Management of Castration-Resistant Prostate Cancer
Management of Castration-Resistant Prostate Cancer
The four treatments approved for use in patients with CRPC include docetaxel plus prednisone, cabazitaxel, abiraterone acetate and sipuleucel-T. This section will review the findings of landmark studies that led to FDA approval of each agent and highlight some of the advantages and adverse effects of each modality (Table 1).
Prior to 2004, treatment for CRPC was typically palliative, with an expected survival of 6–12 months. The only chemotherapy regimen used in patients with CRPC was mitoxantrone plus prednisone. This regimen improved the quality of life but did not provide a survival benefit. In 2004, two landmark randomized-controlled trials demonstrated that treating patients with docetaxel-based chemotherapy (an inhibitor of microtubule depolymerization) provided a survival benefit for these patients. The TAX 327 study found that men given docetaxel and prednisone (D/P) lived a median of 2.4 months longer and reported improved pain control and better quality of life compared with patients treated with mitoxantrone and prednisone. The SWOG-9916 trial obtained similar results with a slightly different regimen of docetaxel and estramustine. Common toxicities reported by at least 15% of patients on docetaxel included alopecia, diarrhea, peripheral neuropathy, peripheral edema and dyspnea. In summary, these two large studies disproved the notion than CRPC was refractory to chemotherapy and led to the approval of the D/P combination as the first-line treatment for patients with CRPC.
In 2007, Armstrong et al. designed a prognostic model using baseline variables from subjects of the TAX 327 study to predict death among men with metastatic CRPC. The model utilizes ten variables of the patient's cancer parameters, various markers, and quality of life to allow the clinician to make an estimate of the patient's survival duration. This model is useful in making clinical prognostications and providing patients more personalized statistics. It may also prove useful in considering additional approved or experimental therapies at earlier points during docetaxel treatment.
Cabazitaxel (Jevtana®, Sanofi-Aventis, NJ, USA) is a potent inhibitor of microtubule depolymerization that, unlike docetaxel, is resistant to P-glycoprotein, an ATP-dependent drug efflux pump that can sometimes be expressed by cancer cells. Preclinical and clinical trials revealed that cabazitaxel demonstrated activity in patients with known docetaxel-resistant CRPC. The TROPIC (a Phase III) trial compared cabazitaxel with mitoxantrone in 735 men with CRPC whose cancer had progressed despite having been previously treated with docetaxel-based chemotherapy. The median survival time was 2.4 months greater for the patients treated with cabazitaxel compared with those given mitoxantrone. Cabazitaxel usage also resulted in higher rates of PSA reduction and tumor response compared with mitoxantrone. However, compared with patients given mitoxantrone, those given cabazitaxel had a higher risk of death within 30 days of the last dose of the drug, which was attributable to neutropenia, a side effect seen in 94% of patients receiving cabazitaxel (82% of cases were grade 3 or higher). Therefore, any patient given this agent should be monitored appropriately, especially men at high risk for neutropenic complications. Other common side effects include diarrhea (47%), fatigue (37%) and nausea (34%). In June 2010, cabazitaxel was the first chemotherapy drug approved by the FDA for use in patients with metastatic CRPC refractory to docetaxel-based chemotherapy. An additional Phase III trial will evaluate cabazitaxel versus docetaxel as a first-line treatment for metastatic CRPC.
Abiraterone acetate (AA; Zytiga®, Janssen Biotech, PA, USA)) and its metabolite, abiraterone, are highly selective, potent irreversible inhibitors of CYP17A1 enzymes 17α-hydroxylase (an unintended target of the drug; an enzyme that plays no role in inhibiting cancer cell proliferation but is necessary for cortisol production) and C17,20-lyase (the desired target of the drug; necessary for production of androgens that enable prostate cancer cell proliferation). It has a similar mechanism of action to ketoconazole but is approximately ten times more potent. Ketoconazole is a drug that has demonstrated anti-tumor activity and was used to treat CRPC for over 30 years, but was withdrawn from clinical use because of its short half-life and side effects secondary to its nonselectivity.
A recent Phase III trial of post-docetaxel CRPC patients found that patients subsequently treated with AA experienced a greater overall survival of 3.9 months compared with those receiving placebo. All secondary end points, including progression-free survival and PSA response rate (defined as the proportion of patients with a decrease ≥50% from pretreatment) favored the treatment group as well. Since the results at interim analysis exceeded pre-planned criteria for study termination, the study was terminated early and patients in the placebo group were offered AA if they met appropriate criteria. The most common adverse events, which were primarily grade 1 and 2 events, included back pain (30%), nausea (30%), constipation (26%), bone pain (25%) and arthralgias (27%). Additionally, adverse events associated with 17α-hydroxylase blockade included those of mineralocorticoid excess (edema, hypokalemia and hypertension), cardiac disorders and liver function test abnormalities. Grade ≥3 side effects experienced by patients were minimal in Phase II and III trials of the agent, and the most common adverse events, fatigue and anemia, occurred less than 10% of the time. AA was approved by the FDA for use in post-docetaxel CRPC in April 2011.
