The leading agents for palliative care and the prevention of skeletal-related events for patients with bone metastases are zoledronic acid (Zometa) and denosumab (Xgeva, Prolia). Additionally, some studies have suggested that corticosteroids can relieve pain associated with bone metastases.

Other options provide therapeutic relief for patients, and some are associated with an extension in overall survival (OS). External radiation therapy can be used when metastases are limited to a few locations. Another option, radiopharmaceuticals, can provide both systemic and localized care. The only FDA-approved agent in this class for men with prostate cancer is radium-223 (Xofigo). This agent helps relieve bone pain by treating bone metastases while also preventing prostate cancer from further spreading to the bones. Radium-223 has been shown to improve OS for men with bone-metastatic castration-resistant prostate cancer (CRPC).

Prognostic and Predictive Uses of CTCs in mCRPC

Circulating tumor cells (CTCs) have been recognized as a potential source of prostate cancer seeding to distant metastatic sites (typically bone) for over a century, and with ongoing improvements in isolation and characterization methodology, CTCs are now being more rigorously investigated as potential predictive biomarkers in men with mCRPC.

In 2008, a multicenter prospective study showed that CTCs were an accurate independent predictor of OS for men with mCRPC.

In this study, 276 patients with progressive mCRPC who were initiating a new line of chemotherapy were evaluated for the presence of CTCs by blood draw before treatment, and at monthly intervals thereafter.

Interestingly, the CTC counts were also significantly better (

= .0218) than prostate specific antigen (PSA) decrement algorithms (ie, 30% PSA reduction) at predicting OS. Patients whose baseline CTC counts when from unfavorable to favorable saw improved OS versus those with favorable baseline CTCs who turned unfavorable. The results confirmed the prognostic value of baseline CTCs, and also showed for the first time that post-treatment CTCs could predict survival in mCRPC.

The SWOG S0421 trial, a phase III study examining the use of docetaxel three times per week (with or without atrasentan) in men with mCRPC and bone involvement further explored the use of CTCs.

The findings suggested that an early (cycle 1) rise in CTCs while on docetaxel might portend a poor outcome, and could influence management strategies, so as to potentially forego additional docetaxel in favor of another treatment option in such a patient.

In the phase III ALSYMPCA trial, which led to the FDA approval of radium-223, 921 men with mCRPC with two or more bone metastases, no visceral metastases, and who were unsuitable for, or had received prior docetaxel were randomized to radium-223 or pla-cebo for 6 intravenous injections.

The results of the study showed a survival benefit of 3.6 months in the final analysis for patients on radium-223 versus placebo (median 14.9 vs 11.3 months; HR, 0.70;

Since CTCs are widely associated with the development of bone metastases, a study assessed the viability of using these markers to predict response to radium-223.5 In the study, blood samples were collected from 46 patients with mCRPC treated with radium-223 at baseline, at cycle 3, and at progression, and were centrally analyzed using the CellSearch methodology. Response was defined in the study as >50% decrease in CTCs at cycle 3 relative to baseline or &le;5 CTCs, progression was defined as >50% increase in CTCs or >5 CTCs, and stabilization was defined as neither response nor progression.

Results of this study showed that a CTC response was observed in 29% of patients (n = 8), disease stabilization in 42% of patients (n = 12), and progression in 29% of patients (n = 8). Notably, those with 5 or fewer CTCs at cycle 3 had a greater likelihood of remaining on treatment, with 88% (14/16) remaining on treatment after cycle 3, versus 50% (6/12) with >5 CTCs at cycle 3 (

CTCs at baseline also tended to identify patients likely to continue past cycle 3, with 87% (13/15) of those with &le;5 CTCs at baseline remaining on treatment after cycle 3 versus 54% (7/13) of those with >5 CTCs (

= .09). Although requiring further validation, the authors suggest the response to radium-223 and its use beyond cycle 3 can be predicted using CTCs as a biomarker.

Further advances in the characterization of CTCs, which move beyond their simple enumeration also have the potential to advance the use of this diagnostic

New technologies that aim to characterize genetic changes in CTCs (such as mutations that may confer resistance to selected therapies) will likely provide further information about drug resistance and enable clinicians to distinguish among available treatment choices in the increasingly complex setting of mCRPC.

de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302-6309.

Goldkorn A, Ely B, Quinn DI, et al. Circulating tumor cell counts are prognostic of overall survival in SWOG S0421: a phase III trial of docetaxel with or without atrasentan for metastatic castrationresistant prostate cancer. J Clin Oncol. 2014;32(11):1136-1142.

Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014;15(7):738-746.

Parker C, Nilsson S, Heinrich D, et al.; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Suárez C, Castellano D, Angel J, et al. Determining viability of circulating tumor cells (CTCs) as a predictive biomarker for response in patients (pts) with metastatic castrate resistant prostate cancer (mCRPC) treated with radium 223 (Ra). J Clin Oncol. 33, 2015 (suppl; abstr e16051).

Miller S. New circulating tumor cell technology could advance personalized medicine in prostate cancer. Nanomedicine (Lond). 2013;8(5):683-684.

