Abiraterone Acetate (CB7630)
by
Howard Hansen
8/6/08, updated 3/12/2010
Introduction
References 13-16 are
the most recent publications on Abiraterone Acetate.
They have been
published on-line in the Journal of Clinical Oncology. The links to the
abstracts are free, but the papers themselves require a subscription to the
JCO.
A phase II trial
(13) with the results for Abiraterone Acetate use for patients who had prior
taxotere who were HRPC (CRPC). A phase I trial
(14) with clinical activity for Abiraterone Acetate even in patients who had
already had ketoconazole. Reference (15) adds to the above information in
the paper entitled, "Significant and Sustained Antitumor Activity in
Post-Docetaxel, Castration-Resistant Prostate Cancer With the CYP17
Inhibitor Abiraterone Acetate and finally reference (16) is an interesting
editorial with the title, "Castration-Resistant Prostate Cancer—Hormone
Therapy Redux).
Abiraterone acetate is an orally available inhibitor of
17-alpha hydroxylase and C17,20-Lyase, enzymes responsible for adrenal
androgen formation. It is being developed for use in both the second
line hormone therapy and second line chemotherapy settings.
Abiraterone is at least 10-fold more potent
than ketoconazole in vitro. Studies
completed include Phase I/II in chemotherapy-naive patients and phase II in
patients who previously received docetaxel. A trial with patients who had
previously used ketoconazole has also been completed.
The focus of this paper is on the results of the phase I and II clinical
trials. The original phase III trial has closed and a new one started
in the spring of 2009 (no prior chemo, no prior keto.) If the phase III trial proceeds as planned, there is a
potential that this drug will become available in late 2011 or in 2012(a
guess.) With the recent purchase of Cougar Technologies by Johnson and
Johnson we will have to wait and see if there are new developments.
There is a list of references on Abiraterone below. Not all of them
have been used in writing this paper, but are included as an additional
resource for further reading.
Definitions
(see reference 12.)
agonist: an agent that binds to a receptor on
a cell's surface and promotes a specific cellular activity; a drug or
substance that promotes the activity of another drug. Contrast with
antagonist. A typical agonist in hormone therapy are Lupron and Zoladex
which are LHRH analogs that suppress testicular production of testosterone
by binding to the LHRH receptor in the pituitary gland.
antagonist: something that works against something else; an agent
that prevents the activation of a specific cellular function by binding to a
cell's receptors; a drug or substance that blocks or reverses the action of
another drug or chemical. Contrast with agonist.
adrenocorticotropic hormone (ACTH or corticotropin).
A pituitary hormone that stimulates the outer portion of the adrenal glands
to secrete various hormones including cortisol, DHEA and androstenedione.
ligand. An ion, a molecule, a molecular group, a substance or messenger
that binds to another chemical entity at a receptor to form a larger complex
which is then activated.
Strategies for Androgen Receptor Antagonism
- Create better androgen receptor antagonists.
- Target androgen receptor
chaperone proteins, e.g., heat-shock
protein 90 and histone deacetylase
inhibitors (e.g.,
valproic acid, vorinostat).
- Inhibition of hormones that
stimulate androgen receptor
signaling, e.g., abiraterone acetate
-- the present focus of this paper. Said to be similar to the use
of aromatase inhibitors in breast cancer.
Abiraterone
Acetate vs Ketoconazole
A paper by TA Yap et
al(2), includes a comparison of Abiraterone and ketoconazole. Ketoconazole
is an antifungal with weak and nonspecific CYP17 inhibitory properties and
is used "off-label" in prostate cancer as a second-line hormonal therapy. In
the case of ketoconazole, one sees significant decreases in DHEA, DHEA-S,
and androstenedione. When progressive disease develops following a response,
androgen levels become elevated which suggests incomplete target inhibition
and that resistance is due to poor target blockade.
For
Abiraterone Acetate, at disease progression, no rise in steriods downstream
of CYP17 were observed. This indicates durable, irreversible CYP17
inhibition. The suppression of upstream steroids was accomplished by
repressing ACTH through the addition of low-dose dexamethasone (.5mg/day) at
disease progression. The phase I protocol had this included in it and it
effectively reversed abiraterone acetate resistance, resulting in successful
salvage of four of 15 patients, even though some had previously had
progressive disease on the same dose of dexamethasone.
Prior
Ketoconazole in Abiraterone Treated Patients
In the J. Clin
Oncology paper on the phase I results (Attard et al (4)), the patients were
all ketoconazole naive as well as chemotherapy naive. A paper
presented at the
2008 ASCO annual meeting by C. Ryan et al (5) evaluated the response rate of
men who had prior ketoconazole use and then took abiraterone. They indicated
that the mechanism of action of abiraterone is similar to keto -- keto
inhibiting multiple adrenal CYP enzymes including CYP17.
