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Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
the Specialty urologypracticejournal.com
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer Neal D. Shore* and Michael S. Cooksony From the Carolina Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina (NDS), and Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (MSC)
Abstract
Abbreviations and Acronyms
Introduction: Although androgen deprivation therapy results in clinical and/or disease biochemical remission, disease will ultimately progress from androgen sensitivity to a castration resistant status. Therapeutic options for men with metastatic castration resistant prostate cancer have changed dramatically in the last decade. We review potential sequencing of these therapeutic options based on the currently available published literature. Methods: Since 2010 the Food and Drug Administration has approved 5 new castrate resistant prostate cancer therapies, all with proven survival benefit. These breakthrough therapies and their impact on the disease landscape prompted the AUA in 2013 to establish its first castrate resistant prostate cancer guideline, creating a framework for urologists to better understand their expanded role in the treatment of men with advanced prostate cancer. Results: Currently, 5 new agents, sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223 dichloride, have been approved by the Food and Drug Administration to treat castrate resistant prostate cancer on the basis of randomized clinical trials. These approvals, and other anticipated novel therapies, highlight the need for the AUA guidelines to be updated regularly to inform the clinician about this rapidly evolving disease state and the importance of adopting these new therapies. Conclusions: In less than 3 years multiple new therapeutics have been approved for the treatment of metastatic castration resistant prostate cancer. The mechanisms of action as well as the modes of delivery are largely unique. Recognizing the sequencing order for these new therapies requires an understanding of the published peer reviewed literature as well as clinical judgment and experience. This article provides a review of the literature as well as guidance to assist clinicians who desire to treat metastatic castrate resistant prostate cancer.
ADT = androgen deprivation therapy AUA = American Urological Association CRPC = castration resistant prostate cancer FDA = Food and Drug Administration mCRPC = metastatic castration resistant prostate cancer PSA = prostate specific antigen
Key Words: prostatic neoplasms, castration-resistant
When ADT is appropriately initiated, most patients will respond favorably with clinical and/or biochemical disease remission but they will ultimately experience disease progression from androgen sensitivity to a castration resistant status.1 Options for men with mCRPC have changed dramatically in the last decade. Before 2004 when primary ADT failed, treatments were administered solely for symptom relief. Landmark chemotherapy studies demonstrated improved survival with intravenous docetaxel for patients with mCRPC.2,3 Since 2010 Submitted for publication January 17, 2014. * Financial interest and/or other relationship with Algeta, Astellas, Bayer, Ferring, Dendreon, Janssen, Medivation and Sanofi. y No direct or indirect commercial incentive associated with publishing this article. 2352-0779/$36.00 Ó 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION Published by Elsevier
AND
the FDA has approved 5 CRPC therapies, sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223 dichloride, all with proven survival benefit based on randomized clinical trials.4,5 These breakthrough therapies and their impact on the mCRPC landscape prompted the AUA to establish its first CRPC guideline in 2013, creating a framework for urologists to better understand their expanded role in the management of men with advanced prostate cancer.4 These approvals, and other novel therapies anticipated to be forthcoming, highlight the need to inform the clinician about this rapidly evolving disease state by periodic updates of the CRPC guidelines and the importance of adoption of new CRPC therapies. The AUA CRPC guideline was developed to help clinicians understand not only the spectrum of presentation of advanced prostate cancer, but also to recognize at which point in the
RESEARCH, INC.
