Evidence Review Updates
, , ,
Prostate Pathway:
Adenocarcinoma, Metastatic, Hormone Naïve, Low Volume Disease ¹ ² ³ ⁴
2
Recommended
POS86: Abiraterone 1,000 mg Daily + Prednisone 5 mg Daily + LHRH Agonist
Treatment(s)
If Docetaxel Eligible and Medically Preferred and Medical Castration Indicated:
POS91: Docetaxel 75 mg/m q21 Days Without Prednisone x 6 Cycles with Medical Castration
2 bicalutamide x 30 days, beginning administration 7 days prior to
The committee recommends
initiation of LHRH agonist. Longer-term use of bicalutamide is optional and at physician discretion
with awareness for withdrawing at first rise of PSA.
If Docetaxel Eligible and Medically Preferred and Surgical Castration Indicated:
POS78: Docetaxel 75 mg/m q21 Days Without Prednisone x 6 Cycles with Surgical Castration
If Ineligible for Docetaxel and Abiraterone Not Financially Feasible:
POS92: LHRH Agonist Every 12 Weeks Until Progression or Toxicity + Bicalutamide 50 mg Daily x
30 Days
The committee recommends bicalutamide x 30 days. Begin administration 7 days prior to
initiation
Efficacy of LHRH agonist. Longer-term use of bicalutamide is optional and at physician discretion
with awareness for withdrawing at first rise of PSA.
Committee Vote for
Primary Recommendation
Deciding Factor for
¹ Medical or surgical castration recommended. Leuprolide provided as a selection below.
² Consider concurrent radiation therapy if node positive only disease.
Primary Recommendation
³ If a deep remission (PSA < 0.2 ng/mL) achieved and side effects intolerable, intermittent androgen deprivation therapy
6 dosing
agree,could
1 disagree,
0 abstain
be considered.
Evidence Statement
⁴ The committee
recommends physician
discretion
when determining
eligibility for
The G8and
Screening
Assessment
Two
trials demonstrate
a survival
advantage
for the addition
ofdocetaxel.
abiraterone
prednisone
is one tool that may assist in determining chemotherapy eligibility.
to androgen deprivation therapy (ADT) in the metastatic, castration-sensitive prostate cancer
setting. The first trial randomized patients with newly diagnosed metastatic, node positive or
high risk locally advanced prostate cancer to receive ADT with or without daily abiraterone
1000 mg and prednisone 5mg (James et al, 2017). Treatment was continued until disease
progression. Of the trial population, 52% had metastatic disease. The three year survival
was 83% and 76% for abiraterone and placebo groups respectively (hazard ration for death,
0.63; 95% confidence interval, 0.52 to 0.76; P<0.001). A second trial randomized patients
with newly diagnosed, high risk metastatic castration-sensitive prostate cancer to receive
ADT with or without daily abiraterone 1000 mg and prednisone 5 mg (Fizazi et al, 2017). At a
median follow up of 30.4 months, patients in the combination group had significantly longer
median overall survival than the placebo group (not reached vs. 34.7 months). 2 Radiographic
progression free survival was also significantly longer with abiraterone. Rates of
hypertension were greater in the abiraterone groups for both trials.
Docetaxel given concurrently with androgen deprivation therapy (ADT) was compared to ADT
alone in the front line setting in hormone sensitive metastatic prostate cancer patients
(Sweeney et al, 2015). Patients were randomized to receive either androgen deprivation
therapy (ADT) alone or with six cycles of docetaxel given at a dose of 75 mg/m every three
weeks. Patients were prospectively stratified according to low or high volume of disease
burden. The median overall survival was 57.6 months for patients receiving combined
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 1
Evidence Review Updates
therapy and 44.0 months for those receiving ADT alone (hazard ratio for death 0.61, 95% CI
0.47, 0.80 P<0.001).
Docetaxel with or without zoledronic acid was studied in combination with ADT in high risk
locally advanced or metastatic prostate cancer patients beginning long term hormonal
therapy (James et al, 2015). Treatment groups included a standard of care (SOC) arm with
ADT only, SOC with docetaxel, SOC with zoledronic acid, and SOC with both docetaxel and
zoledronic acid. Median survival was 67 months for the SOC arm, and 77 months for the SOC
with docetaxel arm (hazard ratio 0.76, 95% CI 0.63, 0.91; p = 0.003). The addition of
zoledronic acid did not improve survival.