A phase I study,
dose escalation was performed in both fasted and fed states at doses of 250,
500, 750 and 1000 mg daily. All patients were chemotherapy-naive. Patient records were retrospectively reviewed
for prior use of ketoconazole and response as well as reasons for
discontinuing keto(disease progression or toxicity.) Of the 30 evaluable
patients, 19 had received prior keto and 11 had no prior keto.
|
Category |
Response (PSA Decline > 50%
|
Median Time to Disease Progression |
| All Patients |
10 patients of 30 (53%) |
|
| Prior Ketoconazole (a,b) |
10 patients of 19 (52%) |
21 Weeks |
| No Prior Ketoconazole |
6 patients of 11 (55%) |
|
(a) "Non-responders"
on Keto - 3 of 4 patients had discontinued keto due to toxicity and they
responded to abiraterone. 7 of 15 patients who had progressed on keto has a
PSA decline on abiraterone with median time to progression of 17 weeks.
(b) "Responders" on
Keto - 16 of 19 pts (84%) had previously
experienced a 50% decline in PSA while on ketoconazole. 15/19
(79%) had discontinued keto due to progressive disease and four (21%) had
discontinued ketoconazole due to toxicity. The median duration of keto
therapy in these 19 patients was 15 months (range 4.2-38 months).
The authors state
that their results support the hypothesis that there may be no cross
resistance between ketoconazole and Abiraterone.
Status of Abiraterone Acetate
There are
multiple clinical trials in progress for abiraterone. Only two are
currently recruiting patients:
An update as of 4-21-2010 for trials that are still open. There are now
7 trials listed as open.
An update as of 4-21-2010 for trials that are now closed. There are now
6 closed trials.
Phase I Clinical Trial - Results
Attard G, et
al (4) have now published the phase I results in the J. Clinical Oncology.
The dose range tested was from 250mg to 2000mg.
Patients: 21
patients, all Chemo-naive; no prior ketoconazole. Drugs previously used
included DES, dexamethasone, HDACi, pan-CDKi, pamidronate, pan-ERBi.
All were castrate.
Abiraterone was associated with increased levels of
ACTH(5x) and steroids upstream of CYP17(10x to 40x) and with suppression
of serum testosterone (to less than 1ng/dl), downstream androgenic steroidsJ(reduced
1.5x to 3x), and estradiol(to <80 pg/dl) in
all patients.
Antitumor effect was seen
at all doses, but 1000 mg was selected for phase II.
PSA
Responses: 30% reduction 14/21 (66%); 50% reduction 12/21 (57%) and 6 of 21
(29%). Duration of PSA responses: 69 to ≥
578 days.
Measurable
disease response: 5/8 (62%) confirmed partial responses.
Bone:
Resolving disease seen in two patients.
Toxicities - The increased levels of ACTH lead to secondary mineralcorticoid
excess which is characterized by hypertension(seen in 6 patients),
hypokalemia (seen in 10 patients) and low-limb edema (seen in 1 patient.)
The study used a mineralocorticoid receptor antagonist - eplerenone 50 to
200mg/day. If necessary, they also used .5mg dexamethasone daily to suppress
ACTH. Grade 2 fatigue and anorexia were both reported in 2 patients.
Adrenal insufficiency was not observed (interestingly, (7) states, "Adrenal
insufficiency has not been consistently observed."
Phase II Clinical Trial - Results
Data from Phase II clinical trials of abiraterone is available from papers
presented at the ASCO 2008 GU Symposium (10) and at ASCO Annual Meeting 2008
(11). These trials provide data on abiraterone in both docetaxel pretreated
patients and docetaxel naive patients. Results from abstracts have been
updated with results presented at the meeting.
Chemo-Naive Phase II (from Phase I/II trial) (10)
Patients: n=54, median of 3 prior hormonal treatments, bone metastases in
70%, measurable disease in 29.
Measurable disease response:
15 of 29 (52%) Partial Response.
8 of 29 (28%) Stable Disease for > 3 months.
PSA response:
PSA
decline ≥ 50%: 70% (38/54).
PSA
decline ≥ 30%: 80% (43/54).
Time to PSA progression (TTPP): median 231 days (54 patients), some still on
study at 2.5 years.
On progression, patients received .5mg/day dexamethasone to decrease
upstream steriods (ACTH reduced to less than 3x baseline levels.)
