Metastatic Castration-resistant Prostate Cancer
Metastatic Castration-resistant Prostate Cancer
The role of castration as a therapeutic approach in prostate cancer has been well established since the initial observation by Huggins. Castration could be curative in localized disease in combination with radiation therapy but, unfortunately, this approach is not curative in metastatic disease; in this setting, resistance inevitably arises. However, a conceptual shift in the understanding of prostate cancer has recently occurred, as it has become clear that castration resistance does not necessarily imply resistance to hormonal manipulations and many CRPCs remain dependent on androgen receptor (AR)-mediated signaling and the activation of downstream genes.
Evidence has been accumulated showing that circulating and intraprostatic androgen levels remain significantly higher despite the dramatic reduction of serum testosterone. This indicates that recurrence is not always and invariably due to true androgen independence, but rather to functional adaptation that allows for continued response under low levels of circulating androgens. Several mechanisms have been identified in order to explain this phenomenon, including AR gene mutations, AR splice variant expression, AR gene overexpression, increased expression of proteins acting as transcriptional coactivators and upregulation of the enzymes involved in androgen synthesis, namely CYP17 α-hydroxylase and C17–20-lyase (CYP17). Therefore, despite castration levels of androgen, in CRPC, the AR signalling pathway remains active. Several pathways are thought to be involved in castrate-resistant phenotype pathogenesis, and each of these pathways are potential targets for new drugs. Consequently, new agents have been developed in order to interfere with the AR pathway or to inhibit CYP17 in order to potently block androgen synthesis (Table 1).
Abiraterone is a pregnenolone-derived 3-pyridyl steroidal agent that selectively and irreversibly inhibits the CYP17A1 microsomal enzyme, encoded by the CYP17A1 gene, which has two distinct activating properties: one is its 17-α-hydroxylase property, which catalyzes the 17-α-hydroxylation of C21 steroids that are necessary for the synthesis of cortisol in the adrenal gland, and the other is its 17,20-lyase property, which catalyzes the scission of the C17–21 bond, converting C21 compounds to C19 steroids in the sex steroid synthesis pathway in the both adrenal gland and the testis.
CYP17A1 inhibition blocks two critical steps in testosterone biosynthesis: the conversion of pregnenolone to 17-OH-pregnenolone and the conversion of 17-OH-pregnenolone to dehydroepiandrosterone. Inhibition of CYP17 also results in deficient cortisol synthesis and, consequently, in the upregulation of the hypothalamic–pituitary–adrenal pathway with elevated levels of adrenocorticotropic hormone. This leads to an increase in the steroid levels upstream of the CYP17A1 block, including corticosterone and deoxycorticosterone. This metabolic condition stimulates both the glucocorticoid and the mineralocorticoid receptor, and their excess prevents adrenocortical insufficiency. However, this secondary effect also generates a syndrome of secondary mineralocorticoid excess characterized by fluid retention, hypertension and hypokalemia, which often requires intervention. In order to prevent this side effect, abiraterone is usually administered together with prednisone.
Abiraterone was investigated in Phase I/II study in chemotherapy-naive CRPC patients: in this trial, a decline in PSA of ≥50% was observed in 67% of patients, a radiological partial response was observed in 37.5% of patients and decreases in circulating tumor cell (CTC) counts were also documented.
Two Phase II studies were conducted in docetaxel-pretreated patients. In one of these studies, among 47 patients treated with abiraterone 1 g daily alone or with prednisone, PSA reductions of ≥30, ≥50 and ≥90% were found in 32 (68%), 24 (51%) and seven patients (15%) patients, respectively. Among the 30 patients evaluable by Response Evaluation Criteria In Solid Tumors (RECIST), eight (27%) had a partial response. The other study enrolled 58 patients, including 27 patients with known previous ketoconazole exposure: 36% of the patients had a 50% decline in PSA levels, and the median time to PSA progression was 169 days (95% CI: 82–200 days).
Subsequently, in a large, randomized, double-blind Phase III trial (COU-AA-301) using a 2:1 randomization, 1195 docetaxel-refractory CRPC patients received either abiraterone 1 g/daily or placebo; both arms received prednisone 5 mg twice daily. The study was unblinded at the time of the first interim analysis because of an OS improvement of 3.9 months favoring abiraterone (14.8 vs 10.9 months; hazard ratio [HR]: 0.646; 95% CI: 0.54–0.77; p < 0.001). An updated OS analysis conducted before crossover showed a median OS improvement of 4.6 months (HR: 0.74; 95% CI: 0.64–0.86; p < 0.0001). Abiraterone also improved time to PSA progression (8.5 vs 6.6 months; p < 0.0001), radiographic PFS (rPFS; 5.6 vs 3.6 months; p < 0.0001), with 50% PSA declines (confirmed: 29.5 vs 5.5%; p < 0.0001).