http://dx.doi.org/10.1016/j.urpr.2014.02.014 Urology Practice 1 (2014), 2-6
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
3
Figure. Summary flowchart. H&P, history and physical.4
disease state the new agents are appropriate for use. Thus, 6 index cases were developed to represent the most common scenarios encountered in clinical practice. Accordingly, patients with CRPC were categorized based on the presence or absence of metastatic disease, severity of symptoms, overall performance status and whether they had received prior docetaxel chemotherapy (see figure). These guidelines are designed to assist sequencing of therapies for the CRPC population but are by no means absolute with regard to the ideal sequencing selection, which this article will further address after the summary of the 6 index cases. Index Cases Index case 1 is asymptomatic with an increasing PSA, despite a testosterone level less than 50 ng/dl and no radiographic evidence of metastases. Clinicians should recommend observation with continued ADT to patients with nonmetastatic CRPC. Since all agents have potential side effects and no treatment has been shown to extend survival or demonstrate a clinically meaningful delay in the development of metastasis in this M0 CRPC scenario, we must first do no harm. Clinicians might
offer first generation antiandrogens or first generation androgen synthesis inhibitors to select patients, although no survival benefit has been demonstrated with these therapies. However, in the patient with M0 CRPC clinicians should not offer chemotherapy, immunotherapy or newly approved oral hormonal therapy outside the context of a clinical trial. Index case 2 has asymptomatic or minimally symptomatic radiographic evidence of metastases and no history of docetaxel chemotherapy. Clinicians may offer sipuleucel-T, abiraterone plus prednisone or docetaxel. They may offer first generation antiandrogen therapy, first generation androgen synthesis inhibitors or observation to index 2 patients who do not want or cannot have one of the aforementioned standard therapies. Index case 3 has symptomatic metastatic disease, good performance status and has not received docetaxel. Docetaxel chemotherapy is appropriate and abiraterone plus prednisone may be offered. Clinicians may also offer ketoconazole plus steroid, mitoxantrone or radionuclide therapy (strontium or samarium) to patients who do not want or cannot have one of the standard therapies. They should not offer treatment with either estramustine or sipuleucel-T to index 3 patients.
4
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
Index patient 4 is symptomatic with evidence of metastases, poor performance status and has not received docetaxel. Clinicians may offer abiraterone plus prednisone in this setting. They may offer ketoconazole plus steroid or radionuclide therapy to patients who are unable or unwilling to receive abiraterone plus prednisone. Clinicians may offer docetaxel or mitoxantrone chemotherapy in select cases, specifically when the poor performance status is directly related to cancer symptoms. However, based on FDA recommendations, patients should not be offered sipuleucel-T in this setting. Index case 5 is symptomatic with metastases, good performance status and has received docetaxel. Clinicians should offer abiraterone plus prednisone, cabazitaxel or enzalutamide in this setting. If the patient received abiraterone plus prednisone before docetaxel chemotherapy, he should be offered cabazitaxel or enzalutamide. Clinicians may offer ketoconazole plus steroid if abiraterone plus prednisone, cabazitaxel or enzalutamide is unavailable. Clinicians may also offer retreatment with docetaxel to select patients who were benefitting at the time of its discontinuation (due to reversible side effects). Index case 6 has symptomatic metastases, poor performance status and has received docetaxel. Clinicians should offer palliative care to these patients. Alternatively, for select patients, they may offer abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid or radionuclide therapy. Clinicians should not offer systemic chemotherapy or immunotherapy to these patients. The guidelines also address bone health, and state that clinicians should offer all patients with CRPC preventive treatment to reduce the risk of fractures and skeletal related events.4 Clinicians may choose either denosumab or zoledronic acid for skeletal events related to bony metastases and mCRPC. Since publication of the CRPC guideline, radium-223 was approved by the FDA after demonstrating a survival advantage for patients with symptomatic bone metastases and no known visceral metastases regardless of prior exposure to docetaxel.5 This approval and that of additional agents, coupled with earlier indications (pre-chemotherapy enzalutamide) for existing agents, exemplify the rapidly changing CRPC landscape. Thus for urologists, in the expanding role as the primary caregivers of men with advanced prostate cancer, thorough knowledge of the various treatment options, clear understanding of risks/benefits of the various agents and enhanced collaboration with other specialists are required.
