Current Management of Prostate Cancer

PHAR 6477 ISBP IIIB2 Current Management of Prostate Cancer Part 2 M.L. Ch a ve z, P harm. D ., F A A CP Risk & T r e a tme n t of Prostate Cancer GS; Gleason score; PSA: p rostatespe cific antigen; AS: act ivesur veillanc e;RP: radial prostatectomy; EB RT: external beam radi ation the rap...

PHAR 6477 ISBP IIIB2 Current Management of Prostate Cancer Part 2 M.L. Ch a ve z, P harm. D ., F A A CP Risk & T r e a tme n t of Prostate Cancer GS; Gleason score; PSA: p rostatespe cific antigen; AS: act ivesur veillanc e;RP: radial prostatectomy; EB RT: external beam radi ation the rapy; ADT:and rogen depri vation the rapy; PLND: pelvic lymph node dissection Prostat ecanc er.NCC N Gui deli nes Recurrence Risk Expected Sur vival Trea tment Options Inter m edia te (Favorable) : T2 b-T2c G S = 7 PSA 10 -20 n/mL Predominant GS 3, or % of (+) biopsy cores <50%, or 1 NCCN intermediate risk factor < 10 years Observation or EBRT ± brachytherapy or brachytherapy alone ≥ 10 years RP + PLND if predicted probability of lymph node metastasis >2% EBRT ± ADT (4 -6 mo) ± BT or brachytherapy alone Inter m edia te (Unfavorable) : T2 b-T2c G S = 7 PSA 10 -20 n/mL Predominant GS 3, or % of (+) biopsy cores <50%, or 1 NCCN intermediate risk factor < 10 years Observation or EBRT ± ADT (4 -6 mo) ± brachytherapy or brachytherapy alone ≥ 10 years EBRP + PLND if predicted probability of lymph node metastasis 2% EBRT ± ADT (4 -6 mo) ± BT or brachytherapy alone Case continued • JK the 65 yo AA man with no significant comorbidities has received prostate cancer screening every 2 years. His PSA was 18 ng/mL and he had an abnormal DRE. A prostate biopsy was positive for adenocarcinoma, with the tumor involving more than 50% of only 1 lobe (T2b); Gleason score 4+3. His life expectancy is 15 years. He has intermediate risk (favorable). • What is appropriate treatment for JK? A. Active surveillance B. Active surveillance plus dutasterside only C. Radiation therapy + short term androgen deprivation therapy + brachytherapy D. Radiation therapy + long term androgen deprivation therapy Androgen Deprivation Therapy (ADAT) • Bilateral orchiectomy • Luteinizing -hormone releasing hormone (LHRH) agonist or antagonist (medical castration) • Agonist • Antagonists • Antiandrogens • Goal: testosterone level <50 ng/dL Hypothalamus Pituitary Testes Adrenal Gland Prostate DHT Hypothalamic - Pituitary - Adrenal (HPA) Axis LHRH (GnRH) ACTH LH DHEA Testosterone Androgen Receptor DHT -dihydrotestosterone Hypothalamus Pituitary Testes Adrenal Gland Prostate DHT LHRH Agonists (downregulation over time) LHRH (GnRH) ACTH LH DHEA Testosterone Androgen Receptor then LHRH A g o n i s ts • In itially → trans ie n t s timu la to ry phase of 1 - w ee k s – A n tian d ro g en the ra p y shou ld p recede or be co - admi n iste red for a t lea st 1 w eek to prevent tumor flare • Te st o s te rone l e v els di m in ish to c a s tra tion le v els wi thin 14 to 28 d a y s of the ra p y • Leup rolide is equi v ale n t to e s tro g en, wit h out c aus ing c a rdi o v ascu lar e ffects • M e ta -anal y s is sh o w s LHRH agonists a re eq u iv ale n t wi th respect to e ffic acy and to xici ty LHRH Agonists for T r e a tme n t of P r o s t a t e C a ncer Gen eric Name Brand Name Dosing Drug Interactions Adverse Effects Leuprolide Lupron 7.5 mg IM monthly, 22.5 mg IM every 3 months, 30 mg IM every 4 months, or 45 mg IM every 6 months May diminish the effects of antidiabetic agents Acute: tumor flare, gynecomastia, hot flashes, erectile dysfunction, edema Long