In the prechemotherapy setting, a large Phase III trial (COU-AA-302) randomized almost 1000 patients with asymptomatic or minimally symptomatic CRPC to either abiraterone and prednisone or prednisone alone; the coprimary end points were rPFS and OS. Abiraterone significantly improved rPFS (16.5 vs 8.2 months; HR: 0.52; 95% CI: 0.45–0.61; p < 0.0001). The OS analysis favored the abiraterone arm over prednisone (median: 35.3 vs 30.1 months; HR: 0.79; p = 0.0151), but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). Abiraterone also delayed the time to the initiation of chemotherapy, opiate need for cancer pain, PSA progression and declines in performance status.
Based on these data, the FDA and EMA approved abiraterone for the management of both docetaxel-naive and -pretreated patients.
Orteronel (TAK-700) is a CYP17 inhibitor with relative selectivity for 17,20-lyase over 17-α-hydroxylase. This selectivity improves the drug safety profile when compared with agents inhibiting both enzymes in testosterone synthesis. TAK-700 has fewer mineralcorticoid effects than abiraterone, and therefore, the coadministration of prednisone may be unnecessary, making orteronel an attractive drug for long-term therapy.
In a Phase I/II open-label study in patients with mCRPC, TAK-700 lowered PSA levels and testosterone and dehydroepiandrosterone levels in all patients treated with doses of at least 300 mg twice daily. At a dose of orteronel 400 mg with prednisone 5 mg, both twice daily, 54% of 84 evaluable patients experienced a PSA reduction of 50% or more at 12 weeks. Two ongoing randomized, placebo-controlled Phase III trials are evaluating orteronel in patients with progressive CRPC who are either chemotherapy naive (NCT01193244) or pretreated with docetaxel (NCT01193257). The latter study was recently unblinded and terminated at the interim analysis because orteronel plus prednisone did not meet the primary end point of improved OS when compared with placebo (HR: 0.886; p = 0.1898); nevertheless, an improvement in rPFS (HR: 0.76; p = 0.00038) was observed. In a post hoc subset analysis, substantial regional differences were seen in terms of OS benefit, with a reduction in risk of death of 30% only in non-US, non-European countries (HR: 0.709).
Galeterone (TOK-001) inhibits androgen biosynthesis by inhibiting CYP17. Interestingly, the biological activity of this molecule varies according to its concentration: at low concentrations, it inhibits CYP17A1 activity; at moderate concentrations, it acts as an AR antagonist; and at high concentrations, it induces AR degradation. Data from the Phase II ARMOR2 trial in 25 progressive CRPC patients confirmed safety and efficacy compared with the Phase I ARMOR1 trial; at a maximum of a 3.4-mg/day dose, 54% of patients experienced a >50% PSA decline.
New-generation Hormonal Therapies
The role of castration as a therapeutic approach in prostate cancer has been well established since the initial observation by Huggins. Castration could be curative in localized disease in combination with radiation therapy but, unfortunately, this approach is not curative in metastatic disease; in this setting, resistance inevitably arises. However, a conceptual shift in the understanding of prostate cancer has recently occurred, as it has become clear that castration resistance does not necessarily imply resistance to hormonal manipulations and many CRPCs remain dependent on androgen receptor (AR)-mediated signaling and the activation of downstream genes.
Evidence has been accumulated showing that circulating and intraprostatic androgen levels remain significantly higher despite the dramatic reduction of serum testosterone. This indicates that recurrence is not always and invariably due to true androgen independence, but rather to functional adaptation that allows for continued response under low levels of circulating androgens. Several mechanisms have been identified in order to explain this phenomenon, including AR gene mutations, AR splice variant expression, AR gene overexpression, increased expression of proteins acting as transcriptional coactivators and upregulation of the enzymes involved in androgen synthesis, namely CYP17 α-hydroxylase and C17–20-lyase (CYP17). Therefore, despite castration levels of androgen, in CRPC, the AR signalling pathway remains active. Several pathways are thought to be involved in castrate-resistant phenotype pathogenesis, and each of these pathways are potential targets for new drugs. Consequently, new agents have been developed in order to interfere with the AR pathway or to inhibit CYP17 in order to potently block androgen synthesis (Table 1).
Abiraterone
Abiraterone is a pregnenolone-derived 3-pyridyl steroidal agent that selectively and irreversibly inhibits the CYP17A1 microsomal enzyme, encoded by the CYP17A1 gene, which has two distinct activating properties: one is its 17-α-hydroxylase property, which catalyzes the 17-α-hydroxylation of C21 steroids that are necessary for the synthesis of cortisol in the adrenal gland, and the other is its 17,20-lyase property, which catalyzes the scission of the C17–21 bond, converting C21 compounds to C19 steroids in the sex steroid synthesis pathway in the both adrenal gland and the testis.
CYP17A1 inhibition blocks two critical steps in testosterone biosynthesis: the conversion of pregnenolone to 17-OH-pregnenolone and the conversion of 17-OH-pregnenolone to dehydroepiandrosterone. Inhibition of CYP17 also results in deficient cortisol synthesis and, consequently, in the upregulation of the hypothalamic–pituitary–adrenal pathway with elevated levels of adrenocorticotropic hormone. This leads to an increase in the steroid levels upstream of the CYP17A1 block, including corticosterone and deoxycorticosterone. This metabolic condition stimulates both the glucocorticoid and the mineralocorticoid receptor, and their excess prevents adrenocortical insufficiency. However, this secondary effect also generates a syndrome of secondary mineralocorticoid excess characterized by fluid retention, hypertension and hypokalemia, which often requires intervention. In order to prevent this side effect, abiraterone is usually administered together with prednisone.
