Medical management of prostate cancer can include active surveillance, radiation therapy, surgery, hormone therapy, and chemotherapy depending on the cancer's risk level and stage. Investigations may involve PSA testing, biopsy, imaging, and disease staging. Androgen deprivation therapy is an important treatment option and can be accomplished through surgical or chemical castration. Docetaxel and cabazitaxel chemotherapy may provide benefits for advanced or metastatic disease.

1. Medical management of
prostate cancer
Dr Mohit Changani

2. Introduction
Primarily a disease of elderly with 3/4th of the cases being >65 years
of age
Most of the cancers in prostate are adenocarcinoma
A very slow growing cancer with milder symptoms until the cancer
reaches an advanced stage
Prostate cancer can metastasize in the bones, lymph nodes, liver,
lungs and other organs
NCCN guidelines for patients 2019 2

3. Few facts
The 2nd highest incidence of all cancers amongst men worldwide and is the 5th leading
cause of cancer death in men
1 out of 9 man may develop prostate cancer
Not all men diagnosed with prostate cancer requires treatment
Age is the most common risk factor, higher the age, higher is the risk
Family history increases the risk
Sports Medicine – Open 2020;6(13):2020 3

4. Investigations
Laboratory
• Complete blood cell count
• Blood biochemistry
• Serum PSA (total, free, percentage
free)
• Plasma acid phosphatases
(prostatic/total)
Radiographic
• Transrectal ultrasonography (for
biopsy guidance)
• Biopsy/Needle biopsy of prostate
(transrectal, transperineal)
• Chest radiograph (high risk for
metastatic disease)
• Computed tomography of pelvis
• Radioisotope bone scan (PSA >20)
• Magnetic resonance imaging with
endorectal coil
4

5. Investigations
PSA (Prostate Specific Antigen)
• Normal: ~0.4 ng/ml (upper limit 2.6 ng/ml)
• Mild elevation 4 ― 10 ng/ml
• A value of greater than 4 ng/mL, serum PSA detection rates for prostate
cancer approach, a specificity of 91%
• Significant elevation >10 ng/ml
• Levels > 20 ng/ml – positive predictive value of 65% for metastatic
skeletal involvement
• Levels > 100 ng/ml – positive predictive value of 86% for metastatic
skeletal involvement
• Levels ≤ 10 ng/mL rarely demonstrate metastatic disease.
David MK. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. 5

6. Staging
Buyyounouski MK et al. CA Cancer J Clin 2017;67:245–253 6

7. Risk Stratification
Risk group Clinical/Pathological features
Very low Has all of the following:
• T1c
• Grade group 1
• PSA <10ng/ml
• Fewer than 3 prostate biopsy fragments/core positive, ≤50% cancer in
each fragment/core
• PSA density <0.15 ng/ml/g
Low Has all of the following but doesn’t qualify for very low risk:
• T1 – T2a
• Grade group 1
• PSA < 10 ng/ml
Intermediate Has all of the following
• No high or very high risk group features
• Has one or more intermediate risk factors (IRF)
• T2b - T2c
• Grade group 2 or 3
• PSA 10 = 20 ng/ml
High Has no very high risk features and at least one high risk features
• T3a OR
• Grade group 4 or 5 OR
• PSA > 20 ng/ml
NCCN Guidelines version 2.2020: Prostate Cancer 7
Favorable
intermediate
Has all of the following
• 1 IRF
• Grade group 1 or 2
• < 50% biopsy core +ve
Unfavorable
intermediate
Has one or more of the following
• 2 or 3 IRFs
• Grade group 3
• ≥50% biopsy core +ve
Risk group Clinical/Pathological features
Very high Has at least one of the following
• T3b – T4
• Primary Gleason pattern 5
• 2 or 3 high risk features
• > 4 cores with grade group 4 or 5

8. Treatment
• According to the NCCN guidelines, based on the risk as well as
associated life expectancy, the treatment is recommended
NCCN Guidelines version 2.2020: Prostate Cancer 8
Very low and low risk group
Life expectancy
≥ 20 yrs
10 – 20 yrs
< 10 yrs
• Active surveillance
• 6 monthly PSA monitoring
• EBRT (External Beam Radio Therapy) or Brachytherapy
• Radical Prostactomy (RP)
• Pelvic Lymph Node Dissection (PLND)
Favorable intermediate risk group
Life expectancy
≥ 10 yrs • Active surveillance
• 6 monthly PSA monitoring
• EBRT (External Beam Radio Therapy) or Brachytherapy alone
• Radical Prostactomy (RP) +/- Pelvic Lymph Node Dissection (PLND)
≤ 10 yrs • EBRT or Brachytherapy alone or observation