There is currently no data comparing docetaxel to ADT with abiraterone and prednisone in
the first line, metastatic, castration-sensitive prostate cancer setting. Selection of regimen is
at physician discretion, taking into consideration patient and drug-specific factors.
Evidence suggests luteinizing hormone-releasing hormone (LHRH) agonists are as effective as
orchiectomy. A meta-analysis of 1908 patients receiving LHRH agonists found no difference
in 2-year overall survival (Seidenfeld et al, 2000). LHRH agonists appeared to be preferable to
nonsteroidal antiandrogens which had a trend toward lower survival in eight applicable trials.
A randomized trial of goserelin versus orchiectomy showed no significant difference in
response rates and survival (Vogelzang et al, NJ 1995).
Data for combined androgen blockade (CAB) with LHRH agonists and antiandrogens are
mixed on whether a survival benefit exists. CAB has shown decreased mortality versus LHRH
agonists alone (Crawford et al, 1989). In the metastatic setting, CAB was found to have
significantly longer PFS and median length of survival than leuprolide alone (35.6 vs 28.3
months) (Crawford et al, 1989). A large meta-analysis by the PCTCG found a nonsignificant
improvement in 5 year overall survival in metastatic/locally advanced patients receiving CAB
versus castration alone (25.4 vs 23.6%, P = 0.11) (PCTCG 2000). Another review and metaanalysis also found a significant improvement in survival at 5 years, but not at 2 years
(Samson et al, 2002). Bicalutamide has been studied in combination with LHRH agonists and
shown a trend towards improved overall survival compared to flutamide/LHRH
(Schellhammer et al, 1997).
Reference(s)
The results were statistically inconclusive when continuous and intermittent androgen
Boccon-Gibod
L, Fournier
Bottet P etinal.
Flutamide
orchidectomy
in the treatment
deprivation therapies
wereG,compared
patients
withversus
metastatic
hormone-sensitive
prostate
cancer. However, a 20% greater risk of death with intermittent therapy could not be ruled
of metastatic prostate carcinoma. Eur Urol. 1997;32(4):391-5; discussion 395-6.
out, favoring continuous therapy (Hussain et al, 2013).
http://www.ncbi.nlm.nih.gov/pubmed/9412794
Crawford ED, Eisenberger MA, McLeod DG et al. A controlled trial of leuprolide with and
without flutamide in prostatic carcinoma. N Engl J Med 1989; 321(7): 419-424.
http://www.ncbi.nlm.nih.gov/pubmed/2503724
Fizazi K, Tran N, Matsubara N, et al. Abiraterone plus Prednisone in Metastatic, CastrationSensitive Prostate Cancer. N Engl J Med 2017; 377:352-60.
https://www.ncbi.nlm.nih.gov/pubmed/28578607
Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation
in prostate cancer. NEJM. 2013;368(14):1314-22.
http://www.ncbi.nlm.nih.gov/pubmed/23550669
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 2
Evidence Review Updates
James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously
Treated with Hormone Therapy. N Engl J Med. 2017 Jun;377:338-51.
https://www.ncbi.nlm.nih.gov/pubmed/28578639
James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to firstline long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an
adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar
19;387(10024):1163-77. doi: 10.1016/S0140-6736(15)01037-5. Epub 2015 Dec 21.
https://www.ncbi.nlm.nih.gov/pubmed/26719232
Klotz L, Boccon-Gibod L, Shore ND, et al. The efficacy and safety of degarelix: a 12-month,
comparative, randomized, open-label, parallel-group phase III study in patients with prostate
cancer. BJU Int. 2008 Dec;102(11):1531-8. http://www.ncbi.nlm.nih.gov/pubmed/19035858
Prostate Cancer Trialists; Collaborative Group: Maximum androgen blockade in advanced
prostate cancer: An overview of the randomized trials. Lancet 2000; 355: 1491-1498.
http://www.ncbi.nlm.nih.gov/pubmed/10801170
Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of
monotherapy compared with combined androgen blockade for patients with advanced
prostate carcinoma. Cancer 2002; 95(2): 361-376.
