Ten years ago, the clinician treating metastatic castration-resistant prostate cancer (CRPC) had palliative options for treatment of symptomatic patients, such as the combination of mitoxantrone combined with prednisone, as well as isotope therapy. In 2004, docetaxel-based chemotherapy regimens were shown to provide an overall survival benefit for patients with CRPC.[1,2] Today, the prostate cancer oncologist is in the enviable position of having six US Food and Drug Administration–approved agents to choose from: immunotherapy (sipuleucel-T), hormonal therapies (abiraterone, enzalutamide), radiopharmaceuticals (radium-223), and chemotherapy (docetaxel, cabazitaxel), in addition to agents being administered in clinical trials. In general, the sequencing of these drugs is based upon the entry criteria from the phase III trials that led to their approval. Selection of treatment is based on symptoms, sites of disease (bone vs visceral) and types of prior treatment (docetaxel-ineligible vs pre-docetaxel vs post-docetaxel setting). Unfortunately, there is a lack of useful correlative biomarkers in prostate cancer to help oncologists select treatment. This problem is best illustrated in the post-docetaxel castration-resistant setting, for which there are indications to use all five other approved agents. In this review we will outline an approach to sequencing these new therapies, with particular attention paid to the biology of CRPC.
Patient Care Following Initial Chemotherapy
After the introduction of docetaxel-based chemotherapy, there was a several-year delay in the appearance of new therapies for CRPC. However, work was progressing on several fronts concurrently, with all of these efforts aimed at those patients who had progressed on docetaxel. These included studies of abiraterone acetate, radium 223-dichloride (both discussed previously in this article), enzalutamide, and cabazitaxel. None of these agents have been directly compared in their respective treatment settings. Thus, there are no evidence-based guidelines available for how to sequence these treatments.
As noted, abiraterone acetate was originally shown to benefit patients whose disease had progressed on docetaxel.[22,60,61] In a large trial, 1,195 men were randomized in a 2:1 fashion to receive prednisone with abiraterone or with a placebo. At a planned interim analysis, patients who received abiraterone had an OS advantage (14.8 months vs 10.9 months) and the study was stopped. Patients in the abiraterone-containing arm also demonstrated PFS and PSA response improvements over the placebo arm. Thus, high-level evidence exists for the use of abiraterone acetate before or after docetaxel chemotherapy.
Cabazitaxel is a potent tubulin-binding taxane with activity against docetaxel-resistant cancer cell lines. In a phase III study, 755 men with prostate cancer that had progressed after treatment with docetaxel were randomized to cabazitaxel or mitoxantrone. OS and PFS were significantly better in patients treated with cabazitaxel, as was PSA response rate (39.2% vs 17.8% with mitoxantrone).
Enzalutamide is a second-generation AR antagonist with significantly more potent binding to the AR than the first-generation antagonists (bicalutamide, flutamide, nilutamide). In addition, its function is qualitatively different from that of the older drugs. Enzalutamide-bound AR mostly remains cytoplasmic, whereas the older drugs actually cause nuclear translocation (as discussed previously; see Figure 2). In addition, enzalutamide-bound AR that does translocate to the nucleus does not appear to bind to DNA and so is inactive.
After encouraging results in a phase I/II trial, enzalutamide was analyzed in a randomized placebo-controlled phase III trial in men who had received docetaxel. In that trial, median OS was 18.4 months vs 13.6 months for enzalutamide vs placebo, respectively. Other secondary endpoints were all improved with enzalutamide: PSA response, time to PSA progression, PFS, quality of life, time to skeletal-related events, and soft-tissue response rate. Notably, a small percentage of patients (0.6%) on the enzalutamide arm had seizures.
As noted above, the phase III ALSYMPCA trial, which showed an OS advantage for Ra-223 over placebo, enrolled patients with metastatic prostate cancer who had or had not received docetaxel. The hazard ratio for death in those two groups was almost identical (0.71 vs 0.74%, respectively).
Sequencing of Therapies
Treatment prior to docetaxel
Given the lack of randomized trial data to guide rational or biologically based sequencing of therapies, treatment in asymptomatic or minimally symptomatic patients is selected based upon rapidity of disease progression and toxicity of treatment. Given the fact that there are three clinical trials of newer agents (sipuleucel-T, abiraterone/prednisone, Ra-223) demonstrating improvement in PFS or OS in patients with metastatic disease that is progressing on androgen ablation, the addition of first-generation NSAAs has generally fallen out of favor. In a patient with slowly progressive disease, sipuleucel-T is a reasonable first treatment option, based upon its lack of toxicity and the fact that the current FDA label requires that patients be off systemic corticosteroids for 1 month prior to treatment.
Considerable controversy has arisen over the role of corticosteroids and potential interference with sipuleucel-T activity. A recently reported randomized phase II study demonstrated no difference in immune function in patients who were treated with abiraterone/prednisone either concomitantly with or post completion of treatment with sipuleucel-T. Although survival differences were not a primary endpoint of this study, lack of difference in immune parameters provides some support for the early or concomitant use of abiraterone in this patient population. A similar study is now being designed that will evaluate immune parameters associated with early vs delayed enzalutamide.