addition of first generation nonsteroidal antiandrogens to a less prominent role. In a patient with either low tumor burden or presumed, slowly progressive, high volume disease sipuleucel-T is a reasonable first option, given its lack of toxicity, short duration of administration, unique mechanism of action and potential benefit in a patient with less immunosuppression. Also, the current FDA label requires avoidance of systemic corticosteroids for 1 month before treatment. A phase II trial has shown that concomitant steroid use with abiraterone or 2 weeks after completion of treatment with sipuleucel-T did not impact product characteristics for the successful administration of sipuleucel-T but long-term efficacy for these patients has not yet been evaluated.6 A similar study is now being designed that will evaluate immune parameters associated with concomitant vs 2-week delayed administration of enzalutamide with sipuleucel-T. In a patient with rapid asymptomatic disease progression (perhaps assessed by PSA kinetics and/or radiographic findings) abiraterone plus prednisone is an appropriate first option, especially in patients who demonstrated a sustained response to initial ADT. Likewise, a baseline testosterone level may also guide successfulness of therapy, according to a recent post hoc analysis.7 With the approval and availability of abiraterone acetate for chemotherapy naïve patients since 2012, ketoconazole should be limited to patients with M0 CRPC or when access to abiraterone is precluded. Ra-223 is an appropriate option for patients with bone symptomatic M1 CRPC, especially if the symptomatic bone metastases are too numerous for focal radiation therapy. This option, especially for patients without significant visceral disease, is preferable before receiving chemotherapy. Calculating the every 4-week isotope infusion in 6 cycles must be evaluated before this same patient might benefit from a 6 to 10-cycle course of docetaxel. The Ra-223 phase III trial suggests that hematologic toxicity is not significantly worse in patients who subsequently receive docetaxel, a concern historically associated with earlier generation radiopharmaceuticals.8 Finally, augmenting traditional ADT strategies with either abiraterone acetate or enzalutamide is in clinical trials. However, recognizing the slight survival advantage of combined androgen blockade over luteinizing hormone-releasing hormone agonist monotherapy, these combinations should be more efficacious and thus the importance of these trials. Post-docetaxel/Pre-abiraterone Therapy
Treatment before Docetaxel For treatment of asymptomatic or minimally symptomatic CRPC, there is a paucity of Level 1 evidence to categorically recommend any one approved therapy over another. That stated, a therapeutic may be selected based on rapidity of disease progression as well as toxicity of the potential treatment. Recently, 3 separate phase III clinical trials of newly approved agents (sipuleucel-T, abiraterone/prednisone, Ra223) demonstrated improvement in progression-free survival or overall survival of patients with metastatic disease that progressed with androgen ablation, thus relegating the reflex
Abiraterone, enzalutamide, cabazitaxel and Ra-223 provide survival advantages of similar magnitude for patients experiencing disease progression on docetaxel and prednisone. The eligibility requirements and baseline characteristics for these trials were similar for the most part, albeit there were differences regarding trial population access to approved therapies which may have affected some of the efficacy data. Nevertheless, choosing the order of therapy will largely relate to presumed safety and tolerability profiles of the specific agents. With progression after docetaxel, either oral abiraterone or enzalutamide is most likely an optimal choice based on
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
published adverse event profiles to date. Docetaxel and cabazitaxel chemotherapeutics can cause peripheral neuropathy and myelosuppression. Although no comparative data exist, one might anticipate less fatigue and cytopenias, and no peripheral neuropathies with abiraterone or enzalutamide. Choosing between abiraterone and enzalutamide is unclear, although the use and monitoring of glucocorticoids (eg patients with diabetes or psychiatric issues) may be a consideration for abiraterone, whereas enzalutamide may be contraindicated in patients with neurological impairment or a history of seizure.9,10 A retrospective analysis of the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial revealed that corticosteroid use was an independent poor prognostic factor in patients treated with enzalutamide, although this was a retrospective analysis, and disease burden and other comorbidities may have also been influential in that analysis.11 Of note, there have been anecdotal reports of patients being treated with abiraterone without steroids (or only a 5 mg daily dose, an accrued phase II trial of the M0 CRPC population), although current labeling for abiraterone requires glucocorticoid administration (5 mg prednisone twice daily). Disease progression after abiraterone or enzalutamide suggests cabazitaxel as a next logical choice or a possible rechallenge with docetaxel, followed by the other novel hormonal therapy (ie enzalutamide if abiraterone was used previously and vice versa if enzalutamide was used first). Also, if disease progression is primarily in the bones, Ra-223 is an excellent option, given its well tolerated profile, and it may be well suited for combination therapy with either abiraterone or