| In vitro: |
| Ann Oncol. 2013 Jul;24(7):1807-12. | | Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer progressing after docetaxel and enzalutamide (MDV3100).[Pubmed: 23576708 ] | Androgen receptor (AR) signalling remains critically important in metastatic castration-resistant prostate cancer (mCRPC) as confirmed by recent phase III trials, showing a survival advantage for
Abiraterone Acetate and enzalutamide (MDV3100). The antitumour activity of abiraterone and prednisolone in patients pre-treated with enzalutamide is as yet unknown.
METHODS AND RESULTS:
We investigated the antitumour activity of abiraterone and prednisolone in patients with mCRPC who had progressed following treatment with docetaxel (Taxotere) and enzalutamide. Clinical data were retrospectively analysed for prostate-specific antigen (PSA) and RECIST responses, clinical benefit and survival.
Thirty-eight patients were included in the analysis. The median age was 71 years (range 52-84); metastatic sites included bone disease in 37 patients (97%), lymph nodes in 15 patients (39%) and visceral disease in 10 patients (26%). Abiraterone was well tolerated. Three patients (8%) attained a PSA response, defined as ≥50% decline in PSA confirmed after ≥4 weeks, while seven patients (18%) had a ≥30% PSA decline. The median progression-free survival (PFS) was 2.7 months (95% CI 2.3-4.1). Of the 12 patients assessable radiologically, only 1 (8%) attained a confirmed partial response.
CONCLUSIONS:
Abiraterone and prednisolone have modest antitumour activities in patients with mCRPC pretreated with docetaxel and enzalutamide. |
|
| In vivo: |
| J Clin Oncol. 2009 Aug 10;27(23):3742-8. | | Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer.[Pubmed: 19470933] | It has been postulated that castration-resistant prostate cancer (CRPC) commonly remains hormone dependent. Abiraterone acetate is a potent, selective, and orally available inhibitor of CYP17, the key enzyme in androgen and estrogen biosynthesis.
METHODS AND RESULTS:
This was a phase I/II study of Abiraterone Acetate in castrate, chemotherapy-naive CRPC patients (n = 54) with phase II expansion at 1,000 mg (n = 42) using a two-stage design to reject the null hypothesis if more than seven patients had a prostate-specific antigen (PSA) decline of > or = 50% (null hypothesis = 0.1; alternative hypothesis = 0.3; alpha = .05; beta = .14). Computed tomography scans every 12 weeks and circulating tumor cell (CTC) enumeration were performed. Prospective reversal of resistance at progression by adding dexamethasone 0.5 mg/d to suppress adrenocorticotropic hormone and upstream steroids was pursued.
A decline in PSA of > or = 50% was observed in 28 (67%) of 42 phase II patients, and declines of > or = 90% were observed in eight (19%) of 42 patients. Independent radiologic evaluation reported partial responses (Response Evaluation Criteria in Solid Tumors) in nine (37.5%) of 24 phase II patients with measurable disease. Decreases in CTC counts were also documented. The median time to PSA progression (TTPP) on abiraterone acetate alone for all phase II patients was 225 days (95% CI, 162 to 287 days). Exploratory analyses were performed on all 54 phase I/II patients; the addition of dexamethasone at disease progression reversed resistance in 33% of patients regardless of prior treatment with dexamethasone, and pretreatment serum androgen and estradiol levels were associated with a probability of > or = 50% PSA decline and TTPP on Abiraterone Acetate and dexamethasone.
CONCLUSIONS:
CYP17 blockade by Abiraterone Acetate results in declines in PSA and CTC counts and radiologic responses, confirming that CRPC commonly remains hormone driven. | | Lancet Oncol. 2012 Oct;13(10):983-92. | | Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study.[Pubmed: 22995653 ] |
Abiraterone Acetate improved overall survival in metastatic castration-resistant prostate cancer at a preplanned interim analysis of the COU-AA-301 double-blind, placebo-controlled phase 3 study.
METHODS AND RESULTS:
Here, we present the final analysis of the study before crossover from placebo to Abiraterone Acetate (after 775 of the prespecified 797 death events).Of the 1195 eligible patients, 797 were randomly assigned to receive Abiraterone Acetate plus prednisone (abiraterone group) and 398 to receive placebo plus prednisone (placebo group). At median follow-up of 20·2 months (IQR 18·4-22·1), median overall survival for the abiraterone group was longer than in the placebo group (15·8 months [95% CI 14·8-17·0] vs 11·2 months [10·4-13·1]; hazard ratio [HR] 0·74, 95% CI 0·64-0·86; p<0·0001). Median time to PSA progression (8·5 months, 95% CI 8·3-11·1, in the abiraterone group vs 6·6 months, 5·6-8·3, in the placebo group; HR 0·63, 0·52-0·78; p<0·0001), median radiologic progression-free survival (5·6 months, 5·6-6·5, vs 3·6 months, 2·9-5·5; HR 0·66, 0·58-0·76; p<0·0001), and proportion of patients who had a PSA response (235 [29·5%] of 797 patients vs 22 [5·5%] of 398; p<0·0001) were all improved in the abiraterone group compared with the placebo group. The most common grade 3-4 adverse events were fatigue (72 [9%] of 791 patients in the abiraterone group vs 41 [10%] of 394 in the placebo group), anaemia (62 [8%] vs 32 [8%]), back pain (56 [7%] vs 40 [10%]), and bone pain (51 [6%] vs 31 [8%]).
CONCLUSIONS:
This final analysis confirms that Abiraterone Acetate significantly prolongs overall survival in patients with metastatic castration-resistant prostate cancer who have progressed after docetaxel treatment. No new safety signals were identified with increased follow-up. | | J Clin Oncol. 2012 Feb 20;30(6):637-43. | | Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone.[Pubmed: 22184395 ] | Persistent androgen signaling is implicated in castrate-resistant prostate cancer (CRPC) progression. This study aimed to evaluate androgen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow and to correlate with clinical observations.
METHODS AND RESULTS:
This was an open-label, observational study of 57 patients with bone-metastatic CRPC who underwent transiliac bone marrow biopsy between October 2007 and March 2010. Patients received oral Abiraterone Acetate (1 g) once daily and prednisone (5 mg) twice daily. Androgen receptor (AR) and CYP17 expression were assessed by immunohistochemistry, testosterone concentration by mass spectrometry, AR copy number by polymerase chain reaction, and TMPRSS2-ERG status by fluorescent in situ hybridization in available tissues.
Median overall survival was 555 days (95% CI, 440 to 965+ days). Maximal prostate-specific antigen decline ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of AR, combined with ≥ 10% CYP17 tumor expression, was correlated with longer time to treatment discontinuation (> 4 months) in 25 patients with tumor-infiltrated bone marrow samples. Pretreatment CYP17 tumor expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression.
CONCLUSIONS:
The observed pretreatment androgen-signaling signature is consistent with persistent androgen signaling in CRPC bone metastases. This is the first evidence that Abiraterone Acetate achieves sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Potential admixture of blood with bone marrow aspirate limits our ability to determine the origin of measured testosterone. |
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