In a patient with rapid asymptomatic disease progression, abiraterone/prednisone is a reasonable first treatment option, particularly in patients who have had a long duration of response to first-line hormonal therapy. With FDA approval of abiraterone acetate in chemotherapy-naive patients, the use of ketoconazole appears to be limited to patients who have nonmetastatic castrate-resistant disease or those with metastatic disease who cannot afford treatment with abiraterone.
Ra-223 is a good choice for patients with significant pain from multiple bony lesions, particularly if these metastases are too numerous for local radiation therapy to be feasible. Data from the ALSYMPCA trial suggest that hematologic toxicity is not significantly worse in patients who subsequently receive docetaxel.
Last, combining LHRH agonists with either potent CYP17A inhibitors like abiraterone acetate or AR blockers like enzalutamide are either in clinical trials or in the planning stages for trials. Given the slight survival advantage of CAB over LHRH agonist monotherapy, it seems likely that these combinations would be even more efficacious.
In patients with disease that is progressing on docetaxel and prednisone who have not yet been treated with abiraterone, there are four therapies that provide survival advantages of similar magnitude: abiraterone, enzalutamide, cabazitaxel, and Ra-223. The eligibility requirements for these trials were quite similar, so their patient populations probably were also quite similar. Thus, the major factors in choosing the order of these drugs are the side-effect profiles of the specific agents.
After docetaxel fails, either abiraterone or enzalutamide is probably the best choice for therapy, based on patterns of toxicity. Both docetaxel and cabazitaxel treatment can result in peripheral neuropathy, as well as fatigue, and sequential use can exacerbate pre-existing neuropathy. Although no comparative data exist, one could expect less fatigue and cytopenias with abiraterone or enzalutamide than with a second taxane in a patient who has already been treated with a significant amount of docetaxel. How to choose between abiraterone and enzalutamide is unclear, although many patients are relatively intolerant of glucocorticoids (eg, patients with diabetes, patients with psychiatric issues) and enzalutamide does not require their use. In fact, a retrospective analysis of the AFFIRM trial demonstrates that corticosteroid use is an independent poor prognostic factor in patients treated with enzalutamide. Although there have been anecdotal reports of patients being treated with abiraterone without steroids, current labeling for abiraterone requires glucocorticoid administration. Alternatively, enzalutamide should not be used in a patient with a seizure history, since seizures were observed in the trials of enzalutamide.[63,68] Once abiraterone or enzalutamide are no longer effective, cabazitaxel is a logical choice, followed by the other hormonal therapy (ie, enzalutamide if abiraterone was used first and vice versa if enzalutamide was used first). Alternatively, if disease progression is primarily in the bones, Ra-223 is an excellent option, given the lack of almost any side effects from treatment.
Most patients in the future will have received abiraterone acetate prior to treatment with docetaxel. In these patients, after they progress on docetaxel, the choice is among cabazitaxel, enzalutamide, and Ra-223. The same rationale described above for ordering therapies after docetaxel can be used here, the only difference being the omission of abiraterone. However, the trials that showed the effectiveness of these agents were not done in patients pre-treated with abiraterone. Thus, it is unknown how effective they are in this patient population. In fact, several retrospective studies suggest that each of these therapies is far less effective after treatment with one of the others. One study that analyzed response to docetaxel in patients previously treated with abiraterone found the PSA response rate to be 26%, which is lower than the 45% to 50% response rate originally seen in the phase III studies of docetaxel.[1,2,69] Median OS was only 12.5 months, compared with OS outcomes of 17.5 to 18.9 months reported in the phase III trials. Three studies of patients who received docetaxel followed by either enzalutamide and then abiraterone, or these agents given in the reverse order, only showed minimal responses to the last therapy administered (Table 2).[70-72] This phenomenon should not be surprising since abiraterone inhibits AR signaling by decreasing the amount of testosterone in the cancer cells, whereas enzalutamide also inhibits AR signaling but does so through direct inhibition of the receptor protein. Depending on the mechanism of resistance that develops, the cancer might be resistant to both drugs (as will be described later in this article). Nonetheless, since some significant responses occur, it is reasonable to try each of these agents.
New agents: cabozantinib
Although still in clinical trials, cabozantinib (also called XL184), a dual inhibitor of mesenchymal-epithelial transition (MET) factor and vascular endothelial growth factor receptor 2 (VEGFR2), has shown activity in prostate cancer in a phase II discontinuation trial. In this study 46% of patients had received chemotherapy previously, and 87% of patients had bony disease. The trial was stopped early because of evidence of activity with cabozantinib. All patients received 12 weeks of cabozantinib; 14 patients then continued to be treated with the drug, and 17 were randomized to receive a placebo. The median PFS for men who continued to receive cabozantinib was 23.9 weeks, compared with 5.9 weeks for those who received placebo. A total of 171 patients received 12 weeks of cabozantinib. Based on the PFS difference found in the discontinuation trial, a number of post-hoc analyses were performed for hypothesis generation. Investigators found that 68% of evaluable patients had a decrease in bony disease on bone scan, 67% had a decrease in pain, and 56% had a decrease in opiate use. PSA changes, however, did not correlate with response. If the ongoing phase III studies show an OS advantage for cabozantinib, then the sequencing of therapeutic agents for patients with advanced prostate cancer will only become more complex.