9. Treatment
• According to the NCCN guidelines, based on the risk as well as
associated life expectancy, the treatment is recommended
NCCN Guidelines version 2.2020: Prostate Cancer 9
Unfavorable intermediate risk group
Life expectancy
≥ 10 yrs • RP +/- PLND or EBRT + Short-term ADT ( 4- 6 months ) or EBRT
• Brachytherapy + ADT
< 10 yrs • EBRT, Brachytherapy
• Observation
High and very high risk group
Life expectancy
> 5 yrs • EBRT + ADT ± Docetaxel
• EBRT + Brachytherapy + ADT
• RP + PLNF
≤ 5 yrs • Observations
• ADT
• EBRT

10. Medical management
Active Surveillance
Watchful waiting, expectant management or deferred treatment
Involves active monitoring of the course of the disease
Applicable to younger men with seemingly indolent cancer with the goal to defer treatment and its
associated side effects
Treatment should be started promptly if the cancer progresses
Consists of DRE and PSA every 3–6 months with routine repeat biopsy in 1–2 yrs with definitive
treatment given if disease progresses.
Watchful waiting is used for patients with significant comorbidities and limited life expectancy. It avoids
side effects of treatment in a patient population that is unlikely to develop problems from their disease.
NCCN Guidelines version 2.2020: Prostate Cancer 10

11. Medical management
Active Surveillance
NCCN Guidelines version 2.2020: Prostate Cancer 11
Advantages
• About 2/3rd of men avoid
the treatment
• Side effects of the
definitive therapy avoided
• Quality of life: less affected
• Risk of unnecessary
treatment of small cancer
will be reduced
Disadvantages
• Chances of missed
opportunity for cure
• About 1/3rd of men will
require treatment
• Peroidic follow up MRI
and biopsies may be
necessary

12. Medical management
Androgen Deprivation Therapy (ADT)
NCCN Guidelines version 2.2020: Prostate Cancer 12
The decision to use ADT, and timing, is dependent on disease characteristics and
patient factors
Generally, 2 to 3 yrs of ADT is recommended with high-risk disease treated with
EBRT, and 4 to 6 months of ADT can be considered for intermediate-risk disease
treated with EBRT.
Most commonly used are GnRH agonists alone or with oral antiandrogens
(combined androgen blockade).
ADT alone is used for treatment of metastatic prostate cancer or for select patients
who are not other wise candidates for definitive local therapy.

13. Medical management
Androgen Deprivation Therapy (ADT)
NCCN Guidelines version 2.2020: Prostate Cancer 13
Surgical castration Removes 90-95% of circulating testosterone and results in prompt decline in
testosterone
Bilateral orchiectomy
Gonadotropin
releasing hormone
(GnRH) agonist
Induce initial stimulation of LH and subsequent testosterone release followed
by gradual decline. By days 20-28, testosterone levels are in castration range.
Initial transient elevation in testosterone can exacerbate pain in patients with
metastatic disease. An antiandrogen is commonly used concurrently for 1
month on initiation of LHRH agonist to avoid this flare reaction
Leuprolide
Goserelin acetate
Buserelin Triptorelin
GnRH antagonists Suppress testosterone while avoiding flare reaction Degarelix,Relugolix
Steroidal
antiandrogens
Inhibition of testosterone and dihydrotestosterone (DHT) from binding to the
androgen receptor in prostatic nuclei
Megestrol acetate
Cyproterone acetate
Non steroidal
antiandrogens
Binds to androgen receptors and inhibit binding of testosterone and DHT in
prostatic nuclei
• Flutamide - short half-life requiring multiple daily doses
• Bicalutamide & nilutamide - weekly half-lives & administered once daily.
Bicalutamide
Flutamide
Enzaluamide
Adrenal suppression Suppress synthesis of multiple adrenal steroids
Produces castrate levels of testosterone in 24 hours through inhibition of
adrenal and testicular steroidogenesis but the effect is not durable
Ketocolnazole

