Showing posts with label prednisone. Show all posts
Showing posts with label prednisone. Show all posts

Saturday, June 29, 2019

How much prednisone is needed with abiraterone?

Abiraterone (Zytiga) inhibits the enzymes necessary for the adrenal glands to produce androgens. The adrenals are the secondary source of androgens after the testicles. Unfortunately, the same enzyme is needed for the adrenals to produce cortisol, so a glucocorticosteroid (in the form of prednisone, dexamethasone, or methylprednisolone) has to be replaced when taking abiraterone. When abiraterone is prescribed for men with metastatic hormone-sensitive prostate cancer, 5 mg once daily (5 mg qd) or sometimes 2.5 mg twice daily (2.5 mg bid) is taken for replacement. When abiraterone is prescribed for men with metastatic castration-resistant prostate cancer, 5 mg twice daily (5 mg bid) is taken with it, because the anticipated duration of taking the steroids is shorter. Recently it was found that switching from prednisone to dexamethasone 0.5 mg once a day (0.5 mg qd) can extend the duration of abiraterone effectiveness (see this link).

The danger of taking too little corticosteroid to replace what is lost is a condition called a syndrome of secondary mineralocorticoid excess. This occurs because the pituitary gland reacts to the lack of cortisol by producing a hormone called ACTH. ACTH increases the production of mineralocorticoids (like aldosterone), hormones that increase blood pressure, lower potassium and cause edema in the limbs.

The danger of taking too much corticosteroid may include insulin resistance, a decrease in lean body mass, increase in fat accumulation, and decrease in bone mineral density. It is also immunosuppressive, and may cause tissue breakdown (catabolysis) and gastritis. Adverse effects increase with dose and duration of use.

Glucocorticosteroids have been found to have independent anti-cancer activity (see this link). The effect is short-lived as resistance eventually arises. It is also given to mitigate some of the side effects of chemotherapy ike emesis/nausea and peripheral edema.

Attard et al. conducted a randomized clinical trial among men taking 1000 mg/day abiraterone for metastatic castration-resistant prostate cancer at 22 hospitals in 5 countries in 2013-2014.

  • 41 received it with prednisone 5mg bid (P5 bid)
  • 41 received it with prednisone 5 mg qd (P5 qd)
  • 40 received it with prednisone 2.5 mg bid (P2.5 bid)
  • 42 received it with dexamethasone 0.5 mg qd (D0.5 qd)


The primary outcome measured was mineralocorticoid excess through 24 weeks of treatment as indicated by elevated blood pressure or a blood test for low potassium (hypokalemia). They also measured serum levels of ACTH, which gets elevated if there is not enough glucocorticoid. For side effects of too much glucocorticoid, they measured insulin resistance, loss of lean body mass, gain of body fat, and loss of bone mineral density. For the benefits, they measured suppression of androgen precursors, the % of patients in whom PSA declined by at least 50%, the duration of radiographic progression-free survival, and the patient-reported change in quality of life.



P5 bid
P5 qd
P2.5 bid
D0.5 qd
Mineralocorticoid excess
29%
63%
40%
30%
(95% confidence range)
17%-46%
47%-77%
26%-56%
17%-46%
Grade 3 hypertension
7%
22%
13%
7%
Grade 3 hypokalemia
0%
7%
0%
0%
Change in ACTH (pmol/L)
-1.1
9.0
4.0
-1.8
Change in fasting serum insulin (insulin resistance)
Not statistically significant
Not statistically significant
Not statistically significant
significant
Change in lean body mass
-6%
-3%
-6%
Not statistically significant
Change in total body fat
12%
Not statistically significant
Not statistically significant
19%
Change in bone mineral density
Not statistically significant
Not statistically significant
Not statistically significant
-2%
Androgen precursor suppression
-81%
Not statistically significant
Not statistically significant
-88%
PSA declined by ≥ 50%
63%
78%
60%
88%
Radiographic Progression-free survival
18.5 months
15.3 months
12.8 months
26.6 months
Quality of Life change
Not statistically significant
Not statistically significant
Not statistically significant
Not statistically significant

Although sample sizes were not large enough to directly compare the treatments, the data suggest that P5 bid and D0.5 qd do a good job of preventing mineralocorticoid excess, whereas P5 qd does not. P5 bid and D0.5 qd seem to cause body changes. D0.5 qd seems to have superior oncological effectiveness.

There was tremendous individual variation. It seems prudent to start with the prescribed dose (P5 bid) and monitor body changes, or to start at the lower dose (P5 qd) and to monitor blood pressure and potassium levels.