The success of an oral agent in this patient population has led many to question whether it could successfully be used prior to the use of chemotherapy. COU-AA-302 is an ongoing Phase III trial seeking to determine the efficacy of AA in treating chemotherapy-naive patients with advanced prostate cancer. Experimental therapies TAK-700 and VT-464 have higher affinities for C17,20-lyase than 17α-hydroxylase compared with AA, and early clinical data suggest they may have greater efficacy with a more tolerable side effect profile than AA.
Sipuleucel-T (Provenge®, Dendreon Corporation, WA, USA) was the first autologous immunotherapy approved for any cancer. It is an active cellular immunotherapy: a type of therapeutic cancer vaccine designed to stimulate T-cell immunity against prostatic acid phosphatase, an antigen expressed on the surface of prostate cancer tumor cells.
Integrated data from the first two randomized, placebo-controlled Phase III clinical trials of sipuleucel-T given to patients with advanced prostate cancer found that the median time for survival for patients on the drug improved by 4.3 months compared with patients on placebo (p = 0.11; CI: 1.10–2.05). There was no significant difference in time to progression for patients on sipuleucel-T (11.1 weeks) versus placebo (9.7). Despite this, the investigators concluded that sipuleucel-T imbued a survival advantage to patients with metastatic CRPC. These favorable results led to the FDA approval of sipuleucel-T to treat asymptomatic or minimally symptomatic metastatic CRPC.
The most recent Phase III trial obtained similar statistically significant results: patients receiving sipuleucel-T lived 4.1 months longer than patients on placebo (25.4 vs 21.7 months), with no difference in time to progression between experimental and placebo arms of the study (14.6 vs 14.4 weeks). Most side effects of the drug occurred within 1 day of infusion and typically resolved within 1–2 days. They included chills (51.2%), fever (22.5%), fatigue (16.0%), nausea (14.2%) and headache (10.2%). These side effects are more tolerable than those experienced by patients given the alternative traditional cytotoxic chemotherapy regimen, which include nausea, vomiting, diarrhea, fatigue, alopecia, myelosuppression and peripheral neuropathy.
Approved Treatments for CRPC
The four treatments approved for use in patients with CRPC include docetaxel plus prednisone, cabazitaxel, abiraterone acetate and sipuleucel-T. This section will review the findings of landmark studies that led to FDA approval of each agent and highlight some of the advantages and adverse effects of each modality (Table 1).
Docetaxel Plus Prednisone
Prior to 2004, treatment for CRPC was typically palliative, with an expected survival of 6–12 months. The only chemotherapy regimen used in patients with CRPC was mitoxantrone plus prednisone. This regimen improved the quality of life but did not provide a survival benefit. In 2004, two landmark randomized-controlled trials demonstrated that treating patients with docetaxel-based chemotherapy (an inhibitor of microtubule depolymerization) provided a survival benefit for these patients. The TAX 327 study found that men given docetaxel and prednisone (D/P) lived a median of 2.4 months longer and reported improved pain control and better quality of life compared with patients treated with mitoxantrone and prednisone. The SWOG-9916 trial obtained similar results with a slightly different regimen of docetaxel and estramustine. Common toxicities reported by at least 15% of patients on docetaxel included alopecia, diarrhea, peripheral neuropathy, peripheral edema and dyspnea. In summary, these two large studies disproved the notion than CRPC was refractory to chemotherapy and led to the approval of the D/P combination as the first-line treatment for patients with CRPC.
In 2007, Armstrong et al. designed a prognostic model using baseline variables from subjects of the TAX 327 study to predict death among men with metastatic CRPC. The model utilizes ten variables of the patient's cancer parameters, various markers, and quality of life to allow the clinician to make an estimate of the patient's survival duration. This model is useful in making clinical prognostications and providing patients more personalized statistics. It may also prove useful in considering additional approved or experimental therapies at earlier points during docetaxel treatment.