14. Medical management
Androgen Deprivation Therapy (ADT)
*J Clin Oncol. 2014 May 1;32(13):1324-30. **JAMA Intern Med. 2014 Sep;174(9):1460-7 14
Potosky AL et al
• Conducted a retrospective cohort study in 15170 newly diagnosed patients with
clinically localized prostate cancer who received Primary androgen-deprivation
therapy (PADT)*
• PADT was found to be incurring no survival benefit after adjusting for all
sociodemographic and clinical characteristics*
Lu-Yao GL et al
• Didn’t find long-term overall or disease-specific survival benefit for men with
localized prostate cancer in population-based cohort study of 66,717 patients**
• Placing patients with early prostate cancer on ADT should not be routine
practice

15. Medical management
Androgen Deprivation Therapy (ADT)
Bolla M. J Clin Oncol. 2016 May 20;34(15):1748-56. 15
Addition of short term ADT to radiation was found to
improve overall and cancer specific survival in 3 RCTs with
20 – 60% of patients with intermediate risk prostate cancer
A total of 819 patients staged, cT1b-c, cT2a with no
involvement of pelvic lymph nodes and no clinical evidence
of metastatic spread were enrolled in the trial
• At 7.2 years median follow-up, RT plus ADR significantly improved
biochemical disease free survival as well as clinical progression-free
survival

16. Medical management
Androgen Deprivation Therapy (ADT)
*Horwitz EM. J Clin Oncol. 2008 May 20;26(15):2497-504. Bolla M. N Engl J Med. 2009 Jun 11;360(24):2516-27. 16
ADT with EBRT is an effective primary treatment for patients at high
risk or very high risk
In a trial involving 1521 patients of T2c-T4 prostate cancer received
ADT for months before and after EBRT.*
• At 10 years, those who received additional 2 years of ADT, were superior for all end
points except OS*
EORTC 22961
• Showed superior survival when 2.5 years of ADT were added to EBRT given with 6
months of ADT in 970 patients.**

17. Medical management
Androgen Deprivation Therapy (ADT)
Lancet 2000 Apr 29;355(9214):1491-8. Samson DJ. Cancer. 2002 Jul 15;95(2):361-76. 17
Primary ADT with LN metastasis, adjuvant ADT for LN metastasis after RP have
been found to be beneficial
ADT for castration naïve prostate cancer can be accomplished using bilateral
orchiectomy, an LHRH agonist/antagonist or LHRH agonist + first generation
antiandrogen.
Abiraterone or docetaxel can be added to the above regimen for M1 disease.
Metanalysis data suggest that bicalutamide may provide an incremental relative
improvement in OS by 5% to 20% over LHRH agonist monotherapy.

18. Medical management
Androgen Deprivation Therapy (ADT)
*Dijkstra S et al. Springerplus. 2016 May 17;5:653, **Kolinsky M. Eur Urol. 2016 May;69(5):841-3. #Albertsen PC. Eur Urol. 2014 Mar;65(3):565-73. 18
Antiandrogen monotherapy appears to be less effective than medical or surgical castration and is not
recommended for primary ADT.
Dutasteride + bicalutamide showed no benefit over bicalutamide alone in patients with locally
advanced or metastatic prostate cancer.*
Recently, orchiectomy was shown to be safer than LHRH agonist in a trial involving 499 patients
with advanced prostate cancer who underwent orchiectomy compared to 2866 men who received
LHRH agonist
Orchiectomy was associated with lower risk of fracture, PAD and cardiac related complications.**
In a post hoc analysis of RCT of LHRH agonist vs antagonist, lower risk of cardiac events were
found in patients with existing cardiac diseae with LHRH antagonists.#

19. Medical management
Androgen Deprivation Therapy (ADT)
NCCN Guidelines version 2.2020: Prostate Cancer 19
ADT is the gold standard for the initial management of patients with metastatic
disease at presentation
A PSA value ≤4 ng/ml after 7 months of ADT is associated with improved survival
of patients with newly diagnosed with metastatic prostate cancer
ADT for M1 castration naïve disease are:
• Orchiectomy ± docetaxel
• LHRH agonist alone ± docetaxel
• LHRH agonist plus 1st generation antiandrogen ± docetaxel
• LHRH antagonist ± docetaxel
• Orchiectomy + abiraterone
• LHRH agonist/antagonist + abiraterone

