Treatment Considerations in Metastatic Castration-Resistant Prostate Cancer: A Q & A With Neal Shore, MD, FACS and Oliver Sartor, MD

Neal Shore, MD, FACS

Therapeutic options have grown considerably in recent years for men with metastatic, castration-resistant prostate cancer (mCRPC), and these include oral hormonal agents (abiraterone acetate, enzalutamide), immunotherapies (sipuleucel-T), and agents targeting bone metastases (radium-223). Many of these agents are also life prolonging for men with mCRPC, but the optimal timing and sequencing of the available therapies is not known. In the absence of clearly defined guidance, treatment decisions must consider a range of patient factors, comorbid conditions, and life expectancy.

Targeted Oncologyspoke with two leading experts in the prostate cancer field about the range of available treatments and their current applications in men with mCRPC.

Neal Shore, MD, FACS, is a director and certified physician investigator at the Carolina Urologic Research Center in Myrtle Beach, South Carolina.

Q: What are your main considerations when monitoring and treating patients with mCRPC and bone metastases?

A: The main consideration that should be factored into the treatment of most patients with CRPC is their performance status, specifically, how well are they functioning. Performance status has implications as to how aggressive one would want to be in terms of therapies, how well a patient may tolerate potential side effects, and what may be the therapeutic burden of a specific treatment. The clinician should try to attain some assessment of the patient’s actuarial survival—does he have any other significant comorbidities that may result in his demise much sooner than his advanced prostate cancer. Fortunately for most patients, that’s not the situation, but occasionally, somebody may have a very pronounced comorbidity that might prevent me from ordering certain types of CRPC therapy.

That said, if we assume that the patient has a reasonably good performance status, they’re functioning, and they’re taking care of themselves—perhaps even able to do some work, and they have bone metastases, then the degree of symptomatology is important. Interestingly, often times we see things that don’t always appear to be intuitive—somebody can have a small volume of bone disease and yet be very symptomatic from it, and sometimes, they can have a really voluminous amount of bone disease and have virtually no symptomatology. We often observe proportionality in the number of lesions and symptoms as well. What is also important is whether or not patients have had any preceding therapies—have they had chemotherapy or not? If they have a high volume of bone lesions, do they have any other disease burden, such as in their liver, or an excessive amount of soft tissue disease (eg, lymph node involvement)? These are some of the considerations. When you’re looking from a global perspective, there are always the issues of access and affordability of the different therapies, to the credit of many of the new therapies and the companies that have developed them [access programs]. I do think they’re working very hard on improving global accessibility and affordability.

Q: How might your treatment decisions be impacted with biochemical versus clinical progression?

A: This is a very important question and sometimes, it’s a challenging question, because when there’s clinical progression based on worsening symptomatology that’s cancer related, then that’s usually the most clear-cut indication to initiate or to switch an antineoplastic therapy. After that, I’d say if there’s radiographic progression, specifically—documented clearly—the onset of new lesions in the setting of an existing therapy, then oftentimes that’s a very good metric to consider a new or an additional antineoplastic therapy. When we look at biochemical progression, especially in the CRPC setting, we have to consider that many patients will have fluctuations in their PSA and that some therapies don’t really have a significant modulating impact resulting in declines in PSA, whereas other therapies do. Specifically, the oral targeted agents that work on the androgen/androgen receptor pathway, abiraterone and enzalutamide, are particularly well known to cause PSA declines, and it’s usually very consistent with their therapeutic effect of diminishing pain, and resulting stabilization of disease. Other therapies, such as targeted bone therapies—whether an antiresorptive [agent], such as denosumab or zoledronic acid (which are not indicated for prolonging survival); or whether a bone-targeted agent that has life-prolonging benefits, such as radium 223—these agents typically don't modulate PSA. They have minimal impact on PSA. Similarly, sipuleucel-T, the immunotherapeutic approved in CRPC, does not modulate PSA, and it’s also a life-prolonging agent. 