enzalutamide but those combinatorial data are pending. Post-docetaxel/Post-abiraterone Therapy In time, most patients should receive abiraterone acetate before docetaxel and for disease progression after docetaxel, the choice will be cabazitaxel, enzalutamide or Ra-223, assuming they have not received the later two previously. The presumed positive efficacy results of the PREVAIL pre-chemotherapy trial for enzalutamide may be published sometime this year. Thus, the same aforementioned rationale for ordering therapies after docetaxel can be implemented again, with the only difference being omission of abiraterone. Of note, the trials demonstrating the effectiveness of these agents did not include patients pretreated with abiraterone. Thus, the eventual effectiveness in this population may be different. In fact, several retrospective studies suggest that each of these therapies becomes less effective after treatment with one of the others. A study of the response to docetaxel by patients previously treated with abiraterone revealed a PSA response rate of 26%,12 which is lower than the 45% to 50% response rate originally seen in phase III studies of docetaxel.1,2,12 Median overall survival was only 12.5 months compared to 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 vice versa showed only minimal responses to the last therapy administered.13e15 This
5
phenomenon may be explained by comparable mechanisms of action, as abiraterone inhibits androgen receptor signaling by decreasing the amount of testosterone/metabolites exposed to the receptor, whereas enzalutamide also inhibits androgen receptor signaling but does so through direct inhibition of the receptor protein itself. Hence, cross-resistance and the ability to predict response remain an area of keen research interest. Again, recognizing the lack of randomized trial data to guide rational or biologically based sequencing of therapies, treatment of asymptomatic or minimally symptomatic patients is selected based on rapidity of disease progression and treatment toxicity, an approach that was codified and published by the American Urological Association CRPC Guidelines Committee in May 2013. Drug resistance in the setting of post-docetaxel therapy and the paucity of significant data to guide the sequencing of therapy are important areas of future research. Of course, the dilemma is encountered for sequencing and combination strategies throughout the CRPC management continuum as the novel newer therapies have been approved in a rapid succession timeline. Thus, future protocol designs must consider the challenges raised by patients readily crossing over to recently approved CRPC therapies and, subsequently, the statistical impact on radiographic progression and survival data interpretations. Conclusions The most efficacious CRPC sequencing paradigm is an ongoing consideration. Further prospective data regarding the optimal sequencing and combinations are in progress, and additional immunotherapeutics, novel hormonal agents and chemotherapeutics are accruing in phase II/III trials. Continued progress in achieving prolongation of survival with maintenance of quality of life is now a reality for many patients with CRPC, and the next few years will assuredly augment the recent advances in the management of advanced prostate cancer. References 1. White RD and Lara PN Jr: Toward a common therapeutic framework in castration-resistant prostate cancer: a model for urologic oncology and medical oncology interaction. Urol Oncol 2013; Epub ahead of print. 2. Tannock IF, de Wit R, Berry WR et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502. 3. Petrylak DP, Tangen CM, Hussain MH et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513. 4. Cookson MS, Roth BJ, Dahm P et al: Castration-resistant prostate cancer: AUA Guideline. J Urol 2013; 190: 429. 5. Parker C, Nilsson S, Heinrich D et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213. 6. Small EJ, Lance RS, Redfern CH et al: A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol, suppl., 2013; 31: abstract 5047. 7. Ryan C, Li J, Kheoh T et al: Baseline serum adrenal androgens are prognostic and predictive of overall survival (OS) in patients (pts) with
6
8.
9. 10. 11.
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
metastatic castrate-resistant prostate cancer (mCRPC): results of the COUAA-301 phase 3 randomized trial. Cancer Res, suppl., 2012; 72: abstract LB-434. Vogelzang NJ, Helle SI, Johannessen DC et al: Efficacy and safety of radium223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial. J Clin Oncol, suppl., 2013; 31: abstract 5068. Scher HI, Beer TM, Higano CS et al: Antitumor activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010; 375: 1437. Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187. Scher HI, Fizazi K, Saad F et al: Association of baseline corticosteroid with outcomes in a multivariate analysis of the phase 3 AFFIRM study of enzalutamide (ENZA), an androgen receptor signaling inhibitor (ARSI).
12.
13.
14.
15.
Presented at the 37th European Society for Medical Oncology Congress (abstract 2887), Vienna, Austria, September 28-October 2, 2012. Mezynski J, Pezaro C, Bianchini D et al: Antitumor activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012; 23: 2943. Loriot Y, Bianchini D, Ileana E et al: Antitumor activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol 2013; 24: 1807. Noonan KL, North S, Bitting RL et al: Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24: 1802. Schrader AJ, Boegemann M, Ohlmann CH et al: Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 2014; 65: 30.