http://www.ncbi.nlm.nih.gov/pubmed/12124837
Schellhammer PF, Sharifi R, Block NL, et al. Clinical benefits of bicalutamide compared with
flutamide in combined androgen blockade for patients with advanced prostatic carcinoma:
final report of a double-blind, randomized, multicenter trial. Casodex Combination Study
Group. Urology. 1997 Sep;50(3):330-6. http://www.ncbi.nlm.nih.gov/pubmed/9301693
Seidenfeld J, Samson DJ, Hasselblad V et al. Single-therapy androgen suppression in men
with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med
2000; 132(7): 566-577. http://www.ncbi.nlm.nih.gov/pubmed/10744594
Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormonesensitive prostate cancer. N Engl J Med 2015; 373(8):737-46.
http://www.ncbi.nlm.nih.gov/pubmed/26244877
Vogelzang NJ, Chodak GW, Soloway MS, et al. Goserelin versus orchiectomy in the treatment
of advance prostate cancer: final results of a randomized trial. 1995;46(2): 220-226.
http://www.ncbi.nlm.nih.gov/pubmed/7624991
Updated On
April 2019
, ,
Treatment(s)
The committee
recommends
bicalutamide
x 30
days,Volume
beginning
administration
7 days prior to
Adenocarcinoma,
Metastatic,
Hormone
Naïve,
High
Disease
¹²³
initiation of LHRH agonist. Longer-term use of bicalutamide is optional and at physician discretion
with awareness for withdrawing at first rise of PSA.
Recommended
POS91: Docetaxel 75 mg/m² q21 Days Without Prednisone x 6 Cycles with Medical Castration
If Surgical Castration Indicated:
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 3
Evidence Review Updates
POS78: Docetaxel 75 mg/m² q21 Days Without Prednisone x 6 Cycles with Surgical Castration
If Anti-Androgen Therapy Medically Preferred:
POS86: Abiraterone 1,000 mg Daily + Prednisone 5 mg Daily + LHRH Agonist
If Ineligible for Docetaxel and Abiraterone Not Financially Feasible:
POS92: LHRH Agonist Every 12 Weeks Until Progression or Toxicity + Bicalutamide 50 mg Daily x
30 Days
The committee recommends bicalutamide x 30 days, beginning administration 7 days prior to
initiation of LHRH agonist. Longer-term use of bicalutamide is optional and at physician discretion
with awareness for withdrawing at first rise of PSA.
¹Efficacy
The committee recommends physician discretion when determining eligibility for docetaxel. The G8 Screening Assessment
is one tool that may assist in determining chemotherapy eligibility.
Deciding Factor for
² High volume: visceral metastases and/or 4 or more bone metastases (at least 1 beyond pelvis and vertebral column).
Primary
EvidenceRecommendation
Statement
³ There are insufficient data to favor abiraterone or docetaxel in this setting. The committee recommends a decision be
2
Docetaxel
concurrently
androgen
therapy
(ADT) was compared
to ADT
made basedgiven
on physician
and patientwith
preference,
keepingdeprivation
in mind cost and
convenience.
alone in the front line setting in hormone sensitive metastatic prostate cancer patients
(Sweeney et al, 2015). Patients were randomized to receive either androgen deprivation
therapy (ADT) alone or with six cycles of docetaxel given at a dose of 75 mg/m every three
weeks. Patients were prospectively stratified according to low or high volume of disease
burden. The median overall survival was 57.6 months for patients receiving combined
therapy and 44.0 months for those receiving ADT alone (hazard ratio for death 0.61, 95% CI
0.47, 0.80 P<0.001).
Two trials demonstrate a survival advantage for the addition of abiraterone and prednisone
to androgen deprivation therapy (ADT) in the metastatic, castration-sensitive prostate cancer
setting. The first trial randomized patients with newly diagnosed metastatic, node positive or
high risk locally advanced prostate cancer to receive ADT with or without daily abiraterone
1000mg and prednisone 5mg (James et al, 2017). Treatment was continued until disease
progression. Of the trial population, 52% had metastatic disease. The three year survival
was 83% and 76% for abiraterone and placebo groups respectively (hazard ration for death,
0.63; 95% confidence interval, 0.52 to 0.76; P<0.001). A second trial randomized patients
with newly diagnosed, high risk metastatic castration-sensitive prostate cancer to receive
ADT with or without daily abiraterone 1000mg and prednisone 5mg (Fizazi et al, 2017). At a
median follow up of 30.4 months, patients in the combination group had significantly longer
median overall survival than the placebo group (not reached vs. 34.7 months). Radiographic
progression free survival was also significantly longer with abiraterone. Rates of
hypertension were greater in the abiraterone groups for both trials.
