Metastatic Prostate Cancer

UroResident is written for medical students, residents and attendings and is meant to supplement existing resources by providing citations for all evidence mentioned.  Obviously the AUA guidelines/core curriculum ect, NCCN and other classic resources should be consulted first and supersede the content here. The reader should investigate studies and references and be aware errors may be found on this website. Please contact us if you find any
Updated 09/19/2019                       CTRL + F searches this page only
BIOCHEMICAL  RECURRENCE​ (BCR)
When BCR happens, early ADT has longer times to progression and better 5 year overall survival. (1)  In high risk PCA, up to 30% of patients will have occult LN metastasis found on LN dissection, despite negative workup. (3,4)  After starting ADT, the PSA response can be broken into  3 groups 1) nonresponders; 2) initial decline then drifts upwards rise; 3)  sustained responders.  One of the lead investigators of COU-AA-302 suggests stopping nonresponders after 12 weeks and not automatically stopping if an initial responder begins to drift upward.  At 2 years, bone mets develop in 1/3 of nmCRPC and the average metastasis-free survival is 30mo in nm-CRPC. (31) 

METASTATIC DISEASE - HORMONE SENSITIVE (mHSPC)
Metastatic prostate cancer that is newly diagnosed is assumed to be hormone sensitive and is treated with ADT and all men should be considered for upfront docetaxel for 6 cycles or abiraterone indefinitely initially, but castrate resistance (CR) develops for most inevitably.  mHSPC has a 30% 5yr survival and median survival of approximately 3 years (26,27) with STAMPEDE finding 42mo median survival (43).  CHAARTED update showed a 16.8-month overall survival benefit with ADT + docetaxel over ADT alone in mHSPC in patients with high volume disease and no local therapy previously. (18-update, 22-original CHAARTED TRIAL)  STAMPEDE showed docetaxel + ADT improved OS (HR 0.76) and this was applicable in all men with new M1 diasease (14).  Furthermore, abiraterone acetate plus prednisone (LATITUDE, STAMPEDE) increased OS to standard ADT in patients with metastatic, hormone-sensitive prostate cancer. The median OS was not reached in LATITUDE but showed a HR of 0.62 and 0.63 in STAMPEDE. (15,16,25) There is no head to head data for docetaxel vs. abiraterone. The ENZAMET trial showed that enzalutamide combined with ADT is superior to ADT + 1st generation non-steroidal antiandrogens. (24)  The TITAN study showed Apalutamide improved survival compared to ADT in chemo naive, post chemo, those previously treated locally or new diagnoses mHSPC. (32)

​
METASTATIC DISEASE - HORMONE RESISTANT (mHRPC)
CRPC is actually extremely sensitive to ADT rather than resistant. This causes androgen receptors to multiply exponentially and therefore results in ADT unable to sufficiently block receptors. Once CR develops either abiraterone (LATITUDE / STAMPEDE) or docetaxel (CHAARTED, STAMPEDE) is 1st line currently (14,15,16,17) and some are using a combination of both. While no head to head trials exist, a meta-analysis showed no difference between abiraterone vs. docetaxel. (20)  Nearly 25% of patients with radiographic progression do not have a PSA rise (PSA discordance).  (38,39) Patients w/ mCRPC on abiraterone + ADT who had PSA <0.1 at 6mo were found to have 51%, 56%, and 78% decreased risks of radiographic progression, death, and PSA progression, respectively compared to >0.1 PSA at 6mo. (40)  A meta-analysis found that enzalutamide, apalutamide and abiraterone had statistically signifiant lower disease progression compared to doxetaxel and a non-statistically signficant reduction in overall survival. (41)

Ipatasertib is an oral, investigational, potent small molecule that binds to the ATP-binding pocket of all 3 isoforms of AKT; the agent inhibits AKT serine-threonine kinase activity and has been shown to improve antitumor activity of AR blockade in preclinical prostate cancer models.Ipatasertib combined with abiraterone acetate (Zytiga) plus prednisone led to a significantly superior radiographic progression-free survival (rPFS) and antitumor activity compared with placebo plus abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN loss. (42)



