking for mutations that are not just inherited but also potentially acquired in the tumor. That can be done through an analysis of tumor tissue, or it can be done through a so-called liquid biopsy or blood-based analysis of circulating tumor DNA. That’s typically done with the goal of treatment selection, and there are a couple of treatments that are molecularly selected. One is PARP inhibitors. There are 2 that are approved, olaparib and rucaparib. Another is pembrolizumab, an immune checkpoint inhibitor.

PARP inhibitors can be helpful for patients with mutations in some of the key genes for DNA repair, and the evidence is most clear for 

 mutations. Immune checkpoint inhibitor therapy would be appropriate to consider in patients who have a hypermutated phenotype. 

 is another term that’s often used to identify patients who have a very high mutational burden, and presumably a larger number of abnormal antigens formed through mutations and the making of abnormal proteins, making it more responsive to immunotherapy. That’s the indication for somatic analysis.

These kinds of therapies are typically done at the earliest after progression on a next-generation androgen signaling inhibitor—so not yet in our patient—and in many cases after a round of chemotherapy as well. I’m not sure if there’s an immediate imperative to do somatic mutational testing at this point in the course of his treatment. One could certainly contemplate that to gather that information for the future, but 1 could also do that later. Germline testing for inherited mutations would certainly be recommended. It would be potentially helpful for this patient’s treatment but also to family members.

The question is about a patient like this who is older and has additional comorbidities. This is a common scenario. Many patients with prostate cancer are older than age 62, especially patients with recurrent metastatic disease. These are often folks who had a prostatectomy maybe a decade ago and have had a PSA [prostate-specific antigen] or so-called biochemical relapse and eventually develop metastatic disease. By then they’re often in their mid 70s and beyond. One of the principals of geriatric oncology is to think about biologic age rather than chronologic age. We don’t just treat older folks differently because the number is higher. We look at their health and comorbidities. Of course, comorbidities are more common as people get older, but we do need to consider the healthy, robust 80-year-old as someone who is capable of withstanding all the usual therapies and deserving of that.

In people with compromised organ function or significant comorbidities, we can think about selection of agents. We’ll be a bit less likely to recommend docetaxel chemotherapy. We may think about carefully between abiraterone and apalutamide or enzalutamide in this setting, and the choice there might depend on the types of comorbidities. An example would be folks with diabetes may have a bit of a tougher time with abiraterone because of the prednisone and the blood sugar control issues that develop. Folks with preexisting cardiovascular conditions are at elevated risk on either agent, but the risk is greater with abiraterone, so we may lean toward apalutamide or enzalutamide there. On the other hand, enzalutamide and apalutamide have been associated with an increased risk of falls, so people who are frail and have had a history of falls might be better candidates for abiraterone. That’s a complex discussion, but it would definitely require us to think carefully about which drugs to choose.

I’d be reluctant to omit the doublet therapy unless truly forced to do so. There’s a clear benefit in terms of progression-free survival and overall survival, and metastatic prostate cancer is an aggressive, lethal disease. In an uncommon scenario, even in an 80-year-old with comorbidities, I would recommend leuprolide alone. It certainly has happened, but usually we would work hard to find a way to safely deliver the most effective anticancer therapy.

Prostate cancer expert Tomasz M. Beer, MD, FACP, provides insight on the use of molecular and biomarker testing for a patient with mCRPC.

Role of Molecular Testing in mCRPC

 For initial treatment of metastatic disease when it’s diagnosed, I’d be happy to expand on that. Historically, we have used conventional hormonal therapy, and the classic approach is a month of oral first-generation androgen signaling inhibitor like bicalutamide and conventional ADT [androgen deprivation therapy] with injectable, typically leuprolide. There are other choices as well, of course. Over the last nearly decade, we’ve seen the emergence of clear evidence that intensifying that initial regimen yields better progression-free survival and overall survival, and we now have evidence for doing that with a combination of leuprolide or equivalent with docetaxel, abiraterone, enzalutamide, and apalutamide.

How 1 chooses between those options ends up being an individualized decision. For low-volume patients such as this patient, we don’t have clear evidence supporting docetaxel. We have some evidence, and 1 could parse the data, but the original CHAARTED study did not reveal an advantage in low-volume patients for the additional docetaxel. The subsequent STAMPEDE study suggested that the benefit was there; it’s a debated point. But many practitioners will choose a 2-drug hormonal combination for low-volume patients. For high-volume patients, any of the 4 options are reasonable, and they haven’t been compared head-to-head directly, so it’s difficult to make a strong case for 1 particular choice.

A major component of our decision involves patients’ comorbidities and patient preferences. There are differences among these treatments in adverse effects and cost. It ends up being an individualized discussion, and there’s not 1 single answer for every patient.

The big question in the field is would a triple combination work even better. At ESMO [European Society for Medical Oncology Congress] in September 2021, we saw the presentation of the longer-term follow-up of the PEACE1 study, where Dr Karim Fizazi reported that a randomization between conventional ADT plus docetaxel, with or without abiraterone, showed a benefit in terms of radiographic progression-free survival and also overall survival, arguing that perhaps a triplet is the future. The benefit was clearly seen in higher-risk, higher-volume patients, the data are not as mature in the lower-volume patients, and we have to digest and understand and think about those data. But at least for the highest-risk patients, we’re going to start thinking about triplet combinations.

We do have an upcoming triplet trial, and that’s a trial examining ADT plus docetaxel plus darolutamide. Distinct from the trials of enzalutamide and apalutamide, this study is evaluating a triplet. It will be very interesting to see if it yields results that are in line with what we saw in PEACE1.

In this case, I might have taken a somewhat different approach at 2 points. One is when we saw a rapidly rising PSA after surgery. That would be a place where deploying high-sensitivity imaging such as PSMA [prostate-specific membrane antigen], PET [positron emission tomography]/CT, and Axumin PET/CT would have been something that we would consider. That might have led to a different decision regarding salvage radiation. Second, salvage radiation is typically given with a course of hormonal therapy. Several randomized studies have shown superior results with that combination. Finally, at the moment when the patient was diagnosed with metastatic disease, the standard of care is to use a doublet therapy. I would have considered prescribing leuprolide plus either abiraterone, enzalutamide, or apalutamide, and any of those combinations would have been supported by the data.

Dr Tomasz M. Beer comments on approaching first-line therapy for a patient with metastatic castration-resistant prostate cancer (mCRPC).

Tomasz M. Beer, MD, FACP | Authors

Articles

Future Directions for the Treatment of mCRPC

Approaching Systemic Therapy for mCRPC

Using Darolutamide in Clinical Practice for mCRPC

ARAMIS and ODENZA Trials in CRPC

Role of Molecular Testing in mCRPC

Frontline Treatment Options for mCRPC