term, osteoporosis, obesity, insulin resistance (metabolic syndrome), gynecomastia, osteoporosis Leuprolide Elig ard 7.5 mg SC monthly, 22.5 mg SC every 3 months, 30 mg SC every 4 months, 45 mg SC every 6 months Leuprolide acetate 1 mg/0.2 mL/day SC Triptorelin Trelstar Dep otand LA 22.5 mg IM q 6 m onths, or 11.25 mg IM q 3 months, or 3.75 mg IM q month m Histrelin Vantas 1 implant SC q 12 months (50 mg/implant [delivers ~50 mcg/day]) T umor Fla r e R eaction • Occu rs du rin g in it ia tion of th e ra p y – 4 -3 3 % o f p a tie n ts re c eiving LHRH a g o n ist the ra p y develop tumor flare – E arly mani fe st a tions m a y include v oiding symp toms – L a te -sta g e mani fe st a tions -- if p a tie n ts h a v e skele tal me ta stases → spinal co rd comp ressi o n • LHRH a g oni st the ra p y is co n traindi cat ed in these in stan c es Hypothalamus Pituitary Testes Adrenal gland Prostate DHT LHRH Antagonists (GnRH Antagonists) LHRH (GnRH) ACTH LH DHEA Testosterone Androgen Receptor LHRH Inhibition • LHRH agonists • Goserelin, leuprolide, triptorelin, histrelin • Down regulation of pituitary receptors and decreased testosterone production • Tumor flare may occur in first 1 -2 weeks • Testosterone <50 ng/dL within 7 days • LHRH antagonist • Reduces testosterone more quickly • Degarelix • Testosterone <50 ng/dL with 7 days • No tumor flare • Relugolix • New oral formulation – • Combined LHRH agonist and LHRH antagonist therapy (CAB) Go s e r elin ( Z olad e x): • Dosing – 3.6 mg impla n t e v e ry 28 d a y s – 10.8 mg impla n t e v e ry 12 w ee k s • Adverse effects • Hot flashes • Decreased libido • Gynecomastia • Fatigue • Weight gain Degarlix (Firmagon) • R a p id ly and d irectly lo w er and ro g ens • Does not cause tumor flare • E qu iv ale n t to leu p rol ide in lo w er ing te sto s te rone le v els for up to 1 y ear • Gi v en SC – c auses mo re in je ct rea c tio n s than le u p rol ide Relugolix • HERO study found that oral relugolix was superior to leuprolide in: • Sustaining castration levels of testosterone • Longer castration rate • PSA response • Does not cause tumor flare • Was well tolerated with risk of major cardiovascular even 54 % lower than leuprolide • 12 -months of relugolix was estimated to be $ 27,756 compared to ~$ 11,000 for leuprolide Oral Relugolix for Androgen -Deprivation Therapy in Advanced Prostate Cancer (nejm.org) Hypothalamus Pituitary Testes Adrenal gland Prostate DHT Antiandrogens LHRH (GnRH) ACTH LH DHEA Testosterone Androgen Receptor First Generation Antiandrogens - Drug Brand Name Dosing Adverse Effects Drug Interactions Flutamine Eulexin 250 mg po TID (titrate up) with or without food; capsules can be opened and served with applesauce, pudding or soft food Gynecomastia, hot flashes, impotence diarrhea, hematuria, hepatotoxicity Substrate of CYP1A2 and CYP3A4 Bicalutamide Casodex 50 mg po daily with or without food Gynecomastia, hot flashes, impotence, diarrhea, hematuria, hepatotoxicity Inhibits CYP3A4 May increase concentration of vitamin K antagonists Nilutamide Nlandron 300 mg po daily X 1 month then 150 mg daily with or without food Gynecomastia, hot flashes, diarrhea, impotence, hepatotoxicity, disulfiram - like reaction, decreased night visual accommodation, interstitial pneumonia Substrate of CYP2C19 and weak inhibitor of CYP2C19 Second Generation - Antiandrogen • Enzalutamide (Xtandi) • Prolongs the survival of patients with metastatic resistant PC after chemotherapy • Apalutamide (Erleada) • Prolongs metastasis -free survival and time to progression of patients with non -metastatic resistant