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer Neal D. Shore* and Michael S. Cooksony From the Carolina Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina (NDS), and Department of Urology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (MSC)
Abstract
Abbreviations and Acronyms
Introduction: Although androgen deprivation therapy results in clinical and/or disease biochemical remission, disease will ultimately progress from androgen sensitivity to a castration resistant status. Therapeutic options for men with metastatic castration resistant prostate cancer have changed dramatically in the last decade. We review potential sequencing of these therapeutic options based on the currently available published literature. Methods: Since 2010 the Food and Drug Administration has approved 5 new castrate resistant prostate cancer therapies, all with proven survival benefit. These breakthrough therapies and their impact on the disease landscape prompted the AUA in 2013 to establish its first castrate resistant prostate cancer guideline, creating a framework for urologists to better understand their expanded role in the treatment of men with advanced prostate cancer. Results: Currently, 5 new agents, sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223 dichloride, have been approved by the Food and Drug Administration to treat castrate resistant prostate cancer on the basis of randomized clinical trials. These approvals, and other anticipated novel therapies, highlight the need for the AUA guidelines to be updated regularly to inform the clinician about this rapidly evolving disease state and the importance of adopting these new therapies. Conclusions: In less than 3 years multiple new therapeutics have been approved for the treatment of metastatic castration resistant prostate cancer. The mechanisms of action as well as the modes of delivery are largely unique. Recognizing the sequencing order for these new therapies requires an understanding of the published peer reviewed literature as well as clinical judgment and experience. This article provides a review of the literature as well as guidance to assist clinicians who desire to treat metastatic castrate resistant prostate cancer.
ADT = androgen deprivation therapy AUA = American Urological Association CRPC = castration resistant prostate cancer FDA = Food and Drug Administration mCRPC = metastatic castration resistant prostate cancer PSA = prostate specific antigen
Key Words: prostatic neoplasms, castration-resistant
When ADT is appropriately initiated, most patients will respond favorably with clinical and/or biochemical disease remission but they will ultimately experience disease progression from androgen sensitivity to a castration resistant status.1 Options for men with mCRPC have changed dramatically in the last decade. Before 2004 when primary ADT failed, treatments were administered solely for symptom relief. Landmark chemotherapy studies demonstrated improved survival with intravenous docetaxel for patients with mCRPC.2,3 Since 2010 Submitted for publication January 17, 2014. * Financial interest and/or other relationship with Algeta, Astellas, Bayer, Ferring, Dendreon, Janssen, Medivation and Sanofi. y No direct or indirect commercial incentive associated with publishing this article. 2352-0779/$36.00 Ó 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION Published by Elsevier
AND
the FDA has approved 5 CRPC therapies, sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223 dichloride, all with proven survival benefit based on randomized clinical trials.4,5 These breakthrough therapies and their impact on the mCRPC landscape prompted the AUA to establish its first CRPC guideline in 2013, creating a framework for urologists to better understand their expanded role in the management of men with advanced prostate cancer.4 These approvals, and other novel therapies anticipated to be forthcoming, highlight the need to inform the clinician about this rapidly evolving disease state by periodic updates of the CRPC guidelines and the importance of adoption of new CRPC therapies. The AUA CRPC guideline was developed to help clinicians understand not only the spectrum of presentation of advanced prostate cancer, but also to recognize at which point in the
RESEARCH, INC.