There is currently no data comparing docetaxel to ADT with abiraterone and prednisone in
the first line, metastatic, castration-sensitive prostate cancer setting. Selection of regimen is
at physician discretion, taking into consideration patient and drug-specific factors.
Evidence suggests luteinizing hormone-releasing hormone (LHRH) agonists are as effective as
orchiectomy. A meta-analysis of 1908 patients receiving LHRH agonists found no difference
in 2-year overall survival (Seidenfeld et al, 2000). LHRH agonists appeared to be preferable to
nonsteroidal antiandrogens which had a trend toward lower survival in 8 applicable trials. A
randomized trial of goserelin versus orchiectomy showed no significant difference in
response rates and survival (Vogelzang et al, 1995).
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 4
Evidence Review Updates
Data for combined androgen blockade (CAB) with LHRH agonists and antiandrogens are
mixed on whether a survival benefit exists. CAB has shown decreased mortality versus LHRH
agonists alone (Crawford et al, 1989; Klotz et al, 2010). In the metastatic setting, CAB was
found to have significantly longer PFS and median length of survival than leuprolide alone
(35.6 vs 28.3 months) (Crawford 1989). A large meta-analysis by the PCTCG found a
nonsignificant improvement in 5-year overall survival in metastatic/locally advanced patients
receiving CAB versus castration alone (25.4 vs 23.6%, P = 0.11) (PCTCG 2000). Another
review and meta-analysis also found a significant improvement in survival at 5 years, but not
at 2 years (Samson et al, 2002). Bicalutamide has been studied in combination with LHRH
agonists and shown a trend towards improved overall survival compared to flutamide/LHRH
(Schellhammer et al, 1997).
Reference(s)
The results were statistically inconclusive when continuous and intermittent androgen
deprivation therapies were compared in patients with metastatic hormone-sensitive prostate
cancer. However, a 20% greater risk of death with intermittent therapy could not be ruled
out, favoring continuous therapy (Hussain et al, 2013).
Boccon-Gibod L, Fournier G, Bottet P et al. Flutamide versus orchidectomy in the treatment
of metastatic prostate carcinoma. Eur Urol. 1997;32(4):391-5; discussion 395-6.
http://www.ncbi.nlm.nih.gov/pubmed/9412794
Crawford ED, Eisenberger MA, McLeod DG et al. A controlled trial of leuprolide with and
without flutamide in prostatic carcinoma. NEJM 1989; 321(7): 419-424.
http://www.ncbi.nlm.nih.gov/pubmed/2503724
Fizazi K, Tran N, Matsubara N, et al. Abiraterone plus Prednisone in Metastatic, CastrationSensitive Prostate Cancer. N Engl J Med 2017; 377:352-60.
https://www.ncbi.nlm.nih.gov/pubmed/28578607
Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation
in prostate cancer. NEJM. 2013;368(14):1314-22.
http://www.ncbi.nlm.nih.gov/pubmed/23550669
James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously
Treated with Hormone Therapy. N Engl J Med. 2017 Jun;377:338-51.
https://www.ncbi.nlm.nih.gov/pubmed/28578639
James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to firstline long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an
adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016 Mar
19;387(10024):1163-77. doi: 10.1016/S0140-6736(15)01037-5. Epub 2015 Dec 21.
https://www.ncbi.nlm.nih.gov/pubmed/26719232
Klotz L, Zhang L, Lam A, Nam R, Mamedov A, Loblaw A. Clinical results of long-term follow-up
of a large, active surveillance cohort with localized prostate cancer. J. Clin. Oncol.
2010;28(1):126-131.
http://www.ncbi.nlm.nih.gov/pubmed/15180600
Prostate Cancer Trialists; Collaborative Group: Maximum androgen blockade in advanced
prostate cancer: An overview of the randomized trials. Lancet 2000; 355: 1491-1498.
http://www.ncbi.nlm.nih.gov/pubmed/10801170
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 5
Evidence Review Updates
Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of
monotherapy compared with combined androgen blockade for patients with advanced
prostate carcinoma. Cancer 2002; 95(2): 361-376.