Additional responses were observed.) So far 30 patients have been
treated this way. 5/19 (26%) with no prior dex had ≥50%
PSA Decline, lasting 84+ to 280+ days; 4/11
(36%) who had previously progressed on .5mg/day dex had ≥50% PSA Decline
lasting 81+ to 469+ days; 1 patient maintained SD for 552+ days
. Dexamethasone was used as they have some
evidence that dexamethasone is better than prednisone. This gives a median
TTP of 399 days.
Taxotere (Docetaxel) Pretreated Phase II
Patients:
n=34 patients, 31 reached 3 months on study. (This is
Royal Marsden data only -- the phase II trial also was being run at MSKCC
and UCSF.)
18/34 (55%) had progressed on docetaxel.
16/34 (45%) had stopped docetaxel for toxicity.
Bone mets 27/34 patients.
Measurable disease 19/34 patients.
Measurable disease response:
5 of 19 (26%) Partial Response.
PSA Response:
PSA
decline ≥ 50%:
16/34 (47%).
PSA
decline ≥ 30%: 22/34 (65%).
24/34 (71%) had a PSA decline.
Median TTP: 161 days.
De Bono concluded his presentation with some interpetations -- notably that
it is highly likely that on progressive disease despite abiraterone, the
cause is ligandless activation of the androgen receptor.
A paper from MSKCC covered more Phase II results in a presentation by DC
Danila et al (11). This trial had patients using abiraterone (1000mg QD) and
prednisone (5mg BID) in 28 day cycles, who had progressed on docetaxel based
chemotherapy.
Patients: 43 screened, 38 treated, 29 (76%) had ≥ 3 hormone treatments (ketoconazole
in 17 (45%)) and 26 (68%) 1 line of chemo and 12 (32%) had 2 lines of chemo.
Metastases: bone only in 10, bone and lymph nodes in 15, bone and visceral
diseae in 11 and 2 had soft tissue and no bone disease.
PSA Results:
PSA
decline ≥ 50%: 14/35 (40%) at
3 months.
Durability of Response:
35 evaluable patients (3 are too early),
By 3 months, 11 (31%) had progressed.
By 6 months, 9 (26% had progressed.
After 6 months, 2 (6%) had progressed.
6 patients are still on treatment for 3-6 months and 6 for 6+ months.
Toxicity:
No grade 3 or 4 hypertension or hypokalemia. One pt discontinued treatment
due to transaminitis and myositis.
Phase III Clinical Trial - Plan
Abiraterone Acetate (CB7630) is starting to enroll patients for a phase III
trial (COU-AA-301). The Phase III trial is a randomized,
double-blind, placebo-controlled trial of CB7630 plus prednisone in patients
with metastatic castration-resistant prostate cancer who have failed
docetaxel-based chemotherapy. Patients are allowed to have received up to
two prior chemotherapy regimens before entering the trial.
The trial will
enroll approximately 1,160 patients who will be randomized (2:1) to receive
either CB7630 plus prednisone or placebo plus prednisone at 150 sites. Prior ketoconazole is an exclusion factor. The primary endpoint is overall
survival. The use of prednisone with abiraterone acetate is expected
to prevent the secondary mineralocorticoid excess syndrome.
Summary
Responses at Phase I are unusual since Phase I is addressing drug safety by
using escalating doses of the study drug with only a small number of
patients. Abiraterone has shown excellent results at phase I.
Phase II has also now demonstrated very good response rates. These
results are summarized in the table below. It is hoped that this drug
will continue to see success through its phase III testing.
PSA Response = ≥ 50% Drop in PSA (PSA RR). TTPP = time to PSA progression.
|
Phase |
PSA RR, Chemo & Keto Naive.(4) |
TTPP, Chemo & Keto Naive.(4) |
PSA RR, Chemo-naive, Previous Keto (5) |
TTPP, Chemo-Naive, Previous Keto (5) |
PSA RR, Chemo-naive, (10) |
TTPP, chemo-naive, (10) |
PSA RR, Previous Chemo(taxotere)(10) |
TTPP, previous chemo.(10) |
PSA RR, Previous chemo and previous keto.(11) |
TTPP, Previous chemo and previous keto.(11) |
| I |
12/21
(57%) |
69 to ≥
578 days |
10 patients of 19 (52%) |
21 Weeks. |
- |
- |
- |
- |
- |
- |
| II |
|
|
|
|
38/54 (70%) |
Median 231 days (54 patients) |
16/34 (47%) |
161 days |
14/35
(40%) |
Approx. median of 6 months. |
For patients who have been on ketoconazole and taxotere chemotherapy, the
results of Danilla et al (11) might reflect the expected PSA RR and response
durability.