prostate cancer • D arolutamide ( Nubeqa) • Prolongs metastasis -free survival of patients with non -metastatic resistant prostate cancer Complete Androgen Blockage (CAB) • Most beneficial to prevent flare during initial LHRH agonist therapy • Conflicting data regarding benefit of CAB long term • CAB associated with more adverse events • NCCN states CAB provides modest to no benefit over ADT alone Intermittent Androgen Blockage • LHRH agonist or CAB used for defined period of time, and PSA less than or equal to 4 ng/ml, then maybe followed by break in ADT until PSA returns to pre ‐specified baseline (typically 10 ‐20 ng/mL) • Requires close monitoring during break • Potential advantages • Decreased adverse effects • Decreased costs T r e a tme n t of High Risk, Very High Risk and Metastatic Prostate Cancer R ecur ren ce Risk Treat m ent O pt io n s Hig h (> 5 yea rs) T3a or GS 8/G rade G roup 4 or GS 4+5=9/G rad e G rou p 5 or and PS A > 20 ng/mL Very H igh (> 5 yea rs) T3b‐T 4 O R Prima ry Gleaso n patt er n 5 or >4 core s wit h G S 8‐10/G rad e G rou p 4 or 5 EB RT+l ong‐ term A D T (2 ‐3 yr; cat egory 1 ), EBRT+b rac h yt h e rap y + lon g te rm A D T (1 ‐3 yr; cat e gor y 1) , or RP+PLND *i f ≤5 yea rs: obse rvatio n o r AD T o r EB RT Regiona l(> 5 yea rs) High Risk EBRT + AD T (2‐ 3 yr ; C at egor y 1)± abi raterone and p rednisone or AD T ± abi raterone and prednisone EBRT + ADT + docetaxel GS; Gleason score; PSA: p rostatespe cific antigen; AS: act ivesur veillanc e;RP: radial prostatectomy; EB RT: external beam radi ation the rapy; BT: brac hythe rapy; RP: ADT:and rogen depri vation the rapy; PLND: pelvic lymph node dissection Prostat ecanc er.NCC N Gui deli nes v1.20 www.nccn .org. T r e a tme n t of High - Risk or Very High - Risk Prostate Cancer • Radiation therapy combined with androgen deprivation therapy (ADT) • Increasing evidence supports lon g -term over short -term neoadjunct/concurrent/adjuvant ADT for high -risk patients Abiraterone plus Prednisone • Studies have showed that combining ADT with abiraterone plus prednisone in patients with very high -risk localized nonmetastatic or metastatic castration -sensitive disease prolongs OS compared with ADT alone Abiraterone with Prednisone • Blocks androgen biosynthesis; it also blocks the production of cortisol • Administration of abiraterone with glucocorticoids is necessary to manage adverse events related to mineralocorticoid excess, such as hypokalemia, hypertension, and fluid retention Side Effects Associated with Abiraterone All Grade • Arthralgia • Urinary tract infection • Fluid retention or edema • Hypokalemia • Cardiac disorders – Atrial fibrillation • LFT abnormalities • Hypertension Grade 3/4 Adverse Events • Fatigue • Anemia • Back pain • Bone pain Fizazi K et al. Lancet Oncol 2012;13(10):983 -92; Ryan CJ et al. Proc ASCO 2012;Abstract LBA4518. Prostate Cance r Pro gression • C R PC is clas sif ied as metastat ic or nonmeta sta tic ba sed on standard imaging (te c hnetium bone sc an and CT abd o men/pel v is with IV co ntra st) • Ima gin g is critic alto ma n agin g pr o state ca n cer p ati ents in or d er to corr ectly cat ego rize an d offer a llap pr o pr iate tre atme n t o p tio n s •PSA decline •Testosterone <50ng/dL LHRH •Castration resistance •No metastatic disease Rising PSA •Metastatic disease •Bo ne, LN, visceral metastases Rising PSA Castration - Resistant Prostate Cancer • Usually starts as androgen sensitive prostate cancer that evolves to castration resistant state in which disease progresses despite androgen deprivation therapy • May present