http://www.ncbi.nlm.nih.gov/pubmed/12124837
Schellhammer PF, Sharifi R, Block NL, et al. Clinical benefits of bicalutamide compared with
flutamide in combined androgen blockade for patients with advanced prostatic carcinoma:
final report of a double-blind, randomized, multicenter trial. Casodex Combination Study
Group. Urology. 1997 Sep;50(3):330-6. http://www.ncbi.nlm.nih.gov/pubmed/9301693
Seidenfeld J, Samson DJ, Hasselblad V et al. Single-therapy androgen suppression in men
with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med
2000; 132(7): 566-577. http://www.ncbi.nlm.nih.gov/pubmed/10744594
Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal Therapy in Metastatic HormoneSensitive Prostate Cancer. N Engl J Med. 2015;373(8):737-746.
http://www.ncbi.nlm.nih.gov/pubmed/26244877
Vogelzang NJ, Chodak GW, Soloway MS, et al. Goserelin versus orchiectomy in the treatment
of advance prostate cancer: final results of a randomized trial. 1995;46(2): 220-226.
http://www.ncbi.nlm.nih.gov/pubmed/7624991
Updated On
April 2019
Adenocarcinoma, Metastatic, Castration Resistant, Asymptomatic/Minimally Symptomatic,
Third Line ¹
Treatment(s)
Adenocarcinoma, Metastatic, Castration Resistant, Asymptomatic/Minimally Symptomatic,
If No Prior Second Generation Androgen Pathway Inhibitor (Abiraterone or Enzalutamide) or
Fourth Line and
Beyond,
MSS/pMMR
MSI Unknown or No Prior Chemotherapy ¹
Prior
Enzalutamide
and PriororDocetaxel:
Recommended
POS76:
1,000
mgbenefits.
Daily + Prednisone 5 mg BID Until Progression or Toxicity
ConsiderAbiraterone
potential risks
and
If No Prior Second Generation Androgen Pathway Inhibitor (Abiraterone or Enzalutamide)
and Enzalutamide Medically Preferred or Prior Abiraterone and Prior Docetaxel:
POS59: Enzalutamide 160 mg Daily Until Progression or Toxicity
If Prior Second Generation Androgen Pathway Inhibitor (Abiraterone or Enzalutamide) and
2
No Prior Docetaxel:
POS37: Docetaxel 75 mg/m q21 Days + Prednisone 5mg BID Until Progression or Toxicity If
2
Prior Second Generation Androgen
Pathway Inhibitors (Abiraterone or Enzalutamide) and
Prior Docetaxel:
POS83: Cabazitaxel 20 mg/m q21 Days + Prednisone 10 mg Daily Until Progression
If Minimally Symptomatic Skeletal Only Metastasis:
Prostate59: Referral for Radium 223
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 6
Evidence Review Updates
Cost
¹ The committee recommends physician discretion when determining eligibility for docetaxel. The G8 Screening Assessment
is one tool that may assist in determining chemotherapy eligibility.
Deciding Factor for
Primary Recommendation
Evidence Statement
In patients who have failed the first line treatment recommendation of sipuleucel-T,
treatment will depend on patient-specific factors. A February 2015 cost comparison utilizing
average sales prices, demonstrated that abiraterone is less expensive than enzalutamide.
Based on this data and that these agents are considered to have comparable efficacy and
toxicity in the absence of any head to head clinical trials, the committee recommended
abiraterone in this setting. If patients have risk factors for seizures, abiraterone is preferred.
For patients with elevated LFTs and/or cardiovascular risk factors, the committee prefers
enzalutamide.
In chemotherapy naïve patients, and those with prior docetaxel, abiraterone has shown to
increase median overall survival. In a large randomized phase III trial, 1088 patients with
asymptomatic or mildly symptomatic patients without prior chemotherapy treatment were
randomized to abiraterone plus prednisone or placebo (Ryan et al, 2013). Patients receiving
abiraterone lived significantly longer than those in the placebo group (median OS 34.7 vs
30.3 months, HR = 0.81, 95% CI 0.70-0.93, p=0.0033) (Ryan et al, 2015). This difference
persisted despite the fact that 44% of those in the placebo group eventually received
abiraterone as a subsequent therapy. Abiraterone also significantly increased the median
time to opiate use among patients (33.4 months vs 23.4 months, HR 0.72, 95% CI 0.61-0.85, p
=0.0001).
