REVIEW For reprint orders, please contact: [email protected]
Advances in systemic therapies for metastatic castration-resistant prostate cancer Manish K Pant1, Ahmed Abughaban2 & Jeanny B Aragon-Ching*,1
ABSTRACT The landscape of treatment for metastatic castration-resistant prostate cancer has rapidly evolved during the last 5 years alone. In this review, standard therapies as well as recent advances in the systemic treatment for prostate cancer are explored. Pivotal trial data are summarized with emphasis on indications for various anti-androgen drugs, androgenbiosynthesis inhibitors, chemotherapy, immunotherapy and bone-targeted agents. The clinical, biochemical and radiographic outcomes for men with metastatic castration-resistant prostate cancer are improving with the establishment of several promising novel agents.
Metastatic castration-resistant prostate cancer (mCRPC) is a treatable yet highly morbid and universally fatal disease. Androgen deprivation therapy (ADT) has long been considered the standard therapy for this disease but treatment options after androgen ablation are largely palliative, and include use of immunotherapy, further androgen-directed agents, radiotherapy to dominant sites of bone pain or radiopharmaceuticals, and cytotoxic chemotherapy. Bone-targeting agents including zoledronic acid and denosumab have been shown to reduce skeletal-related events (SREs), and narcotics and low-dose steroids also play roles. Current therapies shown to prolong overall survival in mCRPC include the sipuleucel-T vaccine, chemotherapy options including docetaxel and cabazitaxel, hormonal blocking agents such as enzalutamide and abiraterone, and the bonetargeting alpha-emitter radium-223 dichloride, which pose interesting challenges to sequencing and combination of these agents and discussed herein (see Table 1).
KEYWORDS
• abiraterone acetate • androgen deprivation therapy • chemotherapy • enzalutamide • immunotherapy • metastatic
castration-resistant prostate cancer • radium • zoledronic acid
Androgen deprivation therapy Given the recognition that prostate cancer is a hormonally-driven disease, ADT, which is usually given in a continuous manner, has been the cornerstone of treatment for metastatic hormonesensitive disease. While men typically have a very high response rate to ADT [1] , the inevitable development of castration resistance has historically led to a median overall survival of only about 1–3 years [17–19] . In addition, varying adverse effects from use of ADT are well described in the literature, including hot flashes, cardiovascular ischemia, fatigue, pain, edema, asthenia, headache, constipation, gynecomastia and testicular atrophy. To address whether disease control could be achieved while preserving or improving quality of life with the use of intermittent ADT, an international collaborative study explored the option of treatment after disease progression in 3040 patients with adequate level of function (Eastern Cooperative Oncology Group [ECOG] performance status 0–2), metastatic prostate cancer and prostate-specific antigen (PSA) ≥5 ng/ml. All patients Department of Medicine, Division of Hematology & Oncology, George Washington University Medical Center, 2150 Pennsylvania Avenue, NW Washington, DC 20037, USA 2 Department of Medicine, George Washington University Medical Center, DC, USA *Author for correspondence: Tel.: +1 202 741 2478; Fax: +1 202 741 2487; [email protected] 1
10.2217/FON.14.128 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(14), 2213–2226
part of
ISSN 1479-6694
2213
Review Pant, Abughaban & Aragon-Ching Table 1. Treatment strategies and mechanism of action. Classification
Drug
Mechanism of action
Key trial findings
Androgen ablation
Leuprolide
LHRH analog decapeptide that causes constant stimulation to the anterior pituitary, causing inhibition of gonadotropin secretion GnRH-receptor antagonist that suppresses testosterone production by decreasing LH and FSH
LSG: OS 87% vs DES 78% [1]
Degarelix
Hormonal blockade
Abiraterone acetate Androgen biosynthesis inhibitor: inhibits CYP450C17 (CYP17), a critical enzyme in extragonadal and testicular androgen synthesis Enzalutamide Competitive androgen receptor inhibitor of cells overexpressing the AR gene
Chemotherapy
Mitoxantrone
ARN-509
Synthetic anthracenedione with cell cycle nonspecific cytocidal activity that causes DNA cross-links and strand breaks Semisynthetic taxane that prevents depolymerization of cellular microtubules, resulting in DNA, RNA and protein synthesis inhibition Novel tubulin-binding taxane causing microtubule stabilization Autologous dendritic cell vaccine against PAP antigen Vector-based vaccine that targets PSA through the use of genetically altered poxviruses Bisphosphonate; inhibits bone resorption via actions on osteoclast activity Monoclonal antibody against RANK-ligand that prevents osteoclast formation Targeted alpha emitter binds to areas of increased bone turnover in bone metastases; emits high-energy alpha particles of short range (1.50 ng/dl, PSA level ≥2, and ECOG performance status ≤2. By day 3,
future science group
Review
the median testosterone levels were ≤50 ng/dl in 96.1 and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively. By contrast, for patients receiving leuprolide, the median testosterone levels increased by 65% from baseline by day 3 (median testosterone level 6.30 ng/ml; p 50 ng/dl while under treatment with GnRH analog therapy [25] , as well as to avoid clinical testosterone flares. Androgen biosynthesis inhibitors & anti-androgen signaling ●●Mechanisms of resistance