Articles

Clinical Articles

Bone Metastases a Major Concern in Prostate Cancer

Therapeutic options have grown considerably in recent years for men with metastatic, castration-resistant prostate cancer (mCRPC), with studies currently looking to combine these new options. The treatment armamentarium now contains several agents that have shown improvements in overall survival, including new oral hormonal agents (abiraterone acetate, enzalutamide), immunotherapies (sipuleucel-T), and agents targeting bone metastases (radium-223).

To gain insight into treatment trends and strategies, Targeted Oncology spoke with three leading experts in the prostate cancer field about the range of available treatments and their current applications for 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.

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

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&rsquo;s 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&rsquo;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&rsquo;re functioning, and they&rsquo;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&rsquo;t always appear to be intuitive&mdash;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&rsquo;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&rsquo;re working very hard on improving global accessibility and affordability.

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

This is a very important question and sometimes, it&rsquo;s a challenging question, because when there&rsquo;s clinical progression based on worsening symptomatology that&rsquo;s cancer related, then that&rsquo;s usually the most clearcut indication to initiate or to switch an antineoplastic therapy. After that, I&rsquo;d say if there&rsquo;s radiographic progression, specificallydocumented clearly&mdash;the onset of new lesions in the setting of an existing therapy, then oftentimes that&rsquo;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&rsquo;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&rsquo;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&mdash;these agents typically don&rsquo;t modulate PSA. They have minimal impact on PSA. Similarly, sipuleucel-T, the immunotherapeutic approved in CRPC, does not modulate PSA, and it&rsquo;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&rsquo;s particularly nice in bone-targeted agents is that you can see, when they&rsquo;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&rsquo;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&rsquo;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.

How have the results of key trials, such as COU-AA-302 and PREVAIL, impacted treatment decisions?

COU-AA-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 COU-AA-302 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).

Should radium-223 be administered before chemotherapy? What patients do you consider candidates for this agent?

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&rsquo;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&rsquo;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&rsquo;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&rsquo;t see any problems [in ALSYMPCA] with concomitant therapy. [Considering these data] in the overwhelming majority of my patients now, I&rsquo;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&rsquo;s also important to note [its use in combination] because what we&rsquo;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&rsquo;ve seen no untoward or new safety signals, and there&rsquo;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, and we plan to do a similar study with enzalutamide. It&rsquo;s my feeling, however, that many clinicians are already giving these drugs concomitantly.

Phillip J. Koo, MD, a radiologist of Memorial Hospital and University of Colorado Hospital.

What do you envision for the role of radium-223?

Radium-223 is a game-changing therapeutic radiopharmaceutical. When it comes to unsealed sources of radiation, this is the first one that has shown an OS benefit. That has never been done with radiopharmaceuticals in the past.

There are also secondary benefits, including delaying time to first skeletal-related event. It is also the first alpha emitter that has been approved. The beauty of an alpha emitter is that it packs a more powerful punch, so it travels a shorter distance. You are actually hitting the disease harder and you are not hitting healthy cells as much, so the complication rates are decreased. Because of those reasons, radium-223 is really making a big impact.

Are there any challenges with radium-223?

I think the biggest challenge is that oncologists still see it as a palliative tool. The message is that patients need to get all 6 doses. Oncologists need to figure out a way to get them all 6 doses, if possible. That becomes a lot easier if they are treated earlier in their disease. There are data showing that patients who have lower burden bone disease do better with radium-223, compared with patients who are treated at the end stage of disease.

Why do you think that many oncologists still view it as only a palliative treatment?

I think there is this association of radium-223 as a radiopharmaceutical in the past, such as samarium 153 lexidronam. In clinical practice, those aren&rsquo;t used very often because they do cause significant bone marrow suppression, which prevents oncologists from having the option of giving chemotherapy afterwards, if needed.

I think that is the biggest problem; it is still being put in that same type of class when it really it doesn&rsquo;t belong there. This is because it&rsquo;s an alpha emitter and it actually improves overall survival. ALSYMPCA data have shown that radium-223 can be given safely in the prechemotherapy and post-chemotherapy setting.

Do you think there is potential for radium-223 to be used in combination with other agents?

To me, this makes a lot of sense because radium-223 is very specific for bone. It targets the bone. It doesn&rsquo;t target visceral disease, it doesn&rsquo;t target nodal disease, and it has no known effect to the soft tissues. If you can hit the bone disease using radium-223 and hit soft-tissue disease with drugs like abiraterone (Zytiga) or enzalutamide (Xtandi) simultaneously, you will get a great effect.

If you look at the data from the University of Texas MD Anderson Cancer Center&rsquo;s series that was published, it showed that use of abiraterone resulted in an improved benefit with the addition of radium-223. These combination therapies make a lot of sense. There are no crossover side effects when the 2 are put together.

There are also trials that have combined radium-223 with chemotherapy. At the Genitourinary Cancers Symposium held earlier this month, there were some preliminary data that showed it was safe, although I do not believe the chemotherapy doses were at the same level as they typically are.

However, this is still promising. There is risk with radium-223 and chemotherapy because there is bone marrow suppression with those drugs, but it is an area that should be interesting to learn more about.