20. Medical management
Chemotherapy
*https://www.rxlist.com/taxotere-drug.htm#clinpharm as accessed on 04th oct 2020. **J Clin Oncol. 2008 Jan 10;26(2):242-5. N Engl J Med. 2004 Oct 7;351(15):1502-
12. #N Engl J Med. 2004 Oct 7;351(15):1513-20
20
Docetaxel is approved for the treatment of metastatic castrate-resistant prostate cancer
(mCRPC)
Acts by disrupting the microtubular network in cells that is essential for mitotic and
interphase cellular functions*
TAX 327 trial
• Compared docetaxel plus prednisone to mitoxantrone plus prednisone in 1006 patients.**
• Docetaxel was associated with higher medial OS which was maintained on extended follow up**
SWOG 9916 study
• Showed improved survival with docetaxel when combined with estramustine#

21. Medical management
Chemotherapy
*Lancet Oncol. 2013 Feb;14(2):117-24. **J Clin Oncol. 2018 Apr 10;36(11):1080-1087. 21
In the phase II trial
• Biweekly regimen of docetaxel was evaluated in 346 men with mCRPC
• 2 week regimen was found to be impart longer survival (19.5 vs 17 months, p=0.015) as
compared to 3 week regimen*
• Biweekly regimen also favored time to progression and PSA decline rate*
Docetaxel is also included as upfront option for castration naïve cancers
CHAARTED trial
• Evaluated docetaxel + ADT vs ADT alone
• The combination arm experienced a longer OS (57.6 vs 47.2 months, p=0.002)**

22. Medical management
Chemotherapy
Lancet. 2016 Mar 19;387(10024):1163-77. 22
The STAMPEDE trial
• The multi arm, multi stage phase 3 trial included patients with M0 and M1 castration naïve
prostate cancer patients
• M1 populations showed the survival benefit by adding docetaxel to ADT (median OS 5.4 vs 3.6
years)

23. Medical management
Chemotherapy
NCCN Guidelines version 2.2020: Prostate Cancer 23
Cabazitaxxel is a semisynthetic taxane derivative for mCRPC, previously treated
with docetaxel regimen
TROPIC trial
• Observed 2.4 month improvement in OS with the use of cabazitaxel which was sustained in updated
analysis with followup of 25.5 months
• It was associated with febrile neutropenia, fatigue, nausea vomiting, anaemia and thrombocytopenia.
PROSELIA study
• Evaluated cabazitaxel in patients of mCRPC who progressed on docetaxel
• Lower dose was non inferior to higher dose for median OS (13.4 vs 14.5 months)
• It should be given with steroids along with supportive care like antiemetics and antidiarrhoeal agents

24. Medical management
Immunotherapy
NCCN Guidelines version 2.2020: Prostate Cancer 24
Sipuleucel T is the first in a new class of cancer immunotherapeutic agent approved by FDA
This “vaccine” involves collection of WBC fraction containing, antigen presenting cells from each patients, exposure of the
cells to the prostatic acid phosphatase granulocyte macrophage colonystimulating factor (PAP-GM-CSF) and subsequent
reinfusion of the cells
In the pivotal phase 3 study
• Medial survival in the vaccine arm was found to be 25.8 months as compared to placebo 21.7 months.
• Sipuleucel T treatment resulted in 22% reduction in mortality risk
It is recommened to be used as initial therapy for asymptomatic or minimally symptomatic patients with mCRPC

25. Medical management
Immunotherapy
NCCN Guidelines version 2.2020: Prostate Cancer 25
Pembrolizumab is an anti PD1 antibody for the treatment of “unresectable or metastatic microsatellite
instablilty high or mismatch repair deficient solid tumors who have progressed on prior treatment”
A limited number of additional patients with mCRPC treated with pembrolizumab have been reported
In a case report
• Patient with treatment refractory, progressive metastatic disease experienced complete response
In another study
• 10 patients with CRPC and non visceral metastasis with disease progression on enzalutamide were treatment with pembrolizumab
• 3 of the 10 patients showed a near completed PSA response
• Of the remaining patients, 3 showed stable disease and 4 displayed no evidence of clinical benefit

26. Medical management
Immunotherapy
NCCN Guidelines version 2.2020: Prostate Cancer 26
NAAC guidelines support the use of pembrolizumab in patients with MSI-H or d MMR mCRPC
whose disease has progressed through at least one line of systemic therapy for M1 CRPC

27. Thank you
27