Despite the success with ADT use, progression to castration resistance is almost inevitable. Several mechanisms have been hypothesized to explain the development of resistance to ADT leading to hormone-refractory or androgen-independent
www.futuremedicine.com
2215
Review Pant, Abughaban & Aragon-Ching disease. The first includes alterations, such as point mutations or overexpression, in the androgen receptor gene (AR) that occurs in a minority of patients [26,27] . The second proposed mechanism is increased mitogen-activated protein kinase signaling, mediated by oncogenes such as ERBB2 or HRAS, that cause ligand- independent activation of the androgen receptor [28] . Stemming from reports that androgen receptor gene methylation leads to decreased or absent androgen receptor expression in some hormone refractory malignancies, the third category of hormone-resistance mechanisms is based on the concept that the growth- and survivalpromoting functions of the androgen receptor can be bypassed by alternative signaling pathways, rendering the androgen receptor irrelevant to disease progression [29] . Micro-array analysis of isogenic prostate cancer xenograft models has suggested that a modest increase in androgen receptor mRNA is the only change consistently associated with the development of resistance to anti-androgen therapy [30] , and many of the differential gene-expression changes detected during therapy for castration-resistant tumors reflects a reactivation of the androgen response pathway even in the absence of exogenous hormone [30,31] . Since there may be a unique set of genes that reflect potential mechanisms of reactivation, specifically an upregulation of the androgen receptor and key enzymes for steroid biosynthesis, these resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. ●●Abiraterone acetate
Anti-androgen withdrawal has been used as a therapeutic maneuver in a subset of patients [32] , which in theory led to the principle of secondary hormonal manipulation use [33] . The understanding that the tumor remains dependent on the androgen receptor despite castration resistance brought about the emergence of novel androgen-biosynthesis inhibitors. The administration of abiraterone acetate, a first-in-class inhibitor of CYP450C17, a critical enzyme in extragonadal and testicular androgen synthesis, has been one of the successes in the era of further hormonal manipulation. In a pivotal trial, COU-AA-301 [3] , 1195 mCRPC patients previously treated with docetaxel were randomized to either 5 mg of prednisone twice daily plus 1000 mg of abiraterone daily (n = 797 patients), or the same prednisone regimen plus
2216
Future Oncol. (2014) 10(14)
placebo (n = 398 patients). It was found that the abiraterone arm achieved an overall survival advantage of 3.9 months over the placebo arm. Subsequently, in a study of chemotherapynaïve patients termed the COU-AA-302 trial [4] , the median time to radiographic PFS was 16.5 months in the abiraterone–prednisone group and 8.3 months in the prednisone-alone group. However, the median overall survival was not statistically reached for the abiraterone–prednisone group and was 27.2 months (95% CI: 26.0–not reached) in the prednisonealone group. There was a 25% decrease in the risk of death in the abiraterone–prednisone group (hazard ratio [HR]: 0.75; 95% CI: 0.61–0.93; p = 0.01), indicating a strong trend toward improved survival with the abiraterone–prednisone arm. Although the pre-specified boundary for significance (p ≤ 0.001) was not reached at the observed number of events, significantly more deaths were observed in the prednisone-only group (34%) compared with the abiraterone–prednisone group (27%). These trials have led to the routine use of abiraterone in both the post- and pre-chemotherapy arenas. ●●Enzalutamide
Another androgen-targeting agent, in the form of a novel anti-androgen, called MDV3100, which was later named enzalutamide, was selected from a library of compounds for its androgen receptor inhibition of cells overexpressing the AR and with increased potency over bicalutamide, and entered pre-clinical and clinical studies [34] . The promising results from the use of enzalutamide culminated in a Phase III randomized study called the AFFIRM trial, which showed that mCRPC patients previously treated with one or two chemotherapy regimens (at least one of which contained docetaxel) randomized to receive enzalutamide had a median overall survival of 18.4 months, compared with 13.6 months in the placebo arm, with similar rates of adverse events among the two groups [5] . Although there were similar rates of adverse events among the two groups, rates of fatigue, diarrhea and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. The superiority of enzalutamide over placebo was shown for all secondary end points, including PSA-level response rate (54 vs 2%; p
Advances in systemic therapies for metastatic castration-resistant prostate cancer Manish K Pant1, Ahmed Abughaban2 & Jeanny B Aragon-Ching*,1
ABSTRACT The landscape of treatment for metastatic castration-resistant prostate cancer has rapidly evolved during the last 5 years alone. In this review, standard therapies as well as recent advances in the systemic treatment for prostate cancer are explored. Pivotal trial data are summarized with emphasis on indications for various anti-androgen drugs, androgenbiosynthesis inhibitors, chemotherapy, immunotherapy and bone-targeted agents. The clinical, biochemical and radiographic outcomes for men with metastatic castration-resistant prostate cancer are improving with the establishment of several promising novel agents.