as biochemical relapse without metastasis; in about 20 -30% of these patients will progress and have metastases within 2 years Non - Metastatic Resistant Prostate Cancer m 0 CRPC Nonmetastatic Asymptomatic or minimally symptomatic Apalutamide Darolutamide Enzalutamide Sipuleucel -T Asymptomatic but risk for tumor recurrence Abiraterone Apalutamide Darolutamide Doxetaxel Enzalutamide CRPC Without Metastasis Negative for distant metastases Maintain castrate serum levels of testosterone (<50 ng/dL) • Clinical trial • Observation • Secondary hormone therapy Apalu tamide Indication for M 0 • Androgen receptor inhibitor • Used when P S A doublin g tim e les s ≤ 1 0 mo n ths • Study of a palu tamid e 240 m g orally /d a y v e rsu s placebo • Must be given with prednisone • Me ta stasis ‐fre e su rvi va l 40. 5 mo n th s v s 16. 2 mo n th s w ith placebo • No signifi ca n t di ffe rence in OS a t fi rst anal y sis • ADR: rash (24 % vs 5.5 %), fractu re (11 % vs 6.5 %), h ypot h y roidism (8 % vs 2 %) – Bone health support re commended En z alu tamide for M0 . • Androgen receptor inhibitor • Study of e n za lu ta mid e 160m g orally daily v e rsu s placebo • Me ta stasis‐f re e su rvi va l 36. 6 mo n th s v s 14. 7 mo n th s w ith placebo • No signifi ca n t di ffe rence in OS • ADR‐ • R ash 24% vs 5.5% • Falls and fractu res 17% vs 8%, • H yper tensio n 12 % v s 5% – Ca rd io v a scular , mental cognitive impairment, and seizures no ted – Bone health support re commended . Darolutamide • Second generation androgen receptor inhibitor • Study demonstrated OS at 3 years was higher compared to placebo • Adverse effects were similar to apalutamide and enzalutamide • Is costly Sipuleucel - T (Provenge) • Patients WBCs are sent to a laboratory for recombinant technology processing • Antigen presenting cells (APCs) are isolated and cultured with an immunogen, (prostatic acid phosphatase, an antigen expressed in prostate cancers), and GM -CSF • The vaccine is then reinfusion to the patient • Three doses of treated cells are by given IV infusion over 1 hr as one dose every 2 weeks • Adverse effects: chills, fevers, fatigue, acute infusion reaction • Premedicate with APAP and an antihistamine 30 min prior . Kantoff PW, Higano CS, Shore ND, et al. N Engl J Med. 2010 Jul 29;363(5):411 -22. Day 1 patient undergoes leukopheresis Day 2 -3 Sipuleucel -T is manufactured Day 3 -4 Patient is infused https://www.researchgate.net/figure/ Sipuleucel T : C o s t • Co s t: $9 3 ,00 0 .00 • Co s t inc ludes le u k aphe res is and dr u g but not sup p orti v e c a re • Median improvement in o v e rall su r vi v al improvement is 4.1 mo n ths compared to placebo • Mi n imal d e tec table e ffect on di s ease p rog ress ion as mea s u red b y P S A or ot h er objec tiv e res p onse cri teria Plos ker GL . Drug s2011 7(1):10 1–8. Lo ngoDL. N Eng l JMed 2010.363 :479 –81 . Metastatic Castration Resistant Prostate Cancer (mCRPC) Causes of mCRPC • Mu lt iple poss ible mechan ism s / r esi s tance – An d ro g en rece p tor amp lifi c a tion – And ro g en rece p tor mu ta tio n s and gene expression – Loss of a po pt osis – Inc reased a cti v ity of g ro wt h -sti m u lat o ry p a th w a y s Castration Resistant Prostate Cancer Continue ADT Nonmetastatic Disease Asymptomatic or minimally symptomatic Asymptomatic but at risk for tumor recurrence Metastatic Bone only metastases Visceral and bone metastases From NCCN 2022, American Urological Assoc. guidelines 2020., NICE guidelines Treatment of Asymptomatic (or Minimally Symptomatic) CRPC • Sipuleucel -T as first line: