Abiraterone Acetate: a Promising Drug
Abiraterone Acetate: a Promising Drug
Abiraterone acetate (CB7630), a pregnenolone analog, is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosysnthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.
The cornerstone of treatment for advanced prostate cancer is medical castration by androgen deprivation therapy (ADT). Despite initial responses, almost all patients will eventually develop disease progression. Historically, disease progression despite continuous ADT has been defined as hormone-resistant or androgen-independent disease. The current standard of care for such patients with metastatic disease is docetaxel-based chemotherapy. Unfortunately, responses are not durable, and almost all patients will progress with a median survival of approximately 18 months. Second-line chemotherapy is an unmet need, with mitoxantrone chemotherapy yielding modest activity and no proven survival benefits. A large placebo-controlled Phase III trial failed to demonstrate improved survival with satraplatin, a novel orally administered platinum. A recent preliminary report demonstrated enhanced survival with second-line cabazitaxel, a novel taxane, compared with mitoxantrone in the Phase III TROPIC trial. However, a need exists for novel, conveniently administered and tolerable options in this elderly population with generally multiple comorbidities.
Over the last decade, it has been recognized that, despite the failure of ADT, most tumors are still dependent on androgen receptor (AR) signaling for proliferation. Hence, this stage of prostate cancer is not always hormone resistant or androgen independent. The more suitable term is thus castration-resistant prostate cancer (CRPC), since the resistance occurs at castrate androgen levels and not in the complete absence of androgens or androgen signaling. Indeed, many CRPC patients will still respond, in some cases for a number of years, to sequential administration of secondary hormonal manipulations. Herein, we review compounds being developed to abrogate androgen-mediated signaling, with a focus on abiraterone acetate.
Abstract and Introduction
Abstract
Abiraterone acetate (CB7630), a pregnenolone analog, is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosysnthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.
Introduction
The cornerstone of treatment for advanced prostate cancer is medical castration by androgen deprivation therapy (ADT). Despite initial responses, almost all patients will eventually develop disease progression. Historically, disease progression despite continuous ADT has been defined as hormone-resistant or androgen-independent disease. The current standard of care for such patients with metastatic disease is docetaxel-based chemotherapy. Unfortunately, responses are not durable, and almost all patients will progress with a median survival of approximately 18 months. Second-line chemotherapy is an unmet need, with mitoxantrone chemotherapy yielding modest activity and no proven survival benefits. A large placebo-controlled Phase III trial failed to demonstrate improved survival with satraplatin, a novel orally administered platinum. A recent preliminary report demonstrated enhanced survival with second-line cabazitaxel, a novel taxane, compared with mitoxantrone in the Phase III TROPIC trial. However, a need exists for novel, conveniently administered and tolerable options in this elderly population with generally multiple comorbidities.
Over the last decade, it has been recognized that, despite the failure of ADT, most tumors are still dependent on androgen receptor (AR) signaling for proliferation. Hence, this stage of prostate cancer is not always hormone resistant or androgen independent. The more suitable term is thus castration-resistant prostate cancer (CRPC), since the resistance occurs at castrate androgen levels and not in the complete absence of androgens or androgen signaling. Indeed, many CRPC patients will still respond, in some cases for a number of years, to sequential administration of secondary hormonal manipulations. Herein, we review compounds being developed to abrogate androgen-mediated signaling, with a focus on abiraterone acetate.