ABIRATERONE ACETATE IN HORMONE RESISTANT CARCINOMA PROSTATE

A 52 year gentleman a case of prostatic metastases (HRPC) came from African continent for further treatment.He had already taken a course of docetaxel( 8 sessions of 80 mg/m2) and Extandi(Enzalutamide).

He had progressed after these medications.Presently he had multiple bone metastases(painful) , preserved performance , preserved renal and hepatic functions (raised alkaline phosphatase around 800 U/L.).His PSA levels were 234 ng/ml.

Because the bony pain was not getting relieved by routine NSAIDS, tramadol and fentanyl patches; we decided to go for Samarium Radioactive therapy.

Three radionuclides are currently approved for the treatment of bone pain: first-generation phosphorus-32 (32P), second-generation strontium-89 (89Sr), and third-generation samarium- 153 (153Sm). These radionuclides all localize to regions of enhanced bone turnover and deliver high local doses of radiation through the emission of beta particles. The mechanism of bone targeting varies for each of them. 32P is targeted to bone through inorganic phosphate pathways and, in a similar manner, 89Sr is taken up as a calcium analog. 153Sm, however, is the only agent in its class targeted to bone via chelation to the aminotetraphosphonate EDTMP (ethylenediaminetetra- methylenephosphonic acid). Side effects are limited to transient and relatively mild platelet and neutrophil suppression. Repeated doses can be used in patients whose marrow reserve is adequate at the time of administration. The short physical half-life of 153Sm (1.9 days) results in a more rapid delivery of radiation than either 32P (14.3 days) or 89Sr (50.5 days).

Metastatic bone disease contributes significantly to the morbidity and mortality associated with prostate cancer. Patients with bone metastasis complain of bone pain as well as of symptoms arising from bone marrow failure, nerve entrapment, and spinal cord compression. There is a direct relationship between the extent of osseous involvement and patient survival.He has lower hemoglobin 10.5 gm/dl and had girdle pain around the waist with paresthesia in right lower limb.

we started him on concurrent Gabapentin for neuralgic symptoms and also started him on Abiraterone acetate.

Abiraterone inhibits 17 α-hydroxylase/C17,20 lyase (CYP17A1), an enzyme which is expressed in testicular, adrenal, and prostatic tumor tissues. CYP17 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17-α-hydroxy derivatives by its 17 α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its C17,20 lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17 activity by abiraterone thus decreases circulating levels of testosterone.

This drug has been now commonly used in patients with docetaxel resistant carcinoma prostate.In September 2010, an independent panel found that the interim results of the phase III clinical trial in previously treated docetaxel patients were so successful that it would have been unethical to keep half the trial participants on placebo, and all patients began receiving the drug. Overall survival was increased by 3.9 months according to this trial (14.8 months versus 10.9 months for placebo). It was approved by the FDA in April 2011.

The dosage of the medication is 1000 mg( 250 mg four tablets on empty stomach).The medicine is now available in India by Ranbaxy(ZELGOR).The medicine is used along with prednisolone 5 mg twice a day as the trials have proven the combination being more successful than the monodrug therapy.

The common side effects (>5 %)are joint swellings, muscle pain, hypokalemia,hot flushes,gastrointestinal side-effects etc.The patients with liver dysfunction ; we need to tailor the dosage to 250 mg once a day.

In our patients ; we had to stop ketoconazole that we had started as an interim drug as the Abiraterone interacts with the CYP3A4 drugs.

The patient is tolerating the medication well and is only complaining of fatigability.

So our patient is treated with combination of multiple drugs; Samarium 153 for painful bony metastases, Abiraterone for prevention of the progression of the malignant disease, Gabapantin for neuralgia and Zoledronic acid (bisphosphonates) to prevent Skeletal Related Events(SRE).