Metastatic castration-resistant prostate cancer (mCRPC) is a treatable yet highly morbid and universally fatal disease. Androgen deprivation therapy (ADT) has long been considered the standard therapy for this disease but treatment options after androgen ablation are largely palliative, and include use of immunotherapy, further androgen-directed agents, radiotherapy to dominant sites of bone pain or radiopharmaceuticals, and cytotoxic chemotherapy. Bone-targeting agents including zoledronic acid and denosumab have been shown to reduce skeletal-related events (SREs), and narcotics and low-dose steroids also play roles. Current therapies shown to prolong overall survival in mCRPC include the sipuleucel-T vaccine, chemotherapy options including docetaxel and cabazitaxel, hormonal blocking agents such as enzalutamide and abiraterone, and the bonetargeting alpha-emitter radium-223 dichloride, which pose interesting challenges to sequencing and combination of these agents and discussed herein (see Table 1).
KEYWORDS
• abiraterone acetate • androgen deprivation therapy • chemotherapy • enzalutamide • immunotherapy • metastatic
castration-resistant prostate cancer • radium • zoledronic acid
Androgen deprivation therapy Given the recognition that prostate cancer is a hormonally-driven disease, ADT, which is usually given in a continuous manner, has been the cornerstone of treatment for metastatic hormonesensitive disease. While men typically have a very high response rate to ADT [1] , the inevitable development of castration resistance has historically led to a median overall survival of only about 1–3 years [17–19] . In addition, varying adverse effects from use of ADT are well described in the literature, including hot flashes, cardiovascular ischemia, fatigue, pain, edema, asthenia, headache, constipation, gynecomastia and testicular atrophy. To address whether disease control could be achieved while preserving or improving quality of life with the use of intermittent ADT, an international collaborative study explored the option of treatment after disease progression in 3040 patients with adequate level of function (Eastern Cooperative Oncology Group [ECOG] performance status 0–2), metastatic prostate cancer and prostate-specific antigen (PSA) ≥5 ng/ml. All patients Department of Medicine, Division of Hematology & Oncology, George Washington University Medical Center, 2150 Pennsylvania Avenue, NW Washington, DC 20037, USA 2 Department of Medicine, George Washington University Medical Center, DC, USA *Author for correspondence: Tel.: +1 202 741 2478; Fax: +1 202 741 2487; [email protected] 1
10.2217/FON.14.128 © 2014 Future Medicine Ltd
Future Oncol. (2014) 10(14), 2213–2226
part of
ISSN 1479-6694
2213
Review Pant, Abughaban & Aragon-Ching Table 1. Treatment strategies and mechanism of action. Classification
Drug
Mechanism of action
Key trial findings
Androgen ablation
Leuprolide
LHRH analog decapeptide that causes constant stimulation to the anterior pituitary, causing inhibition of gonadotropin secretion GnRH-receptor antagonist that suppresses testosterone production by decreasing LH and FSH
LSG: OS 87% vs DES 78% [1]
Degarelix
Hormonal blockade
Abiraterone acetate Androgen biosynthesis inhibitor: inhibits CYP450C17 (CYP17), a critical enzyme in extragonadal and testicular androgen synthesis Enzalutamide Competitive androgen receptor inhibitor of cells overexpressing the AR gene
Chemotherapy
Mitoxantrone
ARN-509
Synthetic anthracenedione with cell cycle nonspecific cytocidal activity that causes DNA cross-links and strand breaks Semisynthetic taxane that prevents depolymerization of cellular microtubules, resulting in DNA, RNA and protein synthesis inhibition Novel tubulin-binding taxane causing microtubule stabilization Autologous dendritic cell vaccine against PAP antigen Vector-based vaccine that targets PSA through the use of genetically altered poxviruses Bisphosphonate; inhibits bone resorption via actions on osteoclast activity Monoclonal antibody against RANK-ligand that prevents osteoclast formation Targeted alpha emitter binds to areas of increased bone turnover in bone metastases; emits high-energy alpha particles of short range (1.50 ng/dl, PSA level ≥2, and ECOG performance status ≤2. By day 3,
future science group
Review
the median testosterone levels were ≤50 ng/dl in 96.1 and 95.5% of patients in the degarelix 240/80 mg and 240/160 mg groups, respectively. By contrast, for patients receiving leuprolide, the median testosterone levels increased by 65% from baseline by day 3 (median testosterone level 6.30 ng/ml; p 50 ng/dl while under treatment with GnRH analog therapy [25] , as well as to avoid clinical testosterone flares. Androgen biosynthesis inhibitors & anti-androgen signaling ●●Mechanisms of resistance
