Prostate cancer treatments

Following biochemical recurrence onset the likelihood of metastases is 37% of five years, signify metastatic castrate sensitive prostate cancer development.

When radiographic metastases appear the therapeutic back bone is androgen deprivation therapy.

About 90% of men with metastatic prostate cancer respond to androgen-deprivation therapy with improvement in symptoms and reduction in serum PSA levels, with the median response duration of approximately 18 months.

Medium androgen  deprivation  therapy(ADT) responsein metastatic castrate sensitive prostate cancer is 18-24 months, well 10% of men have primary ADT resistance.

Biochemical cancer recurrence patients receiving ADT may develop non-metastatic castrate resistant prostate cancer, where there is a PSA rise with no radiographic evidence for metastases.

Metastases free survival in non-metastatic castrate resistant prostate cancer is 30 months, with 33% of patients developing Moni metastases after two years.

The onset of metastatic castrate resistant prostate cancer may be indicated by an increased PSA level, new radiographic metastases, or cancer related symptoms despite castrate testosterone levels.

For patients with high-risk localized and locally advanced disease the addition of combined androgen blockade followed by radical radiation therapy reduced mortality.

Patients treated with radical prostatectomy for high risk disease often require postoperative radiation plus or minus androgen deprivation therapy.

Multiple trials have found that neoadjuvant and concurrent androgen deprivation therapy with radiation therapy in men with high risk localized and locally advanced disease has proven efficacious.

Intermediate risk localized prostate cancer is subdivided into favorable and unfavorable categories.

Unfavorable intermediate risk disease is defined as any primary Gleason pattern 4, percentage of positive biopsy scores 50% or greater and greater than two intermediate risk factors of PSA 10-20, Gleason score 7 and critical stage T2b-c.

Patient with unfavorable intermediate risk disease have a worse outcome than those with favorable intermediate risk disease.

Adjuvant androgen deprivation therapy, after radiation therapy, has also shown an improvement in overall survival.

Subsequent treatments with first generation inhibitors of the androgen receptor, such as flutamide and biclutamide and chemotherapy with docetaxel or other such drugs can provide short term palliation for some.

The median duration of survival with these treatments is approximately 2.5 years.

Following androgen-deprivation therapy with castration serum levels of testosterone is driven by androgens produced within the tumors-castration resistant prostate cancer.

Abiraterone and enzalutamide inhibit residual androgen stimulation of tumor tissue.

Abiraterone inhibits the enzyme cytochrome P450 17A1 critical in the production of androgens and glucocorticoids and is given with low-dose glucocorticoid.

Enzalutamide binds the androgen receptor and inhibits its nuclear translocation, DNA binding, and transcription of androgen dependent genes.

Abiraterone and enzalutamide have improved the duration of survival in men with metastatic, castrate resistant prostate cancer, both before and after the receipt of docetaxel chemotherapy.

Patients with metastatic hormone sensitive prostate cancer of any volume evident on CT or bone scanning should be offered optimal hormonal therapy with testosterone suppression, plus some more effective androgen receptor inhibitor such as  enzalutamide, apalutamide, abiratone or daolutamide.

Alkylating agentestramustine Emcyt 140mg caps 14mg/kg in 3 or 4 divided doses

Anthracenedione

Mitoxantrone Novantrone 2mg/mL soln for IV infusion after dilution 12–14mg/m² every 21 days

Antiandrogens

Abiraterone acetate Zytiga (Janssen Biotech) 250mg tabs 1g once daily (in combination with prednisone 5mg twice daily) on an empty stomach

Bicalutamide Casodex

(AstraZeneca) 50mg tabs 50mg daily

Enzalutamide Xtandi 40mg caps 160mg once daily

flutamide 125mg caps 250mg every 8 hrs

nilutamide Nilandron 150mg. tabs 300mg once daily for 30 days, then 150mg once daily, starting day of or day after surgical castration

Antimicrotubule agents

Docetaxel Taxotere 40mg/mL 75mg/m² once every 3 weeks

Cabazitaxel (Jevtana) 60mg/1.5mL soln for IV infusion 25mg/m² once every 3 weeks with oral prednisone 10mg daily during treatment

Autologous cellular immunotherapy

Sipuleucel-T Provenge (Dendreon) Minimum 50 million autologous CD54+ cells activated with PAP-GM-CSF/250mL dose susp for IV infusion

Autologous use only.