Abiraterone was investigated in Phase I/II study in chemotherapy-naive CRPC patients: in this trial, a decline in PSA of ≥50% was observed in 67% of patients, a radiological partial response was observed in 37.5% of patients and decreases in circulating tumor cell (CTC) counts were also documented.
Two Phase II studies were conducted in docetaxel-pretreated patients. In one of these studies, among 47 patients treated with abiraterone 1 g daily alone or with prednisone, PSA reductions of ≥30, ≥50 and ≥90% were found in 32 (68%), 24 (51%) and seven patients (15%) patients, respectively. Among the 30 patients evaluable by Response Evaluation Criteria In Solid Tumors (RECIST), eight (27%) had a partial response. The other study enrolled 58 patients, including 27 patients with known previous ketoconazole exposure: 36% of the patients had a 50% decline in PSA levels, and the median time to PSA progression was 169 days (95% CI: 82–200 days).
Subsequently, in a large, randomized, double-blind Phase III trial (COU-AA-301) using a 2:1 randomization, 1195 docetaxel-refractory CRPC patients received either abiraterone 1 g/daily or placebo; both arms received prednisone 5 mg twice daily. The study was unblinded at the time of the first interim analysis because of an OS improvement of 3.9 months favoring abiraterone (14.8 vs 10.9 months; hazard ratio [HR]: 0.646; 95% CI: 0.54–0.77; p < 0.001). An updated OS analysis conducted before crossover showed a median OS improvement of 4.6 months (HR: 0.74; 95% CI: 0.64–0.86; p < 0.0001). Abiraterone also improved time to PSA progression (8.5 vs 6.6 months; p < 0.0001), radiographic PFS (rPFS; 5.6 vs 3.6 months; p < 0.0001), with 50% PSA declines (confirmed: 29.5 vs 5.5%; p < 0.0001).
In the prechemotherapy setting, a large Phase III trial (COU-AA-302) randomized almost 1000 patients with asymptomatic or minimally symptomatic CRPC to either abiraterone and prednisone or prednisone alone; the coprimary end points were rPFS and OS. Abiraterone significantly improved rPFS (16.5 vs 8.2 months; HR: 0.52; 95% CI: 0.45–0.61; p < 0.0001). The OS analysis favored the abiraterone arm over prednisone (median: 35.3 vs 30.1 months; HR: 0.79; p = 0.0151), but did not reach the prespecified statistical efficacy boundary (α-level: 0.0035). Abiraterone also delayed the time to the initiation of chemotherapy, opiate need for cancer pain, PSA progression and declines in performance status.
Based on these data, the FDA and EMA approved abiraterone for the management of both docetaxel-naive and -pretreated patients.
Orteronel
Orteronel (TAK-700) is a CYP17 inhibitor with relative selectivity for 17,20-lyase over 17-α-hydroxylase. This selectivity improves the drug safety profile when compared with agents inhibiting both enzymes in testosterone synthesis. TAK-700 has fewer mineralcorticoid effects than abiraterone, and therefore, the coadministration of prednisone may be unnecessary, making orteronel an attractive drug for long-term therapy.
In a Phase I/II open-label study in patients with mCRPC, TAK-700 lowered PSA levels and testosterone and dehydroepiandrosterone levels in all patients treated with doses of at least 300 mg twice daily. At a dose of orteronel 400 mg with prednisone 5 mg, both twice daily, 54% of 84 evaluable patients experienced a PSA reduction of 50% or more at 12 weeks. Two ongoing randomized, placebo-controlled Phase III trials are evaluating orteronel in patients with progressive CRPC who are either chemotherapy naive (NCT01193244) or pretreated with docetaxel (NCT01193257). The latter study was recently unblinded and terminated at the interim analysis because orteronel plus prednisone did not meet the primary end point of improved OS when compared with placebo (HR: 0.886; p = 0.1898); nevertheless, an improvement in rPFS (HR: 0.76; p = 0.00038) was observed. In a post hoc subset analysis, substantial regional differences were seen in terms of OS benefit, with a reduction in risk of death of 30% only in non-US, non-European countries (HR: 0.709).
Galeterone
Galeterone (TOK-001) inhibits androgen biosynthesis by inhibiting CYP17. Interestingly, the biological activity of this molecule varies according to its concentration: at low concentrations, it inhibits CYP17A1 activity; at moderate concentrations, it acts as an AR antagonist; and at high concentrations, it induces AR degradation. Data from the Phase II ARMOR2 trial in 25 progressive CRPC patients confirmed safety and efficacy compared with the Phase I ARMOR1 trial; at a maximum of a 3.4-mg/day dose, 54% of patients experienced a >50% PSA decline.
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