Enzalutamide significantly decreased the rate of radiographic progression (rPFS) and death
versus placebo in patients with MCRPC who had progressed on an LHRH analogue and who
had not yet received cytotoxic chemotherapy or abiraterone (Beer et al, 2014; 2016). In the
phase III PREVAIL trial, eligible patients were randomized to enzalutamide 160mg daily or
placebo. In the final analysis of this trial, enzalutamide significantly reduced the risk of rPFS
by 68% (HR 0.32, 95% CI 0.28-0.37, p<0.0001) (Beer 2016). Median OS was 35.3 months in
the enzalutamide arm (95% CI 32.2-not yet reached) and 31.3 months in the placebo arm
(95% CI 28.8-34.2 months). The most common adverse events in the enzalutamide arm
included fatigue, back pain, constipation, and arthralgia. Enzalutamide should be avoided in
patients with a history of seizure disorder and used with caution in patients at risk of seizures
due to a 0.5% incidence of seizure seen in clinical trials (Xtandi prescribing information,
2016).
In a large trial of castrate-resistant prostate cancer patients, docetaxel has shown improved
median overall survival compared to mitoxantrone (18.9 vs 16.5 months) (Tannock et al,
2004). Patients (n = 1006) were randomized to twice daily prednisone with either docetaxel
75 mg/m² q3weeks, docetaxel 30 mg/m² weekly, or mitoxantrone 12 mg/m² q3weeks.
Docetaxel regimens had a higher PSA response rate, higher reduction in pain, and overall
quality of life than mitoxantrone. Docetaxel given q3weeks had a higher but non-significant
median survival than the weekly regimen (18.9 vs 17.4 months).
As defined by the International Society of Geriatric Oncology, standard of care eligible
patients fit into three categories: young, healthy/fit geriatric, and vulnerable geriatrics (Droz
et al, 2014). Fit patients have a G8 health status score of more than 14. Vulnerable patients
are those with a G8 score of less than 14, whose impairments can be reversed with medical
attention prior to receiving chemotherapy.
Cabazitaxel prolonged survival in a phase III trial in patients who have previously failed
docetaxel (de Bono et al, 2010). In the TROPIC trial, 755 patients with metastatic castrateresistant disease were randomized to prednisone plus either cabazitaxel or mitoxantrone.
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 7
Evidence Review Updates
Median survival was 15.1 months in the cabazitaxel group and 12.7 months for mitoxantrone
(HR for death = 0.70, 95% CI 0.59 – 0.83, p < 0.0001). An updated analysis reported that
cabazitaxel significantly increased the probability of surviving ≥ 2 years (cabazitaxel 27% vs
16% for mitoxantrone) (Bahl et al, 2013). Development of serious peripheral neuropathy
with cabazitaxel was low similar to mitoxantrone (0.8% of patients developed grade 3 or
higher). Cabazitaxel has black box warnings for neutropenic deaths and severe
hypersensitivity reactions (Jevtana® prescribing information). The PROSELICA trial
randomized metastatic castration resistant prostate cancer patients to either standard dose
cabazitaxel at 25 mg/m2 or 20 mg/m2 in a non-inferiority design (Eisenberg et al, 2017).
Median survival was similar between the two dosing cohorts and met the trial’s noninferiority endpoint. However, toxicity was significantly reduced with the lower dose. Grade
4 neutropenia was reduced from 48.6% to 21.3% and neutropenic sepsis/infection was
reduced from 6.1% to 2.2%. Based on these results, consensus was made to recommend
cabazitaxel 20 mg/m2.
Reference(s)
Radium-223 is an effective option for patients with symptomatic bone metastases who are
ineligible or who refuse docetaxel. In a phase III trial, 921 patients with metastatic prostate
cancer were randomized to receive best supportive care (BSC) plus radium-223 or placebo
(Parker et al, 2013). Patients were included if they had received, were ineligible for, or
declined docetaxel. BSC included external beam radiotherapy, glucocorticoids,
antiandrogens, ketoconazole, or estrogens. Radium-223 significantly increased overall
survival (14.9 months vs 11.3 months). Radium-223 also significantly increased time to first
skeletal-related event versus placebo (15.6 months vs 9.8 months). In order to be eligible to
receive radium-223, a patient must have adequate blood counts including an absolute
neutrophil count of greater than or equal to 1.5x109/L, platelet count of greater than or
equal to 100x109/L, and a hemoglobin of greater than or equal to 10g/dL (Xofigo®
prescribing information).
