Management of Metastatic Castration-resistant Prostate Cancer


survival (2.8 versus 1.4 months; p<0.0001), extended time to PSA progression (6.4 months versus 3.1 months; p=0.001), increased radiographic tumour response rates (14.4 versus 4.4 %; p=0.0005) and increased PSA response rates (39.2 versus 17.8 %; p=0.0002). There were no differences between the two treatment arms with respect to pain responses or time to pain progression.


In subset analyses, the survival advantage of cabazitaxel persisted regardless of whether patients had measurable disease or pain, or whether progression had occurred while receiving docetaxel or following a treatment holiday. In addition, the survival benefit of cabazitaxel was most pronounced for men with Eastern Cooperative Oncology Group (ECOG) performance status 0–1 (versus 2), and for patients with disease progression within three months of docetaxel initiation (versus ≥three months of docetaxel initiation).15


The last


observation implies that cabazitaxel may be effective even in men with truly docetaxel-refractory disease.


The most common serious adverse events related to cabazitaxel were haematological, including grade ≥3 neutropenia in 82 % of patients (febrile neutropenia in 8 %).15


This degree of myelosuppression begs


the question of whether a lower dose of cabazitaxel (e.g. 20 mg/m2) may have been more appropriate, and a randomised trial comparing the safety and efficacy of these two doses (25 mg/m2 versus 20 mg/m2) is now being conducted (see Table 2). Use of growth factor support should be strongly considered, as reflected in several national guidelines.16


Other non-haematological toxicities included grade ≥3


diarrhoea (6 %), and grade ≥3 fatigue (5 %). Encouragingly, although peripheral neuropathy (all grades) was observed in 14 % of patients receiving cabazitaxel, only 1 % developed grade 3 neuropathy.


Abiraterone Acetate with Prednisone


Ectopic (adrenal, intra-tumoural, paracrine) androgen production in the setting of gonadal ablative therapies represents an important resistance mechanism in CRPC (see Table 1 and Figure 2). Abiraterone acetate (Zytiga™, Janssen) is an oral, potent, selective and irreversible inhibitor of the steroidogenic enzyme CYP17, blocking both its 17α-hydroxylase and its C17,20-lyase activity.17


As a result,


extra-gonadal androgen production is impaired through the inability to convert pregnenolone to dihydroepiandrostenedione and progesterone to androstenedione. In an initial Phase I study in men with chemotherapy-naïve CRPC, it was shown that the primary toxicities of abiraterone (hypertension, hypokalaemia and peripheral oedema) were related to a syndrome of secondary mineralocorticoid excess due to feedback upregulation of mineralocorticoid synthesis and were largely reversible after administration of an aldosterone receptor antagonist or a corticosteroid.18


For this reason, in several subsequent trials,


abiraterone was combined with low-dose prednisone, which may also enhance the efficacy of abiraterone.


The initial efficacy of abiraterone in CRPC was investigated in several Phase II trials. In patients with chemotherapy-naïve metastatic CRPC, ≥50 % PSA declines were seen in approximately 65 % of men, and radiographic tumour responses occurred in about 35 % of men,19


with


responses noted even among men who had prior ketoconazole exposure.20


Finally, in patients with docetaxel-refractory metastatic


CRPC, ≥50 % PSA declines were observed in approximately 40 % of men and objective tumour responses occurred in about 20 % of cases.21,22 Notably, the use of a corticosteroid upon PSA progression frequently led to subsequent secondary PSA declines, suggesting a reduction in


EUROPEAN UROLOGICAL REVIEW


the promiscuous androgen receptor (AR) activation by upstream steroidal precursors that are increased by feedback mechanisms.


To conclusively evaluate the efficacy and safety of abiraterone, a pivotal multicentre placebo-controlled blinded randomised Phase III trial (Abiraterone acetate in castration-resistant prostate cancer previously treated with docetaxel-based chemotherapy; COU-AA-301) was conducted in men with docetaxel-pre-treated ketoconazole-naïve metastatic CRPC.23


Figure 2: The Androgen Signalling Axis in Castration-resistant Prostate Cancer


Adrenal gland


A


Abiraterone, Orteronel


AR HSP HSP A AR MDV3100 A CoAct AR Transcription


A = androgen; AR = androgen receptor; CoAct = transcriptional co-activators; CRPC = castration-resistant prostate cancer; HSP = heat shock protein.


Table 3: Comparison of the Two Pivotal Second-line Trials for Men with Metastatic Castration-resistant Prostate Cancer – COU-AA-301 Versus Treatment of Hormone-refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-containing Regimen


Cabazitaxel/Prednisone Abiraterone/Prednisone (TROPIC)


Median baseline PSA 144 ng/ml Pain at baseline


46 %


Presence of visceral 25 % disease


Two (or more) prior 31 %


chemotherapies Median overall survival


Median time to 15.1 months 8.8 months


tumour progression Median time to PSA 6.4 months progression


PSA response rate 39 %


(≥50 % PSA decline) Objective response rate 14 % Pain response


9 %


(COU-AA-301) 129 ng/ml


44 % 29 %


30 % 14.8 months 5.6 months 10.2 months 29 %


14 % 44 %


PSA = prostate-specific antigen; COU-AA-301 = Abiraterone Acetate in Castration-Resistant Prostate Cancer Previously Treated With Docetaxel-Based Chemotherapy; TROPIC = Treatment of Hormone-refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-containing Regimen.


This trial randomised men (2:1) to receive either abiraterone 1,000 mg daily plus prednisone 10 mg daily (n=797) or placebo plus prednisone (n=398). The trial met its primary end-point, demonstrating a median overall survival of 14.8 months in the abiraterone arm and 10.9 months in the placebo arm (hazard ratio


93


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