http://dx.doi.org/10.1016/j.urpr.2014.02.014 Urology Practice 1 (2014), 2-6
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
3
Figure. Summary flowchart. H&P, history and physical.4
disease state the new agents are appropriate for use. Thus, 6 index cases were developed to represent the most common scenarios encountered in clinical practice. Accordingly, patients with CRPC were categorized based on the presence or absence of metastatic disease, severity of symptoms, overall performance status and whether they had received prior docetaxel chemotherapy (see figure). These guidelines are designed to assist sequencing of therapies for the CRPC population but are by no means absolute with regard to the ideal sequencing selection, which this article will further address after the summary of the 6 index cases. Index Cases Index case 1 is asymptomatic with an increasing PSA, despite a testosterone level less than 50 ng/dl and no radiographic evidence of metastases. Clinicians should recommend observation with continued ADT to patients with nonmetastatic CRPC. Since all agents have potential side effects and no treatment has been shown to extend survival or demonstrate a clinically meaningful delay in the development of metastasis in this M0 CRPC scenario, we must first do no harm. Clinicians might
offer first generation antiandrogens or first generation androgen synthesis inhibitors to select patients, although no survival benefit has been demonstrated with these therapies. However, in the patient with M0 CRPC clinicians should not offer chemotherapy, immunotherapy or newly approved oral hormonal therapy outside the context of a clinical trial. Index case 2 has asymptomatic or minimally symptomatic radiographic evidence of metastases and no history of docetaxel chemotherapy. Clinicians may offer sipuleucel-T, abiraterone plus prednisone or docetaxel. They may offer first generation antiandrogen therapy, first generation androgen synthesis inhibitors or observation to index 2 patients who do not want or cannot have one of the aforementioned standard therapies. Index case 3 has symptomatic metastatic disease, good performance status and has not received docetaxel. Docetaxel chemotherapy is appropriate and abiraterone plus prednisone may be offered. Clinicians may also offer ketoconazole plus steroid, mitoxantrone or radionuclide therapy (strontium or samarium) to patients who do not want or cannot have one of the standard therapies. They should not offer treatment with either estramustine or sipuleucel-T to index 3 patients.
4
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
Index patient 4 is symptomatic with evidence of metastases, poor performance status and has not received docetaxel. Clinicians may offer abiraterone plus prednisone in this setting. They may offer ketoconazole plus steroid or radionuclide therapy to patients who are unable or unwilling to receive abiraterone plus prednisone. Clinicians may offer docetaxel or mitoxantrone chemotherapy in select cases, specifically when the poor performance status is directly related to cancer symptoms. However, based on FDA recommendations, patients should not be offered sipuleucel-T in this setting. Index case 5 is symptomatic with metastases, good performance status and has received docetaxel. Clinicians should offer abiraterone plus prednisone, cabazitaxel or enzalutamide in this setting. If the patient received abiraterone plus prednisone before docetaxel chemotherapy, he should be offered cabazitaxel or enzalutamide. Clinicians may offer ketoconazole plus steroid if abiraterone plus prednisone, cabazitaxel or enzalutamide is unavailable. Clinicians may also offer retreatment with docetaxel to select patients who were benefitting at the time of its discontinuation (due to reversible side effects). Index case 6 has symptomatic metastases, poor performance status and has received docetaxel. Clinicians should offer palliative care to these patients. Alternatively, for select patients, they may offer abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid or radionuclide therapy. Clinicians should not offer systemic chemotherapy or immunotherapy to these patients. The guidelines also address bone health, and state that clinicians should offer all patients with CRPC preventive treatment to reduce the risk of fractures and skeletal related events.4 Clinicians may choose either denosumab or zoledronic acid for skeletal events related to bony metastases and mCRPC. Since publication of the CRPC guideline, radium-223 was approved by the FDA after demonstrating a survival advantage for patients with symptomatic bone metastases and no known visceral metastases regardless of prior exposure to docetaxel.5 This approval and that of additional agents, coupled with earlier indications (pre-chemotherapy enzalutamide) for existing agents, exemplify the rapidly changing CRPC landscape. Thus for urologists, in the expanding role as the primary caregivers of men with advanced prostate cancer, thorough knowledge of the various treatment options, clear understanding of risks/benefits of the various agents and enhanced collaboration with other specialists are required.