Do you see the use of radium-223 expanding in the future?

The great thing about radium-223 is that it has a lot of potential in several diseases. We are currently focusing on prostate cancer, but there are clinical trials up and running looking at it for use in patients with breast cancer. We have a site at our own hospitalthe principal investigator is Christine Fisher, MD, who is using this in patients with breast cancer with bone metastases.

The data on that will be accumulating in the near future. I fully expect it to have similar effects in breast cancer because the mechanism of action is the same; it circulates throughout the body and it localizes the bone. Bone metastases tend to have increased surface area of the bone, so it targets those areas. Whether you are dealing with prostate cancer, breast cancer, thyroid cancer, or even sarcomas, physiologically, it makes a lot of sense.

Therapeutic options have grown considerably in recent years for men with metastatic, castration-resistant prostate cancer (mCRPC), with studies currently looking to combine these new options.

Three Experts Provide Insight Into Treating mCRPC

The explosion of new drugs for the treatment of castration-resistant prostate cancer (CRPC) is a welcome advance, but raises questions about how best to sequence these drugs with standard docetaxel chemotherapy. A subanalysis of the ALSYMPCA trial suggests that chemotherapy can be safely administered after treatment with radium-223 (Xofigo), which is the only approved radiopharmaceutical for patients with metastatic CRPC and bone metastasis.

The study, which was presented at the 2015 European Cancer Congress, was a post-hoc analysis of patients enrolled in ALSYMPCA who received chemotherapy post treatment with radium-223 and post treatment with placebo. Follow-up was 3 years.

&ldquo;This study has some limitations, including the fact that it represents a subset of patients based on postrandomization factors, including study drug treatment with radium-223 or placebo, and randomization of the original study does not ensure comparability of the treatment arms,&rdquo; said lead author Oliver Sartor, MD, Tulane Cancer Center, New Orleans, LA.

&ldquo;Given these limitations, this post-hoc analysis indicates that chemotherapy following radium-223 appears to be safe, with no new hematologic concerns and no new detrimental effects on survival. Patients who were earlier in the course of disease and received all 6 injections of radium-223 were able to receive subsequent chemotherapy. This encouraging finding confirms the flexibility and versatility of radium-223, supporting the safety of administering chemotherapy after radium-223 regardless of prior docetaxel use,&rdquo; Sartor stated.

Of 921 patients enrolled in ALSYMPCA, 206 (22%) received chemotherapy post study: 142 from the radium-223 arm and 64 from the placebo arm. Docetaxel was the most commonly used post-study chemotherapy; 70% of the post-radium-223 arm and 72% of the post-placebo arm were treated with docetaxel. Subgroup analysis was performed according to prior docetaxel use.

Demographic and baseline characteristics were generally well balanced between the treatment arms in the chemotherapy post-study drug subgroups for age, baseline ECOG status, extent of disease, prostatespecific antigen (PSA) levels, and other parameters.

Compared with the original ALSYMPCA population, the chemotherapy post-study subgroup patients were younger, had better ECOG performance status, lower disease volume (number of metastases), and lower total alkaline phosphatase levels and lower PSA levels. Compared with the overall ALSYMPCA population, a greater percentage of patients in the post-study drug subgroup received all 6 planned injections of study drug: for those assigned to radium-223, 63% of the overall ALSYMPCA population and 79% of the chemotherapy post-study subgroup got all 6 injections, and 47% and 58%, respectively, of the placebo group got all 6 planned injections.

In both chemotherapy post-study group arms, median hematologic lab values remained constant from the last measurement before chemotherapy to 18 months after chemotherapy. These hematologic values were similar for patients who received prior docetaxel and no prior docetaxel. No treatment differences in hematologic values were observed within the no-prior and prior docetaxel subgroups.

Decreases from baseline in hemoglobin and neutrophil levels were similar in the two treatment arms. Decreases from baseline in platelets tended to be greater in the radium-223 arm compared with placebo, but this was likely due to radium-223 rather than subsequent chemotherapy, according to Sartor. Decreases in platelets were similar in patients who had prior docetaxel and no prior docetaxel. The rates of grade 3 or 4 hematologic adverse events were generally low, but were somewhat higher in the radium-223 arm compared with the placebo arm.

No significant difference in survival was observed between radium-223 and placebo during or within 30 days of completing chemotherapy. Twenty-nine percent of patients in the radium-223 group and 33% in the placebo group died during and within 30 days of completing chemotherapy. The most common cause of death was prostate cancer (90% in the radium-223 arm and 95% in the placebo arm). Median overall survival (OS) from the start of chemotherapy was 18 months after radium-223 and 15.8 months after placebo, which was not statistically different.

Sartor O, Coleman RE, Nilsson S, et al. 3-year follow-up of chemotherapy following radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients (Pts) with symptomatic bone metastases (Mets) from ALSYMPCA. Presented at: European Cancer Congress 2015; Poster session; Vienna, Austria. Abstract 2510.

