Just as we have provided a recent update on the future potential of enzalutamide (MDV3100) in the treatment of prostate cancer, the following offers an update on the future potential of abiraterone acetate (Zytiga®).
Abiraterone acetate (in combination with low-dose prednisone) is currently approved in many countries around the world for the treatment of men with metastatic, castration-resistant prostate cancer (mCRPC) who have previously been treated with at least one cycle of docetaxel-based chemotherapy. In addition, the manufacturer has submitted applications to regulatory authorities for approval of abiraterone acetate (again in combination with low-dose prednisone) for the treatment of men with chemotherapy-naïve mCRPC. Approvals for use in this indication might come as early as late this year (but early in 2013 is more likely), and would be based on data reported earlier in 2012 at the annual meeting of the American Society of Clinical Oncology (ASCO).
Two of the critical factors related to the use of abiraterone acetate are: (a) the fact that it currently needs to be given in association with prednisone to minimize the risk for things like hypertension, hypokalemia, and fluid retention that can occur as a result of increased mineralocorticoid levels and (b) that taking abiraterone acetate in association with food can profoundly increase the degree of absorption of the drug (thereby increasing its therapeutic “strength”). If it could be shown that abiraterone acetate could be used with lower doses of prednisone and/or that lower doses of abiraterone acetate could be given if taken in combination with food with similar effects to those seen from the current standard dose that must be taken without food, then the therapeutic safety of the product might be significantly improved, which would have implications for the long-term use of this drug. At present, however, approved clinical use of this drug is limited as follows:
- 1,000 mg (i.e., four 250 mg tablets) should be taken orally, once daily, in combination with prednisone 5 mg administered orally, twice daily (i.e., a total of 10 mg of prednisone a day).
- The drug must be taken on an empty stomach, and no food should be consumed for at least 2 hours before or 1 hour after the dose of abiraterone acetate is actually taken.
The following is a list of the significant clinical trials currently ongoing that may be expected to have some effect on expansion of the clinical indication or actual use of abiraterone acetate in the future:
- A two-part, multi-center, Phase II clinical trial is exploring the potential for efficacy and safety of two experimental agents (GDC-0068 and GDC-0980) in combination with abiraterone acetate + prednisone as compared to abiraterone acetate + prednisone alone in men with mCRPC who have previously been treated with docetaxel-based chemotherapy
- A small Phase I trial being conducted at the Dana Farber Cancer Institute in Boston is investigating the potential combination of abiraterone acetate + prednisone with XL-184 (cabozantinib) in the treatment of men with mCRPC progressing after prior treatment with chemotherapy.
- A randomized, multi-center, Phase II trial is testing the safety and efficacy of abiraterone acetate + prednisone with and without veliparib (ABT-888, a so-called PARP inhibitor) in the treatment of about 150 men with mCRPC. The patients in this trial have been stratified by their gene fusion status.
- A single-center, Phase II study at the National Institutes of Health Clinical Center in the USA has been designed to investigate the efficacy and safety of abiraterone acetate + AMG 386 (an angiogenesis inhibitor) in about 90 men with mCRPC.
- A multi-center, Phase Ib trial has been designed to test the safety of combining abiraterone acetate + prednisone with two new, investigational agents (BEZ235 and BKM120) in the treatment of men with CRPC who have already progressed after initial treatment with abiraterone acetate + prednisone. This trial is not yet recruiting patients.
- A Phase Ib clinical trial in about 30 patients has been set up to assess the safety of administering escalating doses of abiraterone acetate in combination with docetaxel and prednisone in patients with mCRPC.
- A small Phase I trial being conducted in France and in England is exploring the potential for use of the combination of cabazitaxel + abiraterone acetate + prednisone in the treatment of men with mCRPC.
- A randomized, double-blind, placebo-controlled, multi-center, Phase III trial of abiraterone acetate + prednisone vs. a placebo + prednisone is fully enrolled with 1,088 men with asymptomatic or mildly symptomatic, chemotherapy-naïve mCRPC. Data from this study were reported at ASCO this year (as indicated above). The data reported were based on just one of the two endpoints of the study (progression-free survival), but the blinded element of the study has now been stopped and all patients have been given the option to switch to abiraterone therapy, so we will never know the true survival benefit of abiraterone acetate compared to a placebo in this group of patients.