addition of first generation nonsteroidal antiandrogens to a less prominent role. In a patient with either low tumor burden or presumed, slowly progressive, high volume disease sipuleucel-T is a reasonable first option, given its lack of toxicity, short duration of administration, unique mechanism of action and potential benefit in a patient with less immunosuppression. Also, the current FDA label requires avoidance of systemic corticosteroids for 1 month before treatment. A phase II trial has shown that concomitant steroid use with abiraterone or 2 weeks after completion of treatment with sipuleucel-T did not impact product characteristics for the successful administration of sipuleucel-T but long-term efficacy for these patients has not yet been evaluated.6 A similar study is now being designed that will evaluate immune parameters associated with concomitant vs 2-week delayed administration of enzalutamide with sipuleucel-T. In a patient with rapid asymptomatic disease progression (perhaps assessed by PSA kinetics and/or radiographic findings) abiraterone plus prednisone is an appropriate first option, especially in patients who demonstrated a sustained response to initial ADT. Likewise, a baseline testosterone level may also guide successfulness of therapy, according to a recent post hoc analysis.7 With the approval and availability of abiraterone acetate for chemotherapy naïve patients since 2012, ketoconazole should be limited to patients with M0 CRPC or when access to abiraterone is precluded. Ra-223 is an appropriate option for patients with bone symptomatic M1 CRPC, especially if the symptomatic bone metastases are too numerous for focal radiation therapy. This option, especially for patients without significant visceral disease, is preferable before receiving chemotherapy. Calculating the every 4-week isotope infusion in 6 cycles must be evaluated before this same patient might benefit from a 6 to 10-cycle course of docetaxel. The Ra-223 phase III trial suggests that hematologic toxicity is not significantly worse in patients who subsequently receive docetaxel, a concern historically associated with earlier generation radiopharmaceuticals.8 Finally, augmenting traditional ADT strategies with either abiraterone acetate or enzalutamide is in clinical trials. However, recognizing the slight survival advantage of combined androgen blockade over luteinizing hormone-releasing hormone agonist monotherapy, these combinations should be more efficacious and thus the importance of these trials. Post-docetaxel/Pre-abiraterone Therapy
Treatment before Docetaxel For treatment of asymptomatic or minimally symptomatic CRPC, there is a paucity of Level 1 evidence to categorically recommend any one approved therapy over another. That stated, a therapeutic may be selected based on rapidity of disease progression as well as toxicity of the potential treatment. Recently, 3 separate phase III clinical trials of newly approved agents (sipuleucel-T, abiraterone/prednisone, Ra223) demonstrated improvement in progression-free survival or overall survival of patients with metastatic disease that progressed with androgen ablation, thus relegating the reflex
Abiraterone, enzalutamide, cabazitaxel and Ra-223 provide survival advantages of similar magnitude for patients experiencing disease progression on docetaxel and prednisone. The eligibility requirements and baseline characteristics for these trials were similar for the most part, albeit there were differences regarding trial population access to approved therapies which may have affected some of the efficacy data. Nevertheless, choosing the order of therapy will largely relate to presumed safety and tolerability profiles of the specific agents. With progression after docetaxel, either oral abiraterone or enzalutamide is most likely an optimal choice based on
Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
published adverse event profiles to date. Docetaxel and cabazitaxel chemotherapeutics can cause peripheral neuropathy and myelosuppression. Although no comparative data exist, one might anticipate less fatigue and cytopenias, and no peripheral neuropathies with abiraterone or enzalutamide. Choosing between abiraterone and enzalutamide is unclear, although the use and monitoring of glucocorticoids (eg patients with diabetes or psychiatric issues) may be a consideration for abiraterone, whereas enzalutamide may be contraindicated in patients with neurological impairment or a history of seizure.9,10 A retrospective analysis of the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial revealed that corticosteroid use was an independent poor prognostic factor in patients treated with enzalutamide, although this was a retrospective analysis, and disease burden and other comorbidities may have also been influential in that analysis.11 Of note, there have been anecdotal reports of patients being treated with abiraterone without steroids (or only a 5 mg daily dose, an accrued phase II trial of the M0 CRPC population), although current labeling for abiraterone requires glucocorticoid administration (5 mg prednisone twice daily). Disease progression after abiraterone or enzalutamide suggests cabazitaxel as a next logical choice or a possible rechallenge with docetaxel, followed by the other novel hormonal therapy (ie enzalutamide if abiraterone was used previously and vice versa if enzalutamide was used first). Also, if disease progression is primarily in the bones, Ra-223 is an excellent option, given its well tolerated profile, and it may be well suited for combination therapy with either abiraterone or enzalutamide but those combinatorial data are pending. Post-docetaxel/Post-abiraterone