The explosion of new drugs for the treatment of castration-resistant prostate cancer (CRPC) is a welcome advance, but raises questions about how best to sequence these drugs with standard docetaxel chemotherapy.

Chemotherapy Safe After Radium-223 for Men With mCRPC

Novel combination approaches are currently under exploration that hope to capitalize on the varying mechanisms of action for each newly approved agent for men with metastatic castration-resistant prostate cancer (mCRPC), according to a panel discussion that was led by Raoul S. Concepcion, MD, from Urology Associates, PC, in Nashville, Tennessee.

Chief among the strategies discussed were those involving the alpha particle emitting radiopharmaceutical radium-223 (Xofigo) with the androgen receptor (AR)-targeted agents abiraterone acetate (Zytiga) or enzalutamide (Xtandi). At this time, data from a large prospective clinical trial assessing the combination of an AR-targeted therapy with radium-223 is not yet available. However, despite this lack evidence, many clinicians are commonly administering abiraterone or enzalutamide concurrently with radium-223, explained Daniel P. Petrylak, MD.

&ldquo;I think people combine these agents. There&rsquo;s no data to support that right now, but they do it off-label,&rdquo; explained Petrylak, from the Yale Cancer Center, who encouraged participation in a clinical trial. &ldquo;There&rsquo;s a randomized phase II study looking at radiographic endpoints of enzalutamide plus radium versus abiraterone plus radium versus radium. And there&rsquo;s also a larger randomized trial of abiraterone plus radium versus radium that&rsquo;s going on as a registration study.&rdquo;

In an analysis of patients treated in an expanded access program for radium-223 it was found that concurrent enzalutamide and abiraterone did not appear to impact outcomes with radium-223.1 In those who received radium-223 with concurrent enzalutamide (n = 15), the median overall survival (OS) was 10.7 months. In the concurrent abiraterone arm (n = 25), the median OS was not estimable at the time of the analysis.

&ldquo;I think realistically a lot of people are using combinations, particularly when you get in a situation where the patient has more predominant lymphadenopathy over 3 cm or so, that&rsquo;s very tempting to say, well, let&rsquo;s add some abiraterone on there or enzalutamide,&rdquo; said Celestia S. Higano, MD, from the Seattle Cancer Care Alliance, in the discussion. &ldquo;I think realistically it has been shown in marketing research that a lot of people are automatically using combinations.&rdquo;

Clinical trials are currently exploring combination strategies for patients with mCRPC, including a three-arm phase IIa investigation assessing each AR-therapy with radium-223 or radium-223 alone (NCT02034552). Additionally, a phase III study is looking at abiraterone plus radium-223 in men with bone-metastatic CRPC prior to the administration of chemotherapy (NCT02043678). A similar phase III study is expected to begin enrolling soon to test enzalutamide plus radium-223 (NCT02194842).

In addition to AR-agents, questions remain regarding radium-223 in combination with therapies intended to prevent or delay skeletal-related events, such as denosumab (Xgeva) or zoledronic acid (Zometa). However, the answer to this question could lie in a subgroup analysis from the pivotal ALSYMPCA trial, which led to the approval of radium-223, Higano said.

In this large phase III study,2 those who received zoledronic acid plus radium-223 (n = 250) experienced a median OS of 15.3 months compared with 11.5 months with placebo and zoledronic acid (HR, 0.70). In patients treated without zoledronic acid, those who received radium-223 (n = 364) had a median OS of 14.5 months versus 11.0 months with placebo (HR, 0.74).

In the full population of the study, treatment with radium-223 demonstrated a median OS of 14.9 months compared with 11.3 months with placebo for patients with bone-metastatic CRPC (HR, 0.70, P < 0.001). Additionally, radium-223 was associated with a significant delay in both the median time to first symptomatic skeletal-related events and the time to an increase in the PSA level.

&ldquo;If you look in the ALSYMPCA trial, they did forest plots of patients who were and were not on zoledronic acid,&rdquo; Higano explained. &ldquo;There was an advantage to being on the combination, so that&rsquo;s why I continue my bone drug and I realize denosumab was not in that trial, but they seem to be similar.&rdquo;

Overall, less than half of the patients enrolled in the ALSYMPCA trial were receiving treatment with a bisphosphonate (n = 374; 41%). In addition to this study, the large PROCEED registry showed a similar rate of utilization for bone-targeted agents of around 40%, added Concepcion. The findings enhance the need for further education on the importance of bone health, he concluded.

Shore ND, Vogelzang NJ, Fernandez D, et al. Radium-223 Dichloride in Expanded-Access Setting in the United States: Overall and Concurrent Experience With Abiraterone or Enzalutamide. Presented at: the: American Urological Association Annual Meeting; Tuesday, May 19, 2015; New Orleans, LA. Abstract: MP87-12.

Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

Novel combination approaches are currently under exploration that hope to capitalize on the varying mechanisms of action for each newly approved agent for men with metastatic castration-resistant prostate cancer (mCRPC).

Novel Combinations on the Horizon in Metastatic CRPC

Bone metastases appear most commonly in the ribs, the spine (cervical, thoracic, and lumbar vertebrae, and pelvis), and have also been documented in long bones (femur).