autologous immunotherapy • Stimulates T -cell (patients own antigen presenting cells) • Immunity against prostatic acid phosphatase (PAP) • Indicated for treatment of asymptomatic or minimally symptomatic metastatic prostate cancer Metastatic Bone Only Metastases Abiraterone Docetaxel Enzalutamide Radium -33 Visceral and Bone Metastases Abiraterone Cabazitaxel Docetaxel Enzualutamide Mitoxantrone Docetaxel • Results from the STAMPEDE trial showed that the addition of docetaxel to ADT in the first -line treatment of metastatic castration -sensitive prostate cancer (mCSPC) improved overall survival by a median of 10 months over hormone therapy alone in men with newly diagnosed, advanced , hormone therapy – naive prostate cancer Treatment for Castration -Resistant Prostate Cancer Drug Mechanism Indications Adverse Effects Drug Interactions Dosing Cost Abiraterone acetate with prednisone Androgen synthesis inhibitor that targets cytochrome P450 (CYP)17A1 Used in asymptomatic or mildly symptomatic patients with ADT in naïve mCRPC Hypertension, hypokalemia, edema Avoid concurrent use with inhibitors of CYP2D6 Must be taken with prednisone; take on an empty stomach as food increases bioavailability by up to 10 - fold $5800/mo Enzulatamide (Xtandi) Androgen receptor inhibitor inhibits androgen nuclear translocation and interaction with DNA Used in mCRPC who have not received chemotherapy Gynecomastia, fatigue, hot flashes, musculoskeletal pain, peripheral edema, seizures (0.9% incidences) Metabolized by CYP3A4 and CC8 160 mg (four 40 mg capsules) once daily with or without food $7,450 per month Treatment for Symptomatic Castration - Resistant Prostate Cancer Drug Mechanism Indication Adverse Effects Drug Interactions Dosing Cost Doxetaxel (Taxotere) Binds tubulin, prevents disassembly of microtubules Standard of care for symptomatic mCRPC Myelosuppression, peripheral neuropathy, edema, alopecia, hypersensitivity Avoid use concomitant use CYP3A4 inhibitors 75 mg/m 2IV q 3 weeks; premedicate for 3 day beginning 1 day before with a corticosteroid $2300 per cycle Cabazitaxel (Jevtana) Similar to doxetaxel but lower affinity for p - glycoprotein multidrug resistance transporter, may be effective in doxetaxel resistance Used for mCRPC in patients previously treated with docetaxel Myleosuppression , constipation, mucositis, hypersensitivity Avoid concomitant use with CYP3A4 inhibitors 20 mg/m2 administered every three weeks as a one -hour intravenous infusion with prednisone 10 mg po daily; premedicate 30 minutes prior to administration with an antihistamine, corticosteroid, and H2 antagonist $50,000 per course of 6 cycles Treatment for Symptomatic Castration - Resistant Prostate Cancer Drug Mechanism Indication Adverse Effects Drug Interactions Dosing Cost Radium 223 Emits alpha particles induces double -strand DNA breaks Sympatic bone metastases without visveral metastases Myelosuppression, nausea, vomiting diarrhea, edema, fractures Abiraterone – increases fractures Given IV based on kg of body weight over 1 minute every 4 weeks X 6 injections $68,000 - $82,000 for 6 doses ASCO/CCO Guidelines • Therapies with survival and quality of life (QoL) benefits that should be offered • Docetaxel + prednisone • Abiraterone + prednisone • Enzalutamide • Radium 223 (bone metastases) • Therapies with survival benefit and unclear QoL benefit that may be offered • Sipuleucel‐T (minimally or asymptomatic) • Cabazitaxel + prednisone (after docetaxel) American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) Guidelines for Metastatic castration -resistant