Despite the success with ADT use, progression to castration resistance is almost inevitable. Several mechanisms have been hypothesized to explain the development of resistance to ADT leading to hormone-refractory or androgen-independent
www.futuremedicine.com
2215
Review Pant, Abughaban & Aragon-Ching disease. The first includes alterations, such as point mutations or overexpression, in the androgen receptor gene (AR) that occurs in a minority of patients [26,27] . The second proposed mechanism is increased mitogen-activated protein kinase signaling, mediated by oncogenes such as ERBB2 or HRAS, that cause ligand- independent activation of the androgen receptor [28] . Stemming from reports that androgen receptor gene methylation leads to decreased or absent androgen receptor expression in some hormone refractory malignancies, the third category of hormone-resistance mechanisms is based on the concept that the growth- and survivalpromoting functions of the androgen receptor can be bypassed by alternative signaling pathways, rendering the androgen receptor irrelevant to disease progression [29] . Micro-array analysis of isogenic prostate cancer xenograft models has suggested that a modest increase in androgen receptor mRNA is the only change consistently associated with the development of resistance to anti-androgen therapy [30] , and many of the differential gene-expression changes detected during therapy for castration-resistant tumors reflects a reactivation of the androgen response pathway even in the absence of exogenous hormone [30,31] . Since there may be a unique set of genes that reflect potential mechanisms of reactivation, specifically an upregulation of the androgen receptor and key enzymes for steroid biosynthesis, these resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. ●●Abiraterone acetate
Anti-androgen withdrawal has been used as a therapeutic maneuver in a subset of patients [32] , which in theory led to the principle of secondary hormonal manipulation use [33] . The understanding that the tumor remains dependent on the androgen receptor despite castration resistance brought about the emergence of novel androgen-biosynthesis inhibitors. The administration of abiraterone acetate, a first-in-class inhibitor of CYP450C17, a critical enzyme in extragonadal and testicular androgen synthesis, has been one of the successes in the era of further hormonal manipulation. In a pivotal trial, COU-AA-301 [3] , 1195 mCRPC patients previously treated with docetaxel were randomized to either 5 mg of prednisone twice daily plus 1000 mg of abiraterone daily (n = 797 patients), or the same prednisone regimen plus
2216
Future Oncol. (2014) 10(14)
placebo (n = 398 patients). It was found that the abiraterone arm achieved an overall survival advantage of 3.9 months over the placebo arm. Subsequently, in a study of chemotherapynaïve patients termed the COU-AA-302 trial [4] , the median time to radiographic PFS was 16.5 months in the abiraterone–prednisone group and 8.3 months in the prednisone-alone group. However, the median overall survival was not statistically reached for the abiraterone–prednisone group and was 27.2 months (95% CI: 26.0–not reached) in the prednisonealone group. There was a 25% decrease in the risk of death in the abiraterone–prednisone group (hazard ratio [HR]: 0.75; 95% CI: 0.61–0.93; p = 0.01), indicating a strong trend toward improved survival with the abiraterone–prednisone arm. Although the pre-specified boundary for significance (p ≤ 0.001) was not reached at the observed number of events, significantly more deaths were observed in the prednisone-only group (34%) compared with the abiraterone–prednisone group (27%). These trials have led to the routine use of abiraterone in both the post- and pre-chemotherapy arenas. ●●Enzalutamide
Another androgen-targeting agent, in the form of a novel anti-androgen, called MDV3100, which was later named enzalutamide, was selected from a library of compounds for its androgen receptor inhibition of cells overexpressing the AR and with increased potency over bicalutamide, and entered pre-clinical and clinical studies [34] . The promising results from the use of enzalutamide culminated in a Phase III randomized study called the AFFIRM trial, which showed that mCRPC patients previously treated with one or two chemotherapy regimens (at least one of which contained docetaxel) randomized to receive enzalutamide had a median overall survival of 18.4 months, compared with 13.6 months in the placebo arm, with similar rates of adverse events among the two groups [5] . Although there were similar rates of adverse events among the two groups, rates of fatigue, diarrhea and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide. The superiority of enzalutamide over placebo was shown for all secondary end points, including PSA-level response rate (54 vs 2%; p