Metastatic growth at these sites gives rise to severe bone pain, often requiring powerful analgesia and external beam radiation treatment. Spinal cord or nerve root compression, myelosuppression, and disturbances in calcium metabolism also commonly occur.

A recent review summarized the pathophysiology of bone pain as, &ldquo;components of neuropathic, inflammatory and ischemic pain, arising from ectopic sprouting and sensitization of primary afferent sensory nerve fibers within prostate cancer-invaded bones.&rdquo; It further asserted that metastases arises and is perpetuated by virtue of the cross talk between the osteoclasts and osteoblasts and other factors involved in the bone microenvironment.5 This multifactorial pathophysiology makes it challenging to manage and an imperative to avoid.

The management of bone pain was explored in a study that included 1305 patients with prostate cancer and bone metastases.6 Overall, 76% of the patients had been treated with bone-targeting agents for a variety of causes, including bone pain (34%), high risk of bone complications (33%), number of bone metastases (12%), locations of bone metastases (8%), and prior history of bone complications (6%). Additionally, 27% of the patients with bone metastases needed opioids for the relief of bone pain.

A recent preclinical study has highlighted an unreported mechanism that promotes the growth of bone metastases in prostate cancer.

Using a mouse model they showed that following injection of prostate cancer cells into the intramedullary cavity of the tibia, tumor growth increased pressure within the mouse tibia. In vitro experiments subsequently revealed that pressure applied to osteocytes facilitated prostate cancer growth and invasion, and this was mediated in part by an upregulation of CLL5 and matrix metalloproteinases in osteocytes.

These findings implicate osteocytes, responding to the increased pressure generated by tumor growth, in the orchestration of the metastatic niche within the bone in patients with prostate cancer.

This again emphasizes the clinical imperative to reduce the incidence of bone metastases in prostate cancer.

Impact of Bone Pain on Survival and Quality of Life

Several studies have assessed the impact of bone pain on survival and quality of life. A retrospective analysis examined 599 patients from three randomized controlled trials conducted from 1992 to 1998.

Patients in this analysis had progressive CRPC adenocarcinoma of the prostate and an ECOG performance status of 0 to 2. The Brief Pain Inventory (validated scale) gauged the impact of pain on selected daily activities and quality of life (QOL).

They found a median pain interference score of 17, and a statistically significant association between pain scores and the risk of death. Comparing men with low (<17) and high (&ge;17) pain scores, respectively, the median survival times were 17.6 versus 10.2 months (P <.001). When comparing the same two cohorts, median times to bone progression were 6.7 months and 3.8 months, respectively (P <.001).

Men with pain scores &ge;17 had a 22% greater risk of bone progression than men with pain scores <17. Median times to PSA progression followed a similar pattern, with 4.0 versus 2.9 months for scores of <17 and &ge;17 respectively (P <.001).

Additionally, a study from 2002,9 found that skeletal-related events (SREs) have clinically meaningful and significant impact on health-related QOL, with physical, emotional, and functional wellbeing all declining after pathologic fractures and radiation therapy. Significant declines in preference and utility scores were noted after fractures and radiation. Pain intensity only declined after radiation treatment, but not after other SREs.

Moreover, another study identified an association between skeletal morbidities and patient reported outcomes and survival.

The trial recruited 643 patients, and they received either zoledronic acid or placebo for 15 months. Patients with no SREs at 6 months (landmark) had significantly greater survival at 360 days post landmark (49.7% vs 28.2%; P = .02). Health-related QOL measures in the post landmark period, including pain, were worse in patients who experienced SREs during the landmark period.

Managing Bone Metastases: Bone-Targeted Agents

There are currently a number of treatments that are approved for the management of patients with mCRPC and bone metastases. They include osteoclasttargeting agents, zoledronic acid and denosumab, and radiopharmaceuticals such as &szlig;-particle emitters, strontium-89 chloride and samarium Sm-153 lexidronam, and the &alpha;-particle emitter radium-223 (Xofigo).

A phase III trial of zoledronic acid (a bisphosphonate) versus placebo in 643 patients with mCRPC and bone metastases, without severe bone pain, showed that fewer patients taking zoledronic acid dosed at 4 mg every 3 weeks for 15 months experienced SREs versus placebo (33% vs 44% P = .021); however, survival was not significantly different between the groups. At 24 months of follow-up, zoledronic acid treatment reduced the risk of SREs by 36% versus placebo. Bone pain was also reduced in patients treated with zoledronic acid compared with placebo.

A phase III trial was conducted on denosumab (a monoclonal antibody against a key activator of osteoclastic resorption, RANKL) versus zoledronic acid (TABLE 1).

The primary endpoint was time to first on-study SRE. Overall survival (OS) and investigator-assessed overall disease progression and PSA levels during the study were among key exploratory endpoints.

The study recruited patients with mCRPC and bone metastases who had no prior treatment with bisphosphonates. A total of 1904 patients were randomized, 950 to denosumab and 951 to zoledronic acid. The median time to the first SRE was 20.7 versus 17.1 months for denosumab and zoledronic acid, respectively (HR, 0.82; 95% CI, 0.71-0.95; P = .008). OS and investigator reported disease progression were not significantly different between the groups. Changes in median PSA concentrations and bone pain were also similar between the groups during the study.