Attard G et al(4), phase I authors, state that the antitumor effect of abiraterone acetate could
be explained by durable and profound suppression of serum androstenedione,
DHEA, testosterone and estradiol. Estradiol is suppressed to < 80 pg/dL
(.8pg/mL) which is well below the 10-30pg/mL thought to be optimal. The
clinical significance of suppressing estradiol is not obvious and is not
discussed in the phase I paper. TA Yap et al (2) do discuss some
possible reasons including androgen receptor (AR) point mutations, allowing the
AR to become more 'promiscuous' and subsequently activation by estradiol,
progesterone and antiandrogens. Whether or not this affects bone integrity
has so far not been discussed.
References
1.
O'Donnell A,
Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason M, Harland S, Robbins A,
Halbert G, Nutley B, Jarman M.,
Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor
abiraterone acetate (CB7630) in patients with prostate cancer,
Br J Cancer, 2004 Jun 14;90(12):2317-25.
2. Yap TA, Carden C, Attard G, de Bono JS,
Targeting CYP17: established and novel approaches in prostate cancer, Curr
Opin Pharmacol. 2008 Jul 8. [Epub ahead of print].
3. G. Attard, T. A. Yap, A. H. Reid, C. Parker, M. Barrett, F. Raynaud, M.
Dowsett, D. Dearnaley, G. Lee, J. S. De Bono, Phase I study of continuous
oral dosing of an irreversible CYP17 inhibitor, abiraterone (A), in
castration refractory prostate cancer (CRPC) patients (p) incorporating the
evaluation of androgens and steroid metabolites in plasma and tumor, Journal
of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25,
No. 18S (June 20 Supplement), 2007: 5063.
4. Gerhardt
Attard, Alison H.M. Reid, Timothy A. Yap, Florence Raynaud, Mitch Dowsett,
Sarah Settatree, Mary Barrett, Christopher Parker, Vanessa Martins,
Elizabeth Folkerd, Jeremy Clark, Colin S. Cooper, Stan B. Kaye, David
Dearnaley, Gloria Lee, and Johann S. de Bono, Phase I Clinical Trial of a
Selective Inhibitor of CYP17, Abiraterone Acetate, Confirms That
Castration-Resistant Prostate Cancer Commonly Remains Hormone Driven, J.
Clin. Oncol. 26:2008, 4563-4571.
5. C. Ryan,
M. R. Smith, J. E. Rosenberg, A. M. Lin, M. Taplin, P. W. Kantoff, V. Huey,
J. Kim, E. J. Small, Impact of prior ketoconazole therapy on response
proportion to abiraterone acetate, a 17-alpha hydroxylase C17,20-lyase
inhibitor in castration resistant prostate cancer (CRPC), J Clin Oncol 26:
2008 (May 20 suppl; abstr 5018).
6.
G. Attard, T. A. Yap, A. H. Reid, C. Parker, M. Barrett, F.
Raynaud, M. Dowsett, D. Dearnaley, G. Lee, J. S. De Bono,
Activity, toxicity, and effect on steroid precursor levels of abiraterone
(A), an oral irreversible inhibitor of CYP17 (17α hydroxylase/17,20 lyase),
in castrate men with castration refractory prostate cancer (CRPC), ASCO 2007 Prostate Cancer Symposium,
Abstract No: 264.
7. C. J. Ryan, J. Rosenberg, A. Lin, E. J. Small,
Phase I evaluation of abiraterone acetate (CB7630), a 17-alpha hydroxylase
C17,20-lyase inhibitor in androgen-independent prostate cancer (AiPCa), ASCO 2007 Prostate Cancer Symposium,
Abstract No: 278.
8. Alison Reid, Gerhardt Attard, Mary Barrett, Vasilios Karavasilis, Rhoda
Molife, Emilda Thompson, Christopher Parker, David Dearnaley, Gloria
Lee,
Johann S. De-Bono, 50PD INHIBITION OF ANDROGEN SYNTHESIS RESULTS IN A HIGH
RESPONSE RATE IN CASTRATION REFRACTORY PROSTATE
CANCER (CRPC), (ESMO)European Society for Medical Oncology 2007
Meeting, Lugano, Switzerland.
9. Gerhardt Attard, Alison Reid, Rhoda Molife, Rajesh Sinha, Emilda
Thompson,
Mary Barrett, Gloria Lee, Christopher Parker, David Dearnaley, Johann S. De-Bonom,
abstract #51PD ABIRATERONE, AN ORAL, IRREVERSIBLE, CYP450C17
ENZYME INHIBITOR APPEARS TO HAVE ACTIVITIY IN POST DOCETAXEL
CASTRATION REFRACTORY PROSTATE CANCER
(CRPC) PATIENTS (PTS), (ESMO)European Society for Medical Oncology 2007
Meeting, Lugano, Switzerland.