If we are talking about the biochemical event being PSA as I just described, interestingly, the taxane-based chemotherapies such as docetaxel and cabazitaxel, when we see them having a therapeutic benefit, we will usually also see declinations in PSA. But there are other important serologic/prognostic markers to look at, and that includes alkaline phosphatase, hemoglobin, and LDH. What’s particularly nice in bone-targeted agents is that you can see, when they’re having a good effect, that the bone-specific alkaline phosphatase will often times decrease very significantly. We saw that in the ALSYMPCA trial, the phase III trial that led to the approval of radium 223.  When it comes to looking at biochemical responses in my patients with CRPC, I tell them that we’re going to continue to look at PSA, but we have to stop being so PSA-centric. We also need to look at hemoglobin, alkaline phosphatase, LDH, and of course make sure that their liver and kidney function are remaining stable. It requires a little more of an involved discussion and shared communication with the patient and their caregiver team. I don't typically make a decision to switch any antineoplastic therapy based solely on one biochemical marker, but the decision is in conjunction with symptomatic progression and radiographic progression.

Q: How have the results of key trials such as COUGAR and PREVAIL impacted treatment decisions?

A: The COUGAR trial (COU-302), was really a landmark trial, because it demonstrated for the first time that we had an oral therapy, if given prior to chemotherapy in the M1 CRPC population, that could, in addition to prolong life, also delay radiographic progression and maintain quality of life. Around 18 months later, we saw similar results in the PREVAIL trial. The COUGAR trial was investigating abiraterone acetate given in conjunction with prednisone in a 2:1 randomization. The PREVAIL trial had a very similar design—again a chemotherapy-naïve population with asymptomatic-to-minimally-symptomatic M1 CRPC, and a 2:1 randomization of another agent, enzalutamide, compared with placebo. Just like COU-302, the PREVAIL trial demonstrated survival potentiation as well as delay in radiographic progression-free survival, and maintained quality of life. Both of the drugs have slightly nuanced differences in terms of significant adverse events that could impact their use. In COU-302, there was the potential concern for its use in patients with congestive heart failure, because of the very small risk of fluid retention, and in the PREVAIL trial, there were some contraindications for patients who had a history of seizure or significant cognitive impairment. Otherwise, and fortunately, most patients can be very good candidates for either one of these therapies, which are now approved prior to chemotherapy (although both were approved initially in the postchemotherapy setting).

Q: Should radium-223 be administered prechemotherapy? What patients do you consider candidates for this agent?

A: As one can see, we now have a plethora of life-prolonging CRPC therapies, and because they have all been approved in a relatively short period of time, within the last 5 years, we don't have enough prospective, Level 1 evidence regarding how to best combine and/or sequence these CRPC therapies. When I first started using radium-223, I had built up a population of patients who had progressed after docetaxel and/or cabazitaxel, so these were my initial recipients for radium-223. Since then, I’ve become very comfortable in prescribing radium-223; the dose is given once every 4 weeks for a total of 6 infusions. The infusion lasts 45 to 60 seconds, and there’s no premedication or postmedication. The adverse event profile is also remarkably low, so the patients tolerate it exceptionally well. In the ALSYMPCA trial, patients were able to get concomitant therapy with all that was considered the best standard of care at the time, which could have included estrogen therapy, steroids, androgen receptor signaling inhibitors (such as bicalutamide), androgen biosynthesis inhibitors (such as ketoconazole), and even radiation therapy, and we didn't see any problems [in ALSYMPCA] with concomitant therapy. [Considering these data] in the overwhelming majority of my patients now, I’m giving the radium-223 before chemotherapy, and typically in conjunction with either enzalutamide or abiraterone. 

Typically, I will use radium-223 in a patient who clearly has bone metastatic disease (generally more than 2 lesions. Most patients have at least 6 lesions) and is symptomatic, and we will administer that in conjunction with either abiraterone or enzalutamide. I think it’s also important to note [its use in combination] because what we’ve now seen in the expanded access program that was conducted in North America, Canada, United States, as well as in Scandinavia, Europe and Israel, is that with concomitant use of either abiraterone or enzalutamide and radium-223 (neither of which were available for use during the ALSYMPCA trial) we’ve seen no untoward or new safety signals, and there’s a little bit of early data to suggest that those patients [receiving the combinations] do better regarding overall survival, which intuitively makes sense, because the mechanism of action of the oral hormonals is very different from that of the radium-223. Importantly, we do need more data, and we need more combinatorial trials. At my site, we have just completed an open-label trial of 40 patients getting concomitant abiraterone acetate with radium-223 (submitted to ASCO GU), and we plan to do a similar study with enzalutamide.  It’s my feeling, however, that many clinicians are already giving these drugs concomitantly.