There are a number of toxicity concerns associated with these agents. Nephrotoxicity is a commonly reported adverse event (AE) for bisphosphonates, necessitating monitoring of serum creatinine and appropriate dose adjustment. Denosumab, however, does not cause nephrotoxicity in men with prostate cancer.

An integrated analysis of three randomized phase III trials (5723 patients) confirmed that both drugs are associated with hypocalcemia and osteonecrosis of the jaw (ONJ).13 Hypocalcemia incidence was higher among patients treated with denosumab versus zoledronic acid (3.1% vs 1.3% for grade 3/4). ONJ was found to occur more frequently in patients treated with denosumab than zoledronic acid (1.8% vs 1.3%), but the difference was not statistically significant.

The status of &szlig;-particle emitters strontium-89 chloride and samarium Sm-153 lexidronam has recently been reviewed by Body et al.

Considering the evidence, they conclude that although both agents seem to exert clinically relevant analgesic effects in patients with bone pain in mCRPC, they have not been unequivocally shown to reduce the incidence of SREs or to extend survival.

The toxicities associated with these agents are largely hematological, with marrow toxicity being the major side effect of samarium Sm-153 lexidronam. A temporary increase in bone pain during early treatment occurs in 15% of patients treated with strontium-89 chloride.

The data for the &alpha;-particle emitter radium-223, which selectively binds to areas of increased bone turnover in bone metastases, that secured its approval came from the pivotal phase III ALSYMPCA trial (TABLE 2).

The study randomized 921 patients in a 2:1 fashion to receive six injections of radium-223 or placebo, one injection given every 4 weeks. The primary endpoint was OS. Secondary endpoints included time to first SRE and biochemical endpoints. The efficacy analysis measured radium-223 survival benefit versus placebo seen at an interim analysis.

The final analysis showed median OS of 14.9 versus 11.3 months for radium-223 and placebo respectively, which represented a 30% reduction in the risk of death for patients treated with radium-223 (HR, 0.70; 95% CI, 0.58-0.83; P <.001). Radium-223 treatment significantly prolonged the time to the first SRE (median 15.6 vs 9.8 months; HR 0.66; 95% CI, 0.52-0.83; P <.001). PSA blood levels at week 12 were reduced by &ge;30% in 16% of patients in the radium-223 group and in 6% of patients in the placebo group (P <.001). This was maintained for 4 weeks after the last injection in 14% versus 4% of patients in the radium-223 and placebo arms, respectively (P <.001).

Safety profiles were similar between the treatment arms. One patient experienced grade 3 febrile neutropenia in each group. There was one grade 5 hematological event (thrombocytopenia) in the radium-223 group considered possibly related to the study drug.

The incidence of bone pain was reduced in patients treated with radium-223 versus placebo (10% vs 16%). Significantly more patients in the radium-223 group versus placebo experienced a meaningful improvement in QOL as determined by the Functional Assessment of Cancer Therapy-Prostate score (25 % vs 16%; P = .02).

Newly approved therapies appear to provide the greatest benefits to patients with asymptomatic metastatic prostate cancer, suggesting that earlier detection of metastases is essential to improving care.

A leading question facing the early detection of bone metastases is whether scans should be triggered by a biochemical event or conducted at a fixed interval.

In a study published in 2014, using the SEARCH database, PSA levels, PSA doubling time, and PSA velocity were predictors of metastases in patients with increasing PSA levels after radical prostatectomy.

In the study, data were analyzed from 401 patients undergoing a bone scan for suspected metastatic disease from 1995 to 2012 at six Veteran Affairs Medical Centers. All patients had bone scans, and their PSA levels and PSA kinetics at the time of scan were available. The secondary objective of the study was to use PSA and PSA doubling time (PSA-DT) to rank bone scans according to positivity.

In the study, in patients who were hormone therapy naive, screening for bone metastases should be initiated for a PSA-DT of <9 months. In contrast, there was only a 2% risk of a positive bone scan if the PSA-DT was &ge;9 months. A longer PSA-DT was still associated with a very low risk of a positive scan, even in men with high PSA values.

In men after androgen deprivation therapy (ADT), they could not identify a subgroup where the risk of a positive bone scan was low. Even among patients with very low PSA and PSA-DT, the risk of a positive bone scan was &ge;10%, and the authors recommended that bone scans should begin early in patients after ADT, even before a PSA level of 5 ng/mL was reached.

In a more recent analysis, again using the SEARCH database, they devised a tool to assist physicians in the selection of patients with CRPC who may be in need of bone scans. The table combines PSA and PSA-DT, and stratifies patients according to the risk of having a bone scan. They also point out that the table could be used for the identification of particular populations of patients for specific clinical trials (TABLE 3).

This analysis found that men with a PSA of <5, 5 to 14.9, 15 to 49.9, and &ge;50 ng/mL had scan positivity of 6%, 14%, 29%, and 57%, respectively (P trend <.001). Scan positivity was 11%, 22%, 34%, and 47% for men with PSADT &ge;15, 9 to 14.9, 3 to 8.9, and >3 months, respectively (P trend <.001).