10. J. S. De Bono, G. Attard, A. H. Reid, C. Parker, M.
Dowsett, R. Mollife, T. A. Yap, A. Molina, G. Lee, D. Dearnaley, Anti-tumor
activity of abiraterone acetate (AA), a CYP17 inhibitor of androgen
synthesis, in chemotherapy naive and docetaxel pre-treated castration
resistant prostate cancer (CRPC), J Clin Oncol 26: 2008 (May 20 suppl; abstr
5005).
11. D. C. Danila, D. E. Rathkopf, M. J. Morris, S. F. Slovin, L. H.
Schwartz, K. Farmer, A. Anand, C. Haqq, M. Fleisher, H. I. Scher,
Abiraterone acetate and prednisone in patients (Pts) with progressive
metastatic castration resistant prostate cancer (CRPC) after failure of
docetaxel-based chemotherapy, J Clin Oncol 26: 2008 (May 20 suppl; abstr
5019).
12. Strum, SB and Pogliano, D, A Primer on Prostate
Cancer, Life Extension Media, 2002.
13.
Phase II Multicenter Study of Abiraterone Acetate Plus Prednisone Therapy in
Patients With Docetaxel-Treated Castration-Resistant Prostate Cancer
Daniel C. Danila, Michael J. Morris, Johann S. de Bono, Charles J. Ryan,
Samuel R. Denmeade, Matthew R. Smith, Mary-Ellen Taplin, Glenn J. Bubley,
Thian Kheoh, Christopher Haqq, Arturo Molina, Aseem Anand, Michael
Koscuiszka, Steve M. Larson, Lawrence H. Schwartz, Martin Fleisher, and
Howard I. Scher
JCO published online February 16, 2010, DOI:10.1200/JCO.2009.25.9259
14.
Phase I Clinical Trial of the CYP17 Inhibitor Abiraterone Acetate
Demonstrating Clinical Activity in Patients With Castration-Resistant
Prostate Cancer Who Received Prior Ketoconazole Therapy
Charles J. Ryan, Matthew R. Smith, Lawrence Fong, Jonathan E. Rosenberg,
Philip Kantoff, Florence Raynaud, Vanessa Martins, Gloria Lee, Thian Kheoh,
Jennifer Kim, Arturo Molina, and Eric J. Small
JCO published online February 16, 2010, DOI:10.1200/JCO.2009.24.1281
15.
Significant and Sustained Antitumor Activity in Post-Docetaxel,
Castration-Resistant Prostate Cancer With the CYP17 Inhibitor Abiraterone
Acetate
Alison H.M. Reid, Gerhardt Attard, Daniel C. Danila, Nikhil Babu Oommen,
David Olmos, Peter C. Fong, L. Rhoda Molife, Joanne Hunt, Christina Messiou,
Christopher Parker, David Dearnaley, Joost F. Swennenhuis, Leon W.M.M.
Terstappen, Gloria Lee, Thian Kheoh, Arturo Molina, Charles J. Ryan, Eric
Small, Howard I. Scher, and Johann S. de Bono
JCO published online February 16, 2010, DOI:10.1200/JCO.2009.24.6819
16. Editorial:
Castration-Resistant Prostate Cancer—Hormone Therapy Redux
Anthony W. Tolcher and Josh Cooper
JCO published online February 16, 2010, DOI:10.1200/JCO.2009.25.3781.
Appendix
TA Yap et al (2) describe the androgen biosynthesis pathway as follows:
Androgen biosynthesis pathway. Abiraterone acetate inhibits 17a-hydroxylase,
causing a decline in serum cortisol and a consequent rise in
adrenocorticotrophic hormone (ACTH) that drives the steroid
biosynthesis pathway. This results in the rise of deoxycorticosterone and
corticosterone by a median of 10-fold and 40-fold, respectively. The
elevated deoxycorticosterone levels result in the expected toxicities of
secondary mineralocorticoid syndrome following abiraterone acetate
treatment. Abiraterone acetate also inhibits C17,20-lyase
resulting in a fourfold rise in 11-deoxycortisol and significant declines in dehydroepiandrostenedione (DHEA), androstenedione, and testosterone.
Aldosterone levels fall because of suppression of the renin–angiotensin
pathway by high levels of deoxycorticosterone.
See their paper or the phase I paper in J. Clin Onc
which have this diagrammed nicely.
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