A large number of other agents are in randomized trials in this setting, but efficacy data have not yet been reported; therefore, these drugs are outside of the scope of this review.
The results with docetaxel-based combination therapy have been disappointing. Despite having biological rationales and promising preclinical data, attempts to combine docetaxel with bone-targeted agents (atrasentan, dasatinib, and ZD4054), anti-angiogenesis agents (bevacizumab, aflibercept, lenalidomide, and vitamin D (calcitriol, DN-101)) have all failed to demonstrate a survival benefit. One possible reason for failure in these trials is that the aforementioned agents had modest clinical activity as single agents.[80-82]
Now that we have multiple active agents with different mechanisms of action, the challenge is to generate rational combinations without overlapping toxicities. For example, although abiraterone and enzalutamide dramatically decrease AR signaling, possibly such signaling could be decreased even more by combining these drugs. Such a study is now underway (National Cancer Institute clinicaltrials.gov ID: NCT01650194).
Alternatively, combining agents that target different pathways could increase effectiveness without necessarily increasing toxicity, in a manner analogous to that seen in combination chemotherapy. To that end, trials are either being designed or are ongoing using such approaches. Combination studies have evaluated the safety of docetaxel combined with TAK700 (a CYP17A inhibitor currently in clinical trials), enzalutamide, or Ra-223. A study is currently analyzing the safety of combined treatment with cabazitaxel and abiraterone. Sequential vs combined sipuleucel-T and abiraterone is currently under investigation, and a randomized trial of early vs delayed enzalutamide, focused on evaluating immune markers, is planned in patients treated with sipuleucel-T. A randomized phase II study combining Ra-223 with enzalutamide or abiraterone/prednisone is planned.
Use of biomarkers
In an ideal world, we could perform large randomized studies to decide which sequence of therapies to use for men with CRPC. Of course, such studies would be lengthy, prohibitively expensive, and almost certainly not the best use of resources. With the use of biomarkers, however, it might be possible to distinguish among therapies that will benefit specific patients, although to date no biomarkers have been able to do this. For example, there are a number of ways in which prostate cancer cells can become resistant to androgen blockade. Some of these mechanisms remain responsive to certain hormonal therapies while others do not. Examples include:
Increased AR expression. This phenomenon causes resistance to NSAAs but not necessarily to abiraterone or enzalutamide.
Increased expression of CYP17A. In tumor xenografts, increased CYP17A expression causes resistance to abiraterone. This mechanism of resistance would have far less of an effect on enzalutamide.
AR mutation. Several classes of AR mutants have been described. Mutations that alter the binding of NSAAs were found in a small percentage of prostate cancers. These mutations cause resistance to NSAAs, but it is unknown how they affect other therapies. A number of different AR splice mutants have been described in cell lines and in human tumors that activate AR transcription independent of androgen binding.[90-93] Theoretically, all these mutant receptors will be resistant to abiraterone. A subset of these mutant ARs have abnormal or absent ligand-binding domains, and many of those will also be resistant to treatment with enzalutamide.
Activation of additional pathways to activate the AR. A number of accessory pathways (eg, interleukin (IL)-6, human epidermal growth factor receptor 2 [HER-2]/neu) have been shown to activate the AR in cell lines in the presence of very small amounts of, or the complete absence of, androgen.[95,96] Cancers harboring these activated pathways presumably would be resistant to all hormonal therapies.
Activation of AR-independent pathways. A few such molecular pathways have been identified (eg, Akt signaling), and undoubtedly others will be discovered in the coming years. Cancers in which these pathways were active also would be resistant to hormonal therapies. At some point, analysis of tumors by sequencing, immunohistochemistry, or fluorescence in situ hybridization (FISH) might be used to determine whether any of these mechanisms were at work, and if so, whether they might change management. Implicit in this approach is that tissue from growing tumors will be
assessed throughout the course of the patient’s disease; however, studies have shown that circulating tumor cells can be analyzed by these methods, which might obviate the need for repeated biopsies.
It is an incredibly exciting time to be a prostate cancer oncologist. For the first time ever, we have multiple effective agents available to our patients with metastatic disease. At the same time, however, there are enormous gaps in our understanding of how to use these agents. It is likely that the way we practice prostate cancer oncology will be dramatically different in a few years. Just as molecular studies have been the basis of many of these new therapies, it is hoped that molecular research will clarify clinical practice and improve the lives of men with advanced prostate cancer.
Dr. Petrylak receives consultant fees from Bayer, Bellicum, Dendreon, Sanofi-Aventis, Johnson & Johnson, Exelixis, Ferring, Medivation, Millennium, and Pfizer; and receives grant support from Celgene, Dendreon, Johnson & Johnson, Millennium, Oncogenix, and Progenics. Dr. Hurwitz has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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