prostate cancer. https://www.cancernetwork.com/ ASCO/CCO Guidelines • Therapies with QoL benefit without survival benefit that may be offered • Mitoxantrone + prednisone • Therapies with biology activity and unknown survival or QoL benefits that may be offered • Antiandrogens • Ketoconazole • Low‐dose corticosteroid monotherapy American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO) Guidelines for Metastatic castration -resistant prostate cancer. https://www.cancernetwork.com/ Treatment for Symptomatic mCRPC Drug Mechanism Indications Adverse Effects Drug Interactions Dosing Cost Radium -223 (Xofigo) Alpha particle - emitting radioactive agent Used for mCRPC with symptomatic bone metastases and no known visceral metastatic disease Myelosuppression , nausea, diarrhea, peripheral edema None reported 50 kBq (1.36 microcurie) per kg IV infused over 1 minute; repeat q 4 weeks for 6 cycles total $69,000 for six doses Mitoxantrone Intercalates into DNA resulting into cross -links and strand breaks Used for palliation of symptoms in patients with symptomatic mCRPC who are not candidates for taxane -based therapy Irritant with vesicant properties , mucositis, diarrhea, myelosuppression, cardiomyopathy , bluish discoloration of eyes and urine Avoid concurrent use with immuno - suppressants 12 -14 mg/m2 every 3 weeks (in combination with corticosteroids IV bolus over 5 to 15 minutes or IV intermittent infusion over 15 to 60 minutes $9770 for 10 doses Bone Health and Skeletal - Related Events • Commonly metastasizes to the bone • Higher mortality and morbidities associated with bone metastasis Prostate Cancer releases: Parathyroid hormone - related peptide (PTHrP) Osteoblasts release: Transforming growth factor (TGF) Insulin -like growth factor (IGF) Osteoclasts cause bone resorption: PTHrP binds to osteoblasts, increasing expression of RANKL RANKL binds to RANK, leads to excess osteoclast activation Pain, Weakness, Skeletal Fractures Bone Antiresorptive Therapy • Z oled r onic acid ( Z om e ta) - bisphosphate – Inh ib its o s teocla s tic a cti v ity and s k el e tal c alcium release in duced b y tumo rs – 4 mg IV e v ery 3 – 4 w ee k s – Caut ion in renal impai rme n t • Dose reduce when CrCL < 60mL/mi n – Caut ion: o s teonec rosis of the ja w Bone Antiresorptive Therapy • Denosu m ab (X g e v a ® ) – Fu lly h u man monoc lonal a n tibo dy against NF -kB – Ta rg e ts a t the RANK lig and (rece p tor a c ti v at or of nuclear fa c tor k appa B li g and) – RANK acti v at es o steocla st p recu rso rs – Su b seq u e n t o s teol y sis p romo tes release of bon e - der iv ed g ro wth fa c to rs FizaziK.La nc et 2011:3 7:812-22. Xgeva® (denosumab) [package inser t]. Am gen, Thousand Oa ks, CA. La st upd ated 11/2010. Denosumab (Xgeva®) • Ind ica t ions: 1. P re v e n tion of s k e le tal -re lat ed e v e n ts in bo ne m e ta st ases 2. T re a tme n t of and ro g en de p riv a tion induced bo ne lo s s in men with p ro st at e c ancer • SQ : 60 mg as a single do se, once e v e ry 6 mo n ths • Caut ion: o steonec ros is of the ja w Precision Drugs for Prostate Cancer • PARP inhibitors rucaparib (Rubraca) and olaparib (Lynparza) are used against metastatic castration - resistant prostate cancer with gene repair aberration • BRCA genes ( BRCA1 and BRCA2 ) are normally involved in a different pathway of DNA repair • By blocking the PARP pathway, these drugs make it h ard for prostate tumor cells with an abnormal BRCA gene to repair damaged DNA which causes death of the prostate cancer cells https://www.flickr.com/photos/30478819@N08/50847212991