Premedicate 30 minutes before infusion with acetaminophen and antihistamine.

Give three doses at 2-week intervals. For each dose: give over 60 minutes; do not use filter.

Estrogens

Conjugated estrogens Premarin 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg tabs 1.25mg–2.5mg 3 times daily

Estradiol Estrace 0.5mg, 1mg, 2mg scored tabs 1–2mg 3 times daily

Estradiol valerate Delestrogen 10mg/mL, 20mg/mL, 40mg/mL soln for IM inj 30mg or more every 1 or 2 weeks

Estrogens, esterified Menest 0.3mg, 0.625mg, 1.25mg, 2.5mg tabs 1.25–2.5mg 3 times daily

GnRH analogues

Goserelin acetate Zoladex 3.6mg, 10.8mg SC implant

Advanced prostate cancer: one 3.6mg implant every 28 days or one 10.8mg implant every 12 weeks

Stage B2-C prostatic carcinoma in combination with flutamide: Neoadjuvant therapy Initially one 3.6mg implant, followed in 28 days by one 10.8mg implant; or may use one 3.6mg implant every 28 days prior to surgery/radiotherapy

Histrelin acetate Vantas 50mg SC implant Insert 1 implant SC in the inner aspect of the upper arm q12 months

Leuprolide acetate Eligard 7.5mg 1-month 7.5mg ext-rel susp for SC inj 7.5mg SC once per month; or 22.5mg SC once every 3 months; or 30mg SC once every 4 months; or 45mg SC once every 6 months

Leuprolide acetate Lupron Depot 7.5mg 7.5mg depot susp for IM inj 7.5mg once a month

Lupron Depot–3month 22.5mg

Lupron Depot–4month 30mg

Lupron Depot – 6month 45mg

Leuprolide acetate (various) 5mg/mL soln for SC inj 1mg SC daily

Triptorelin pamoate Trelstar 3.75mg, 11.25mg, 22.5mg pwd for IM inj after reconstitution 3.75mg every 4 weeks or 11.25mg every 12 weeks or 22.5mg every 24 weeks

GnRH antagonist

Degarelix Firmagon 80mg/vial, 120mg/vial pwd for SC inj after reconstitution

Give by SC inj in abdomen once every 28 days Two 120mg injections once, then one 80mg inj once every 28 days.

Docetaxel, abiratone, enzalutamide, , apalutamide are all approved for metastatic prostate cancer, but without head-to-head comparisons optimal treatment is yet to be defined.

Patients who have non-metastatic castrate resistant prostate cancer generally have been managed with watchful waiting until metastatic disease is detected.

Metastatic disease  in patients who have non-metastatic prostate cancer manifest metastasis within the first three years, and bone metastasis develop in 1/3 within two years after the diagnosis.

Patient diagnosed with non-metastatic prostate cancer are considered to have active disease.

Patients with non-metastatic prostate cancer can be treated with androgen receptor inhibitors – apalutamide, enzalutamide , and daralutamide.

Androgen deprivation therapy treatment in metastatic prostate cancer is associated with resistance in approximately 7 to 12 months.

Adding androgen receptor pathway inhibitors such as apalutamide, enzalutamide, abiraterone and darolutamide , the median time to castration resistance has not been reached in most studies and proximately 60% of patients continue to respond to treatment after a follow up of four years.

Evidence from three randomized clinical trials found initiating triplet combination therapy for patients with metastatic hormone sensitive prostate cancer led to the best overall survival and should be offered androgen deprivation therapy plus an androgen receptor pathway inhibitor plus docetaxel, particularly in patients with high volume, high risk or de novo metastatic disease(Hussain, M).

The combination of PARP  inhibitors, and androgen receptor inhibition has a synergistic effect, and is a new standard of care for patients with metastatic castration resistant prostate cancer harboring homologous recombination repair mutations.