Bahl A, Oudard S, Tombal B, et al. Impact of cabazitaxel on 2-year survival and palliation of
tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the
TROPIC trial. Ann Oncol. 2013;24(9):2402-2408. doi:10.1093/annonc/mdt194.
http://www.ncbi.nlm.nih.gov/pubmed/23723295
Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before
chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33.
http://www.ncbi.nlm.nih.gov/pubmed/24881730
Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in men with chemotherapy-naïve
metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study.
Eur Urol. 2016; Jul 28. pii: S0302-2838(16)30437-7. doi: 10.1016/j.eururo.2016.07.032
https://www.ncbi.nlm.nih.gov/pubmed/27477525
Droz JP, Aapro M, Balducci L, et al. Management of prostate cancer in older patients: updated
recommendations of a working group of the International Society of Geriatric Oncology. Lancet
Oncol. 2014 Aug;15(9):e404-e414. http://www.ncbi.nlm.nih.gov/pubmed/25079103
Eisenberger M, Hardy-Bessard A-C, Kim CS, et al. Phase III Study Comparing a Reduced Dose
of Cabazitaxel (20 mg/m(2)) and the Currently Approved Dose (25 mg/m(2)) in Postdocetaxel
Patients With Metastatic Castration-Resistant Prostate Cancer-PROSELICA. J Clin Oncol.
August 2017:JCO2016721076. doi:10.1200/JCO.2016.72.1076.
https://www.ncbi.nlm.nih.gov/pubmed/28809610
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 8
Evidence Review Updates
de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for
metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a
randomized open-label trial. Lancet. 2010;376:1176-54.
http://www.ncbi.nlm.nih.gov/pubmed/20888992
Jevtana® (cabazitaxel) [prescribing information]. Sanofi-aventis, Bridgewater, NJ. November
2013. http://products.sanofi.us/jevtana/jevtana.html
Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic
Prostate Cancer. N Engl J Med. 2013 Jul 18;369(3):213-23.
http://www.ncbi.nlm.nih.gov/pubmed/23863050
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous
chemotherapy. N Engl J Med. 2013;368(2):138-148. doi:10.1056/NEJMoa1209096.
http://www.ncbi.nlm.nih.gov/pubmed/23228172
Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus
prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer
(COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled
phase 3 study. Lancet Oncol. 2015 Feb;16(2):152-60. doi: 10.1016/S1470-2045(14)71205-7.
http://www.ncbi.nlm.nih.gov/pubmed/25601341
Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone
for advanced prostate cancer. N Engl J Med 2004; 351:1502-1512.
http://www.ncbi.nlm.nih.gov/pubmed/15470213
Xofigo® (radium Ra 223) [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals,
May 2013. http://labeling.bayerhealthcare.com/html/products/pi/Xofigo_PI.pdf
Xtandi [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc. October 2016.
http://www.astellas.us/docs/us/12A005-ENZ-WPI.pdf
Updated On
April 2019
Adenocarcinoma, Metastatic, Castration Resistant, Asymptomatic/Minimally Symptomatic,
Fourth Line and Beyond, MSI-H/dMMR
Efficacy
Committee
Vote for
Recommended
Primary Recommendation
Treatment(s)
POS93: Pembrolizumab 200 mg q21 Days Until Progression, Unacceptable Toxicity, or up to
24 Months
Deciding Factor for
Primary Recommendation
16 agree, 0 disagree, 0 abstain
Evidence Statement
For patients whose tumors have tested microsatellite instability-high/mismatch repair deficient
(MSI-H/dMMR) and who have exhausted all other treatment options, immunotherapy has been
shown to result in limited, but durable responses. A single institution case series of 1346 patients
receiving treatment for prostate cancer were tested for tumor mutational burden (Abida et al,
2018). Among the 1033 eligible patients, 32 (3.1%) had MSI-H/dMMR prostate cancer. Of those
patients, 11 received anti-PD-1/PD-L1 therapy with six (54.5%) with a greater than 50% decline in
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 9
Evidence Review Updates
PSA value. At the time of analysis, five of the six were still on therapy for as long as 89 weeks.
The KEYNOTE-028 prostate adenocarcinoma cohort was a nonrandomized phase Ib study
examining the use of pembrolizumab in 23 patients whose tumors were >1% PD-L1 positive
(Hansen et al, 2018). Patients received pembrolizumab 10 mg/kg every two weeks until disease
progression or intolerability for up to 24 months. There were four partial responses resulting in an
objective response rate of 17.4%. In addition, eight patients with stable disease. Median duration
of response was 13.5 months.