Therapy In time, most patients should receive abiraterone acetate before docetaxel and for disease progression after docetaxel, the choice will be cabazitaxel, enzalutamide or Ra-223, assuming they have not received the later two previously. The presumed positive efficacy results of the PREVAIL pre-chemotherapy trial for enzalutamide may be published sometime this year. Thus, the same aforementioned rationale for ordering therapies after docetaxel can be implemented again, with the only difference being omission of abiraterone. Of note, the trials demonstrating the effectiveness of these agents did not include patients pretreated with abiraterone. Thus, the eventual effectiveness in this population may be different. In fact, several retrospective studies suggest that each of these therapies becomes less effective after treatment with one of the others. A study of the response to docetaxel by patients previously treated with abiraterone revealed a PSA response rate of 26%,12 which is lower than the 45% to 50% response rate originally seen in phase III studies of docetaxel.1,2,12 Median overall survival was only 12.5 months compared to 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 vice versa showed only minimal responses to the last therapy administered.13e15 This
5
phenomenon may be explained by comparable mechanisms of action, as abiraterone inhibits androgen receptor signaling by decreasing the amount of testosterone/metabolites exposed to the receptor, whereas enzalutamide also inhibits androgen receptor signaling but does so through direct inhibition of the receptor protein itself. Hence, cross-resistance and the ability to predict response remain an area of keen research interest. Again, recognizing the lack of randomized trial data to guide rational or biologically based sequencing of therapies, treatment of asymptomatic or minimally symptomatic patients is selected based on rapidity of disease progression and treatment toxicity, an approach that was codified and published by the American Urological Association CRPC Guidelines Committee in May 2013. Drug resistance in the setting of post-docetaxel therapy and the paucity of significant data to guide the sequencing of therapy are important areas of future research. Of course, the dilemma is encountered for sequencing and combination strategies throughout the CRPC management continuum as the novel newer therapies have been approved in a rapid succession timeline. Thus, future protocol designs must consider the challenges raised by patients readily crossing over to recently approved CRPC therapies and, subsequently, the statistical impact on radiographic progression and survival data interpretations. Conclusions The most efficacious CRPC sequencing paradigm is an ongoing consideration. Further prospective data regarding the optimal sequencing and combinations are in progress, and additional immunotherapeutics, novel hormonal agents and chemotherapeutics are accruing in phase II/III trials. Continued progress in achieving prolongation of survival with maintenance of quality of life is now a reality for many patients with CRPC, and the next few years will assuredly augment the recent advances in the management of advanced prostate cancer. References 1. White RD and Lara PN Jr: Toward a common therapeutic framework in castration-resistant prostate cancer: a model for urologic oncology and medical oncology interaction. Urol Oncol 2013; Epub ahead of print. 2. Tannock IF, de Wit R, Berry WR et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502. 3. Petrylak DP, Tangen CM, Hussain MH et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513. 4. Cookson MS, Roth BJ, Dahm P et al: Castration-resistant prostate cancer: AUA Guideline. J Urol 2013; 190: 429. 5. Parker C, Nilsson S, Heinrich D et al: Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213. 6. Small EJ, Lance RS, Redfern CH et al: A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol, suppl., 2013; 31: abstract 5047. 7. Ryan C, Li J, Kheoh T et al: Baseline serum adrenal androgens are prognostic and predictive of overall survival (OS) in patients (pts) with
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Proper Sequencing of Treatment for Castrate Resistant Prostate Cancer
metastatic castrate-resistant prostate cancer (mCRPC): results of the COUAA-301 phase 3 randomized trial. Cancer Res, suppl., 2012; 72: abstract LB-434. Vogelzang NJ, Helle SI, Johannessen DC et al: Efficacy and safety of radium223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial. J Clin Oncol, suppl., 2013; 31: abstract 5068. Scher HI, Beer TM, Higano CS et al: Antitumor activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet 2010; 375: 1437. Scher HI, Fizazi K, Saad F et al: Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367: 1187. Scher HI, Fizazi K, Saad F et al: Association of baseline corticosteroid with outcomes in a multivariate analysis of the phase 3 AFFIRM study of enzalutamide (ENZA), an androgen receptor signaling inhibitor (ARSI).
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Presented at the 37th European Society for Medical Oncology Congress (abstract 2887), Vienna, Austria, September 28-October 2, 2012. Mezynski J, Pezaro C, Bianchini D et al: Antitumor activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012; 23: 2943. Loriot Y, Bianchini D, Ileana E et al: Antitumor activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100). Ann Oncol 2013; 24: 1807. Noonan KL, North S, Bitting RL et al: Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann Oncol 2013; 24: 1802. Schrader AJ, Boegemann M, Ohlmann CH et al: Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 2014; 65: 30.