Considering prostate cancer in general, the extent of the disease dictates the best timing and sequencing of treatments in addition to patient-specific factors. These include the site and extent of disease, speed of progression, symptoms experienced, comorbidities, availability of particular treatments, and contraindications of therapeutic agents/procedures.

With novel bone-directed therapies available, trials are currently assessing the best use of these therapies in combination.

Body JJ, Casimiro S, Costa L. Targeting bone metastases in prostate cancer:Improving clinical outcome.

Wang CY, Wu GY, Shen MJ, et al. Comparison of distribution characteristics of metastatic bone lesions between breast and prostate carcinomas.

Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial.

Smith MR, Coleman RE, Klotz L, et al. Denosumab for the prevention of skeletal complications in metastatic castration-resistant prostate cancer: comparison of skeletal-related events and symptomatic skeletal events.

Muralidharan A, Smith MT. Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments.

Body JJ, Henry D, Von Moos R et al. (a) Bone targeting agent (BTA) treatment patterns and the impact of bone metastases (BM) on prostate cancer patients in a real world setting. European Cancer Congress 2015 Vienna abstract # 1527.

Sottnik JL, Dai J, Zhang H, et al. Tumor-induced pressure in the bone microenvironment causes osteocytes to promote the growth of prostate cancer bone metastases.

Halabi S, Vogelzang NJ, Kornblith AB, et al. Pain predicts overall survival in men with metastatic castration-refractory prostate cancer.

Weinfurt KP, Li Y, Castel LD, et al. The significance of skeletalrelated events for the health-related quality of life of patients with metastatic prostate cancer.

Saad F, Gleason DM, Murray R, et al. A randomized, placebocontrolled trial of zoledronic acid in patients with hormonerefractory metastatic prostate carcinoma.

DePuy V, Anstrom KJ, Castel LD, et al. Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer.

Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, doubleblind study.

Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.

Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer.

Moreira DM, Cooperberg MR, Howard LE, et al. Predicting bone scan positivity after biochemical recurrence following radical prostatectomy in both hormone-naive men and patients receiving androgen-deprivation therapy: results from the SEARCH database.

Moreira DM, Howard LE, Sourbeer KN, et al. Predicting bone scan positivity in non-metastatic castration-resistant prostate cancer.

Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

Basch E, Autio K, Ryan CJ, et al. Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patientreported outcome results of a randomised phase 3 trial.

Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy.

Ryan CJ, Saylor PJ, Everly JJ, et al. Bone-targeting radiopharmaceuticals for the treatment of bone-metastatic castrationresistant prostate cancer: exploring the implications of new data.

Bone metastases in metastatic castration-resistant prostate cancer (mCRPC) can invade a range of sites in the skeleton where they precipitate a spectrum of pathological processes that increase morbidity, negatively affect quality of life, and decrease survival.

Preventing and Treating Bone Metastases in mCRPC

Guidelines Evolving for the Treatment of Bone Metastases in CRPC

Androgen deprivation therapy (ADT) has been the standard of care for patients with advanced prostate cancer; however, a majority of patients on hormonal therapy become unresponsive to treatment after an initial response.

Castration-resistant prostate cancer (CRPC) is partially identified by rising levels of prostate-specific antigen (PSA) despite chemical castration, and more than 90% of patients with CRPC develop bone metastases

The metastatic CRPC (mCRPC) treatment portfolio is expanding rapidly. Numerous broad-spectrum and targeted therapies undergoing clinical testing are impacting overall treatment options for patients with CRPC. After approval of docetaxel in 2004, five new agents have been approved by the FDA to treat CRPC: abiraterone acetate (Zytiga), enzalutamide (Xtandi), cabazitaxel (Jevtana), radium-223 (Xofigo), and sipuleucel-T (Provenge).

The NCCN&rsquo;s clinical practice guidelines, a reference for standard of care in the United States, are updated regularly to address new findings. The guidelines represent a consensus statement that is compiled using data from a variety of clinical trials, with the highest level of evidence, labeled category 1, provided by multi-national, multi-institutional, randomized controlled trials.

While most of the updates in 2016 focused on imaging, radiation therapy, diagnostics, and other changes, the preceding updates centered on the use of systemic agents. In first-line therapy for CRPC patients with no visceral metastases, the following therapies have all received a category 1 listing:

Radium-223 for men with symptomatic bone metastases

Enzalutamide for men with asymptomatic or mildly symptomatic bone metastases

This recommendation was based on results from the multinational, double-blind, randomized phase III PREVAIL trial, which examined the effect of enzalutamide administration in asymptomatic or mildly symptomatic chemotherapy-naive men with mCRPC. The trial showed that treatment with enzalutamide significantly improved OS (30% reduction in risk of death) and radiographic PFS (81% reduction in risk of radiographic PFS) in men with chemotherapynaive mCRPC.