Reference(s)
Pembrolizumab was originally approved at a normalized dose of two mg/kg. Later, the FDAapproved dose was modified to a flat dose of 200 mg every three weeks. The dose was based on
population pharmacokinetic modeling that demonstrated the predicted exposure with the flat
dose was within 5% of the normalized dose and did not require further clinical study (Freshwater
et al, 2017).
Abida W, Cheng ML, Armenia J, et al. Analysis of the Prevalence of Microsatellite Instability in
Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. December 2018.
https://www.ncbi.nlm.nih.gov/pubmed/30589920
Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for pembrolizumab
for oncology indications. J Immunother Cancer. 2017;5:43.
https://www.ncbi.nlm.nih.gov/pubmed/28515943
Updated On
Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma:
findings of the KEYNOTE-028 study. Ann Oncol. July 2018. doi:10.1093/annonc/mdy232
https://www.ncbi.nlm.nih.gov/pubmed/29992241
April 2019
Adenocarcinoma, Metastatic, Castration Resistant, Symptomatic, Not a Candidate for Further
Chemotherapy/Androgen Pathway Inhibitors/Radiopharmaceutical Therapies and MSI-H/dMMR
Efficacy
Committee
Vote for
Recommended
Primary Recommendation
Treatment(s)
POS93: Pembrolizumab 200 mg q21 Days Until Progression, Unacceptable Toxicity, or up to
24 Months
Deciding Factor for
Primary Recommendation
16 agree, 0 disagree, 0 abstain
Evidence Statement
For patients whose tumors have tested microsatellite instability-high/mismatch repair deficient
(MSI-H/dMMR) and who have exhausted all other treatment options, immunotherapy has been
shown to result in limited, but durable responses. A single institution case series of 1346 patients
receiving treatment for prostate cancer were tested for tumor mutational burden (Abida et al,
2018). Among the 1033 eligible patients, 32 (3.1%) had MSI-H/dMMR prostate cancer. Of those
patients, 11 received anti-PD-1/PD-L1 therapy with six (54.5%) with a greater than 50% decline in
PSA value. At the time of analysis, five of the six were still on therapy for as long as 89 weeks.
The KEYNOTE-028 prostate adenocarcinoma cohort was a nonrandomized phase Ib study
examining the use of pembrolizumab in 23 patients whose tumors were >1% PD-L1 positive
(Hansen et al, 2018). Patients received pembrolizumab 10 mg/kg every two weeks until disease
progression or intolerability and for up to 24 months. There were four partial responses resulting
in an objective response rate of 17.4%. In addition, eight patients had stable disease. Median
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 10
Evidence Review Updates
duration of response was 13.5 months.
Reference(s)
Pembrolizumab was originally approved at a normalized dose of two mg/kg. Later, the FDAapproved dose was modified to a flat dose of 200 mg every three weeks. The dose was based on
population pharmacokinetic modeling that demonstrated the predicted exposure with the flat
dose was within 5% of the normalized dose and did not require further clinical study (Freshwater
et al, 2017).
Abida W, Cheng ML, Armenia J, et al. Analysis of the Prevalence of Microsatellite Instability in
Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. December 2018.
https://www.ncbi.nlm.nih.gov/pubmed/30589920
Freshwater T, Kondic A, Ahamadi M, et al. Evaluation of dosing strategy for pembrolizumab
for oncology indications. J Immunother Cancer. 2017;5:43.
https://www.ncbi.nlm.nih.gov/pubmed/28515943
Updated On
Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma:
findings of the KEYNOTE-028 study. Ann Oncol. July 2018. doi:10.1093/annonc/mdy232
https://www.ncbi.nlm.nih.gov/pubmed/29992241
April 2019
CLIENT acknowledges that the Via Pathways and Via Portal are information management tools only, and that Via Oncology, LLC has not represented the Via Pathways or Via
Portal as having the ability to diagnose disease, prescribe treatment, or perform any other tasks that constitute the practice of medicine. The clinical information contained in the
Via Pathways and Via Portal are intended as a supplement to, and not a substitute for, the knowledge, expertise, skill, and judgment of physicians, pharmacists and other
healthcare professionals involved with patient care at CLIENT facilities. CONFIDENTIAL AND PROPRIETARY. NOT FOR DISTRIBUTION.
Page 11