Cabazitaxel
Cabazitaxel (Jevtana®, Sanofi-Aventis, NJ, USA) is a potent inhibitor of microtubule depolymerization that, unlike docetaxel, is resistant to P-glycoprotein, an ATP-dependent drug efflux pump that can sometimes be expressed by cancer cells. Preclinical and clinical trials revealed that cabazitaxel demonstrated activity in patients with known docetaxel-resistant CRPC. The TROPIC (a Phase III) trial compared cabazitaxel with mitoxantrone in 735 men with CRPC whose cancer had progressed despite having been previously treated with docetaxel-based chemotherapy. The median survival time was 2.4 months greater for the patients treated with cabazitaxel compared with those given mitoxantrone. Cabazitaxel usage also resulted in higher rates of PSA reduction and tumor response compared with mitoxantrone. However, compared with patients given mitoxantrone, those given cabazitaxel had a higher risk of death within 30 days of the last dose of the drug, which was attributable to neutropenia, a side effect seen in 94% of patients receiving cabazitaxel (82% of cases were grade 3 or higher). Therefore, any patient given this agent should be monitored appropriately, especially men at high risk for neutropenic complications. Other common side effects include diarrhea (47%), fatigue (37%) and nausea (34%). In June 2010, cabazitaxel was the first chemotherapy drug approved by the FDA for use in patients with metastatic CRPC refractory to docetaxel-based chemotherapy. An additional Phase III trial will evaluate cabazitaxel versus docetaxel as a first-line treatment for metastatic CRPC.
Abiraterone Acetate
Abiraterone acetate (AA; Zytiga®, Janssen Biotech, PA, USA)) and its metabolite, abiraterone, are highly selective, potent irreversible inhibitors of CYP17A1 enzymes 17α-hydroxylase (an unintended target of the drug; an enzyme that plays no role in inhibiting cancer cell proliferation but is necessary for cortisol production) and C17,20-lyase (the desired target of the drug; necessary for production of androgens that enable prostate cancer cell proliferation). It has a similar mechanism of action to ketoconazole but is approximately ten times more potent. Ketoconazole is a drug that has demonstrated anti-tumor activity and was used to treat CRPC for over 30 years, but was withdrawn from clinical use because of its short half-life and side effects secondary to its nonselectivity.
A recent Phase III trial of post-docetaxel CRPC patients found that patients subsequently treated with AA experienced a greater overall survival of 3.9 months compared with those receiving placebo. All secondary end points, including progression-free survival and PSA response rate (defined as the proportion of patients with a decrease ≥50% from pretreatment) favored the treatment group as well. Since the results at interim analysis exceeded pre-planned criteria for study termination, the study was terminated early and patients in the placebo group were offered AA if they met appropriate criteria. The most common adverse events, which were primarily grade 1 and 2 events, included back pain (30%), nausea (30%), constipation (26%), bone pain (25%) and arthralgias (27%). Additionally, adverse events associated with 17α-hydroxylase blockade included those of mineralocorticoid excess (edema, hypokalemia and hypertension), cardiac disorders and liver function test abnormalities. Grade ≥3 side effects experienced by patients were minimal in Phase II and III trials of the agent, and the most common adverse events, fatigue and anemia, occurred less than 10% of the time. AA was approved by the FDA for use in post-docetaxel CRPC in April 2011.
The success of an oral agent in this patient population has led many to question whether it could successfully be used prior to the use of chemotherapy. COU-AA-302 is an ongoing Phase III trial seeking to determine the efficacy of AA in treating chemotherapy-naive patients with advanced prostate cancer. Experimental therapies TAK-700 and VT-464 have higher affinities for C17,20-lyase than 17α-hydroxylase compared with AA, and early clinical data suggest they may have greater efficacy with a more tolerable side effect profile than AA.
Sipuleucel-T
Sipuleucel-T (Provenge®, Dendreon Corporation, WA, USA) was the first autologous immunotherapy approved for any cancer. It is an active cellular immunotherapy: a type of therapeutic cancer vaccine designed to stimulate T-cell immunity against prostatic acid phosphatase, an antigen expressed on the surface of prostate cancer tumor cells.
Integrated data from the first two randomized, placebo-controlled Phase III clinical trials of sipuleucel-T given to patients with advanced prostate cancer found that the median time for survival for patients on the drug improved by 4.3 months compared with patients on placebo (p = 0.11; CI: 1.10–2.05). There was no significant difference in time to progression for patients on sipuleucel-T (11.1 weeks) versus placebo (9.7). Despite this, the investigators concluded that sipuleucel-T imbued a survival advantage to patients with metastatic CRPC. These favorable results led to the FDA approval of sipuleucel-T to treat asymptomatic or minimally symptomatic metastatic CRPC.
The most recent Phase III trial obtained similar statistically significant results: patients receiving sipuleucel-T lived 4.1 months longer than patients on placebo (25.4 vs 21.7 months), with no difference in time to progression between experimental and placebo arms of the study (14.6 vs 14.4 weeks). Most side effects of the drug occurred within 1 day of infusion and typically resolved within 1–2 days. They included chills (51.2%), fever (22.5%), fatigue (16.0%), nausea (14.2%) and headache (10.2%). These side effects are more tolerable than those experienced by patients given the alternative traditional cytotoxic chemotherapy regimen, which include nausea, vomiting, diarrhea, fatigue, alopecia, myelosuppression and peripheral neuropathy.
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