- Abiraterone acetate + prednisone is just one of the many therapies included in the complex, multi-stage, multi-arm, randomized, controlled STAMPEDE trial (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy), which is being coordinated from the United Kingdom, is being carried out in the UK and Switzerland, and is much too complicated to try to explain here!
- Another randomized, double-blind, placebo controlled, multi-center, Phase III study of abiraterone acetate + prednisone is being carried out primarily in Russia and China and is scheduled to enroll 290 patients with chemotherapy-naïve mCRPC. Data from this trial are not expected before some time in 2014.
- A small, observational study of continuous treatment with abiraterone acetate + prednisone is still being carried out in about 60 patients with mCRPC at M. D. Anderson Cancer Center in Houston. This trial — which is fully enrolled — is specifically designed to assess levels of androgens and steroid metabolites in plasma from the bone marrow of these patients. Some data from this trial have already been reported.
- A small trial at the University of California, San Francisco (UCSF) is investigating the therapeutic potential of a high daily dose of abiraterone acetate (i.e., 1,000 mg of abiraterone acetate twice a day) with prednisone in the treatment of selected patients with CRPC who demonstrate an initial reponse to a standard daily dose of abiraterone acetate + prednisone.
- A small, randomized, open-label, Phase II clinical trial in about 60 patients has been designed to test the efficacy and safety of administering abiraterone acetate together with sipuleucel-T (concurrent therapy) or starting 6 weeks after completion of treatment with sipuleucel-T (sequential therapy) in chemotherapy-naïve and chemotherapy-treated men with mCRPC.
- A small, open-label, single-arm, Phase II trial at the Dana Farber Cancer Center in Boston is investigating the use of abiraterone + prednisone + dutasteride in the treatment of men with mCRPC.
- The Southwest Oncology Group (SWOG) is conducting a small, prospective, multi-center, open-label, single-arm, Phase II trial of abiraterone + prednisone in men who have an initial, sub-optimal response to standard androgen deprivation therapy. The primary endpoint of the study is the number of men who have an undetectable PSA after treatment with abiraterone acetate + prednisone.
- The IMAAGEN trial is a prospective, multi-center, open-label, single-arm, Phase II study designed to investigate the clinical response to abiraterone actetate + prednisone among men with non-metastatic, castration-resistant prostate cancer (nmCRPC). Patients will be treated with six cycles of therapy and the clinical endpoint will be the percentage of patients that have a drop in their PSA level of ≥ 50 percent.
- A small, randomized clinical trial being carried out at the M. D. Anderson Cancer Center is investigating the long-term response of men with high-risk, clinical stage T1c or T2 prostate cancer to treatment with either neoadjuvant abirtareone acetate + prednisone + an LHRH antagonist or an LHRH agonist alone followed by radical prostatectomy. This trial is enrolling 66 patients who will be followed for up to 8 years.
- A small, open-label, randomized, multi-center Phase II trial of neoadjuvant abiraterone acetate plus leuprolide acetate and prednisone versus leuprolide acetate alone is being carried out at four centers in the USA among about 60 men with high-risk, localized prostate cancer. All patients go on to receive radical surgery and are evaluated for pathologic outcome. Early data from this study were again reported at the ASCO annual meeting this year (by Taplin et al.).
- Another small, open-label, Phase II study being carried out at the Fred Hutchinson Cancer Research Center and affiliated institutions in Seattle is investigating the potential for use of abiraterone acetate + prednisone + an LHRH agonist used prior to and concurrent with radiation therapy in about 25 men with locally advanced prostate cancer.
- A small, Phase II study being conducted at the University of Chicago has been designed to explore the effects of giving abiraterone acetate to patients with CRPC in a fed or an unfed state.
- A multi-center, open-label, Phase II study among 24 to 28 Canadian patients with mCRPC is assessing the short-term safety of abiraterone acetate + prednisone in men treated in a modified fasted state and after meals of various fat contents.