Many new agents approved since 2010 for mCRPC:
Abiraterone = *approved for use before or after disease progression on docetaxel in M1 CRPC
  • 17-lyase/hydrolase inhibitor
  • take 500mg BID & give w/ 7.5 to 10mg prednisone daily
  • can cause overproduction of aldosterone, causing HTN, hypokalemia, fluid retention
  • edema (avoid if CHF) , better to use if old/frail, h/o neurologic disease or falls, mild pain. Give with food.
Enzalutamide =*approved for use before or after disease progression on docetaxel in M1 CRPC
  • 160mg daily
  • 1% risk of seizures
  • CNS toxicity & neuropathy, leading to fatigue (avoid in older/frail patients), better to use if CHF, DM, edema, renal impairment
Apalutamide - SPARTAN 3 results show benefit APA was associated with a 25% reduction in risk of death compared with placebo + ADT (33)
Daralutamide - ARAMIS trial 
Sipuleucel-T= asymptomatic or minimally symptomatic mCRPC (ie no narcotics). May be more effective in African Americans.
cabazitaxel= given if progression occurs after docetaxel. Give 30% reduction in dying form PCa (TROPIC study) (23) Significantly improved a number of clinical outcomes, as compared with the androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling–targeted agent (abiraterone or enzalutamide).  (35)   One RCT of  1,168 men with CRPC used cabazitaxel as first line and found  no difference in OS or PFS vs. docetaxel. (37)
radium223=
​Denosumab
Olaparib - PROFOUND TRIAL is PARP inhibitor that shows benefit, especially in BRCA 1/2, ATM.  This 2020 study found increased OS compared to enzaluatmide in their cohort of patients. (45)
Rucaparib - This PARP inhibitor was FDA approved without a randomized control trial, a very rare event.  It was approved based on the TRITON2 study and this accelerated FDA approval is contigent upon a positive phase 3 RCT, TRITON3 which is ongoing. The FDA approval is ONLY for patients with the BRCA1/2 mutations. (46)

OLIGOMETASTATIC DISEASE
One study reported mid study at a median 27 months follow-up, progression-free survival (PFS) was 12 months in patients treated with standard palliative care plus stereotactic body radiation therapy (SBRT) compared with 6 months in those who received palliative care alone (P=0.001). (13) There are other studies that support this. (19,30)
​
The progression of metastasis determines 2nd line treatment with visceral/liver mets considered a fork in the road because of poor outcome.  Oligo vs. poly metastatic disease have different prognosis.  The control exerted by the primary tumor in metastatic disease may be greater for lower burden disease. (5) If patient enters a new prognostic category like change in performance status, development of new symptoms, new symptomatic bone pathology or visceral mets treatment plan change should probably take place.
CYTOREDUCTIVE RADICAL PROSTATECTOMY (CRP)
CRP may result in survival benefits relative to no local therapy in highly selected patients with metastatic prostate cancer (mPCa) based on some retrospective studies.  (6,7,8,9,10,11,12) CRP has higher rate of complications that RP.  (6)

RADIATION OF PRIMARY TUMOR IN mPCA
​Two RCT (STAMPEDE and HORRAD) have shown EBRT to primary tumor can help some patients achieve improved failure free survival with mPCA, however there was no improval in OS.  (28,29)

BONE HEALTH
See ADT for more information about how hormonal therapy and ADT negatively impact bone health.  
denosumab=120mg subq monthly in metastatic disease. 60mg q6month if no bone mets & taking LHRH. Get annual DEXA, give Vit D + Ca.
radium-223= mCRPC w/ symptomatic bone mets w/o visceral mets
  • IV 1.35 microcurie q4weeks  for 6 doses
  • affects bone marrow much less than older agents (ok to use if low WBC)
  • improved survival but need to make sure they have good performance status for 6 months (takes this long for improved survival)
A recent study showed that radium + abiraterone had lower survival than abiraterone alone. (21)

Zoledronic acid every 12 weeks as good as 4 (2)  Denosumab is for use if renal damage. Radium 223 improves SRE's and OS. 

​SRE have treatment indicated if mCRPC, not mHSPC.  Denosumab is superior to zoledronic acid w/ 18% reduction in time to first SRE.

​Calcium and Vitamin D should be started on all patients with prostate cancer and ADT.

OTHER STUDIES
Metformin was shown in one study to have improved survival in mPCA. (36)
% free PSA was found to be a prognostic indicator in one study: a higher %free PSA in mPCA had worse outcomes, which is the opposite finding when used for working up elevated PSA.  (44) 

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  2. Himelstein AL, Foster JC, Khatcheressian JL, et al. Effect of Longer-Interval vs Standard Dosing of Zoledronic Acid on Skeletal Events in Patients With Bone Metastases: A Randomized Clinical Trial. Jama. 2017;317(1):48-58.
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  13. https://www.medpagetoday.com/meetingcoverage/astro/75777. Accessed 10/19/18
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    **The original CHAARTED trial
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