Oliver Sartor, MD

Oliver Sartor, MD is the Laborde Professor for Cancer Research at Tulane Medical School and Medical Director at the Tulane Cancer Cancer, New Orleans, Louisiana.

Q: What are the main options for treating patients with CRPC and bone metastases?

A: There are six life-prolonging FDA-approved therapies available for men with mCRPC. There are several other therapies that are approved by the FDA, but which are not known to prolong survival. When we see a patient with CRPC, we are thinking about which one of these six therapies should be utilized. All of these treatments—sipuleucel T, abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, and radium 223—are active in bone metastatic disease, and there are prospective clinical trials to indicate that is the case. There are also two therapies that do not prolong survival but are also commonly used, and these include denosumab and zoledronic acid. Whether or not these are important depends on the risk of skeletal-related adverse events, and that in part is driven by the disease burden and what level of disease control you have. I have a tendency to use denosumab in the bone-targeted therapy category, simply because in a head-to-head trial that compared it to zoledronic acid, the other FDA-approved agent for inhibiting skeletal-related events, denosumab was better.

Q: How do you go about selecting among the different available therapies?

When I’m seeing a patient, I’m thinking about a multiplicity of options. In bone-dominant disease, when they do not have visceral metastases, then I have a tendency, for my thoughts, to turn toward radium-223. Radium-223, I think, is appropriate to consider for patients with bone metastatic, osteoblastic disease with patients who do not have visceral or large lymph node metastases. However, decision-making regarding the sequence of therapies we use depends on a whole variety of factors that includes the symptoms that the patient has, the extent of their disease, the pace of their disease, whether or not they have focal symptoms, systemic symptoms, other comorbidities—are they 99 years old, are they 49 years old—and many other factors. The guidelines [for mCRPC] are not particularly helpful—what they would indicate for metastatic prostate cancer to the bone would be the same six therapies that I mentioned earlier. Now, each of these has its own potential niche. The asymptomatic subset has favored the use of sipuleucel T, abiraterone acetate, and enzalutamide, while for those patients with bony metastatic disease and symptoms, then radium-223 figures higher in the hierarchy; for patients who are chemotherapy candidates, first-line chemotherapy may include docetaxel, and second-line [therapy] would be cabazitaxel. In the process of decision-making, we’re trying to think about a variety of options for which these patients might be available, and what fits them in particular.

Q: What patients do you consider candidates for radium-223?

A: I consider radium for bone-dominant disease, osteoblastic metastases, and no visceral metastases. Those are the hallmark considerations for radium-223. Of course, I am also checking blood counts; they should have adequate neutrophil function (typically at least >1500 neutrophils), adequate platelet function (at least >100,000 platelets), and adequate hemoglobin. I generally use radium in patients with a hemoglobin >9 and make sure they don’t have any fecal incontinence or other issues that could lead to difficulty with this agent.

Q: What are the main toxicities and/or overlapping toxicities with radium-223 that must be considered?

A: With radium-223, there is about a 7% risk of grade 3/4 thrombocytopenia, and about a 2% to 3% risk of grade 3/4 neutropenia. There is a risk of anemia, but that does not appear to be exacerbated, even beyond the control group—that is, radium and the control group (placebo) were about the same in the randomized trials. It’s generally quite well tolerated; there is a little bit of fatigue, and the potential for some loose stools, but those generally are the exception rather than the norm.  

Q: Do you use radium-223 prechemotherapy?

Most of my radium-223 use today is prechemotherapy, and either on clinical trial,  in particular with abiraterone plus or minus radium-223, or off clinical trial, we are using some of the new hormones in combination with radium-223, and this appears to be something of interest, although we do need prospective trials to evaluate this concept further.