Abiraterone with prednisone for men with asymptomatic or mildly symptomatic mCRPC

This recommendation was based on interim analyses of the COU-AA-302 trial. In this placebo-controlled, double-blind, randomized phase III study on 1088 asymptomatic or mildly symptomatic patients with chemotherapy-naive PC, abiraterone acetate plus prednisone significantly improved radiographic progression-free survival (PFS) compared with placebo plus prednisone. OS was significantly longer in the abiraterone acetate group than in the placebo group (34.7 vs 30.3 months).

Docetaxel with prednisone for hormone-naive mCRPC

Changes to the NCCN guidelines also recognize the results from CHAARTED trial showing docetaxel can be repurposed in metastatic CRPC. In this study, the median OS was 13.6 months longer with the combination of androgen-deprivation therapy (ADT) plus docetaxel than with ADT alone, and in men with high-volume metastatic disease, median OS was 17.0 months longer.

This treatment is based on results from the ALSYMPCA phase III study in patients with CRPC with symptomatic bone metastases who received docetaxel, who were unfit to receive docetaxel or declined docetaxel. Study interim analysis on 921 patients showed improved OS benefit (median of 14.9 months versus 11.3). Other phase I-IIa studies are ongoing to study the use of radium-223 in combination with docetaxel for mCRPC.

The American Urological Association (AUA) guideline focuses on 6 &ldquo;index patients&rdquo; ranging from men with asymptomatic, nonmetastatic CRPC to those with symptomatic, metastatic disease with a poor performance status and previous exposure to docetaxel.

The AUA guideline was introduced in 2013 in response to the multitude of newly approved therapies for men with CRPC. The index patient guideline design stresses the importance of knowing exactly where the patient fits, which requires adequate history taking, patient evaluation, and focus on symptoms. Overall, there are 22 guideline statements.

Index Patient 1 (asymptomatic non-metastatic CRPC):

Consider observation, ADT, first-generation anti-androgens and androgen synthesis inhibitors. Do not consider: chemotherapy or immunotherapy

Index Patient 2 (asymptomatic or minimally symptomatic, mCRPC without prior docetaxel):

Consider abiraterone, enzalutamide, docetaxel, sipuleucel-T or first-generation hormonal agents

Index Patient 3 (symptomatic, mCRPC with good PS and no prior docetaxel):

Consider abiraterone, enzalutamide, docetaxel, radium-223, and firstgeneration hormonal agents

Index Patient 4 (symptomatic, mCRPC with poor PS and no prior docetaxel):

Consider abiraterone, enzalutamide, first-generation hormonal agents, docetaxel, and radium-223

Index Patient 5 (symptomatic, mCRPC with good PS and prior docetaxel):

Consider abiraterone, cabazitaxel, enzalutamide, additional docetaxel, radium-223, and ketoconazole, if other options are unavailable

Index Patient 6 (symptomatic, mCRPC with poor PS and prior docetaxel):

palliative care, abiraterone, enzalutamide, and ketoconazole or radionuclide

In addition to the index patients, the guideline also issued two statements on bone health, namely prevention using supplemental calcium and vitamin D or with denosumab (Xgeva) or zoledronic acid (Zometa).

The European Society for Medical Oncology (ESMO) is developing a validated and reproducible tool to assess the magnitude of clinical benefit of anticancer interventions, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS), based on initial recommendations from 276 members of the ESMO faculty and a team of 51 expert biostatisticians.

With this scoring tool, ESMO aims to highlight treatments that provide substantial improvements to the duration of survival and/or the quality of life (QoL) of cancer patients and distinguish them from treatments where benefits are more modest, limited, or marginal. ESMO intends to apply this scale prospectively to each new anticancer drug/intervention that will be European Medicines Agency (EMA) approved. Drugs or treatment interventions that obtain the highest scores on the scale will be highlighted in the ESMO guidelines with the aim of prompting rapid endorsement by health authorities across the European Union.

ALSYMPCA trial using radium-223 with chemotherapy or radiotherapy treatment scored 5, the highest score. Abiraterone with or without prednisone and enzalutamide versus placebo treatments scored next highest, 4. The Tropic trial that utilized cabazitaxel and prednisone versus mitoxantrone and prednisone came at the bottom of the list with a score of 2. Based on this analysis, radium-223 demonstrated the highest clinical benefit in patients with mCRPC.

Similar to the ESMO scale, the NCCN evidence blocks are guidelines for treatment providers to effectively collaborate with their patients in the Unites States. Levels of evidence from 1 to 5 are presently based on five elements: efficacy (E), safety (S), quality (Q) and consistency (C) of evidence, and the affordability (A).

The NCCN Evidence Blocks are not alone; however, other tools lack the flexibility to allow comparisons of drugs evaluated in different trials and does not allow assessments of the range of interventions possible across multiple disease scenarios. Additionally, look beyond costs provides a more thorough picture on the true value of the treatment.

For prostate cancer, this work has already been completed for Version 2.2016 of the NCCN Prostate Cancer Guideline. For those with CRPC, each therapy throughout the NCCN treatment algorithm has been ranked, based on the 5 criteria in that setting (for those in the frontline M1 CRPC space, see FIGURE 2).