09 ADT in PCa Flashcards
Castration level of testosterone
< 20 ng/dL (< 0.7 nmol/L)
LHRH agonists
delivered as depot injections on a 1-, 2-, 3-, 6-monthly. The first injection induces a transient rise in LH and FSH leading to the ‘testosterone surge’ or ‘flare-up’ which starts 2-3 days after administration and lasts for abt 1 week. This may lead to clinical flare such as increased bone pain, acute bladder outlet obstruction, obstructive renal failure, spinal cord compression, and cardiovascular death due to hypercoagulation status. Pts at risk are usually those with high-volume symptomatic bony disease. Concomitant therapy with an anti-androgen decreases the incidence of clinical flare but does not completely remove the risk. Chronic exposure to LHRH agonists results in the down-regulation of LHRH-receptors, suppressing LH and FSH secretion and therefore testosterone production. A castration level is usually obtained within 2 to 4 weeks.
LHRH antagonists
immediately bind to LHRH receptors, leading to a rapid decrease in LH, FSH and testosterone levels without any flare. The practical shortcoming of these compounds is the lack of a long-acting depot. Degarelix is LHRH antagonist, standard dosage is 240 mg in the first month followed by monthly injections of 80 mg. Relugolix is an oral LHRH antagonist.
Non-steroidal anti-androgens
Bicalutamide does not suppress testosterone secretion and it is claimed that libido, overall physical performance and bone mineral density (BMD) are frequently preserved. The dosage of Bicalutamide licensed for use in SAB is 50 mg/day, and 150 mg/day for monotherapy. Bicalutamide offers clear bone protection compared with LHRH analogues. Has the potential for liver toxicity, requiring regular monitoring of liver enzymes.
New androgen receptor pathway inhibitors (ARPis): General
Once on ADT the development of castration-resistance (CRPC) is only a matter of time. It is considered to be mediated through two main overlapping mechanisms: AR-independent and AR-dependent mechanism. In CRPC, the intracellular androgen level is increased compared to androgen sensitive cells and an over-expression of the AR has been observed, suggesting an adaptive mechanism. This has led to the development of several new compounds targeting the androgen axis. In mCRPC, abirateron acetate and enzalutamide have been approved. In addition to ADT (sustained castration), abiraterone acetate, apalutamide and enzalutamide have been approved for the treatment of metastatic hormone sensitive PCa (mHSPC) by the FDA and the EMA. Finally, apalutamide, darolutamide and enzalutamide have been approved for non-metastatic CRPC (nmCRPC) at high risk of further metastases.
New androgen receptor pathway inhibitors (ARPis): Abiraterone
Abiraterone acetate is a CYP17 inhibitor (a combination of 17α-hydrolase and 17,20-lyase inhibition). By blocking CYP17, Abi significantly decreases the intracellular testosterone level by suppressing its synthesis at the adrenal level and inside the cancer cells (intracrine mechanism). Abi must be used together with prednisone to prevent drug-induced hyperaldosteronism.
Apalutamide, darolutamide, enzalutamide (alphabetical order)
These agents are novel non-steroidal anti-androgens with a higher affinity for the AR receptor than bicalutamide. While previous non-steroidal anti-androgens still allow transfer of ARs to the nucleus and would act as partial agonists, all three agents also block AR transfer and therefore suppress any possible agonist-like activity. Darolutamide has structurally unique properties. In particular, in preclinical studies, it showed not to cross the BBB.
ADT in Intermediate-Risk PCa: RTOG 0815
ADT in Intermediate-Risk PCa
4-6 months of ADT for unfavourable intermediate risk disease
Which data supports a dichotomization of intermediate-risk prostate cancer into favorable and unfavorable subgroups?
Secondary analysis of NRG Oncology’s RTOG 9408 (Zumsteg et al. JAMA Network Open 2020)
What did the secondary analysis of NRG Oncology’s RTOG 9408 show?
Suggest that benefit is for Unfavourable Intermediate Risk.
ADT in High-Risk PCa
How was the testosterone recovery and QoL in PCS IV study?
18 Mo ADT provides better testosterone recovery and QoL.
What other novel agents have been studied (or ongoing) in high risk PCa?
The next generation is going for ADT intensification with newer antiandrogens.
PARP-inhibitors (Niraparib + ADT + RT) in NRG GU007 trial
STAMPEDE (36 Mo ADT + Abiraterone + RT)
ENZARAD (24 Mo ADT + Enzalutamide + RT)
ATLAS (24 Mo ADT + Apalutamide + RT)
DASL—HiCap (24 Mo ADT + Darolutamide + RT)
STAMPEDE (Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer) Attard et al. Lancet 2022
Role of ADT in the setting of salvage RT to prostate bed
