This is a limited coverage policy for Genomic derived tests that assess risk
in localized (non-metastatic) prostate cancer. The review is focused on the
Decipher Prostate Cancer Classifier Assay (identified as Decipher to
follow). The test is considered reasonable and necessary to help identify men
with localized Prostate Cancer and a life expectancy of at least 10 years who
are good candidates for active surveillance according to the most recent
National Comprehensive Cancer Network (NCCN) guidelines.

Decipher is covered for men with prostate cancer with localized or
biochemically recurrent adenocarcinoma of the prostate (i.e., no clinical
evidence of metastasis) who have a life expectancy of greater than or equal to
10 years if they are a candidate and are considering (or being considered for)
at least 1 of the following:

  * Conservative management and yet would be eligible for definitive therapy (radical prostatectomy (RP), radiation or brachytherapy), or;
  * Radiation therapy and yet would be eligible for the addition of a brachytherapy boost, or;
  * Radiation therapy and yet would be eligible for the addition of short-term androgen deprivation therapy (ADT), or;
  * Radiation therapy with short-term ADT yet would be eligible for the use of long-term ADT, or;
  * Radiation with standard ADT yet would be eligible for systemic therapy intensification using next generation androgen signaling inhibitors or chemotherapy, or;
  * Observation post-prostatectomy yet would be eligible for the addition of post-operative adjuvant radiotherapy, or;
  * Salvage radiotherapy post-prostatectomy yet would be eligible for the addition of ADT.

The following criteria must also be met for coverage:

  *     * The assay is performed on formalin-fixed paraffin embedded (FFPE) prostate biopsy tissue with at least 0.5 mm of linear tumor diameter or FFPE tissue from a prostate resection specimen, and;
    * Result will be used to determine treatment according to established practice guidelines, and;
    * Patient has not received pelvic radiation or ADT prior to the biopsy or prostate resection specimen, and;
    * Patient is monitored for disease progression according to established standards of care.

Other genomic tests that demonstrate an equivalent analytical validity and
clinical validity will be considered reasonable and necessary for the same
indications. Analytical and clinical validity will be assessed as part of a
thorough and comprehensive technical assessment (TA) by the MolDX program and
will similarly attain coverage for indications that are supported by the
evidence and intended use within the scope of this policy.

**Background**

In 2017, over 160,000 men in the United States (U.S.) were diagnosed with
prostate cancer, which accounted for 9.6% of all new cancer diagnoses.1
Clinically localized prostate cancer accounts for ~80% of newly diagnosed
cases.1 The NCCN, classifies these men into risk groups based on clinical and
pathological features, which are intended to be used in conjunction with life
expectancy estimates to select optimal treatment approaches.2 Prostate cancer
is a heterogeneous disease, which to better risk stratify this patient cohort
was the creation of favorable and unfavorable intermediate risk disease groups
developed by Zumsteg and Spratt at Memorial Sloan Kettering, now adopted by
NCCN guidelines.3 Recommendations for the treatment of prostate cancer are
made based on the risk category of the cancer and additional considerations as
noted in see Table 1 below.

The primary treatment decisions in localized prostate cancer that are guided
by prognosis are the use of definitive therapy versus conservative management
with active surveillance, the addition of ADT to radiotherapy, the addition of
brachytherapy to external beam radiotherapy, the use of long versus short-term
ADT with radiotherapy, and the incorporation of newer forms of more potent ADT
such as abiraterone.2 Similarly, the primary treatment decisions after a
patient has undergone a RP include the addition of adjuvant radiotherapy and
addition of ADT to post-operative salvage radiotherapy. These treatment
recommendations are based on multiple trials, though these guidelines provide
little guidance regarding how to select the optimal therapy including how best
to personalize treatment intensification or de-escalation.

**Table 1: NCCN 2018 V4 - Localized Prostate Cancer Risk Stratification and
Treatment**

  |

**Risk Category**  
  
---|---  
  
**Very Low**

|

**Low**

|

**Favorable Intermediate**

|

**Unfavorable Intermediate**

|

**High/Very high**  
  
**Clinical/ pathologic** **features**

|

  * T1c **AND**
  * Gleason score 6/grade group 1 **AND**
  * PSA <10 ng/mL **AND**
  * Fewer than 3 prostate biopsy fragments/cores positive, 50% cancer in each fragment/core **AND**
  * PSA density <0.15 ng/mL/g

|

  * T1-T2a **AND**
  * Gleason score 6/grade group 1 **AND**
  * PSA <10 ng/mL

|

  * T2b-T2c **OR**
  * Gleason score 3+4=7/grade group 2 **OR**
  * PSA 10-20 ng/mL     **AND**
  * Percentage of positive biopsy cores <50%

|

  * T2b-T2c **OR**
  * Gleason score 3+4=7/grade group 2 or Gleason score 4+3=7/grade group 3 **OR**
  * PSA 10-20 ng/mL

|

**High:**

  * T3a **OR**
  * Gleason score 8/grade group 4 or Gleason score 4+5=9/grade group 5 **OR**
  * PSA >20 ng/mL

**Very high:**

  * T3b-T4 **OR**
  * Primary Gleason pattern 5 **OR**
  * >4 cores with Gleason score 8-10/grade group 4 or 5

  
  
**Treatment Options**  
  
** 20 y life expectancy**

|

  * Active surveillance
  * EBRT or brachytherapy
  * RP  PLND (if predicted probability of lymph node metastasis 2%)

|   |   |   |  
  
** 10 y life expectancy**

|

  * Active surveillancea

|

  * Active surveillance
  * EBRT or brachytherapy alone
  * RP  PLND (if predicted probability of lymph node metastasis 2%)

|

  * Active surveillance
  * EBRT or brachytherapy alone
  * RP  PLND (if predicted probability of lymph node metastasis 2%)

|

  * RP  PLND (if predicted probability of lymph node metastasis 2%)
  * EBRT +ADT (4-6 mo.)
  * EBRT +brachytherapy  ADT (4-6 mo.)

|  
  
**< 10 y life expectancy**

|

  * Observation

|

  * Observation

|

  * EBRT or brachytherapy
  * Observation

|

  * EBRT +brachytherapy  ADT (4-6 mo.)
  * Observation

|  
  
**> 5 y life expectancy**

|   |   |   |   |

  * EBRT+ADT (2-3 y)
  * EBRT + brachytherapy + ADT (1-3 y)
  * RP + PLND

  
  


















































































aActive surveillance recommended for patients with 10-20 years life expectancy

PSA - Prostate Specific Antigen; EBRT - External Beam Radiation Therapy; RP -
Radical Prostatectomy; PLND - Pelvic Lymph Node Dissection; ADT - Androgen
Deprivation Therapy

Use of these stratification and treatment approaches has led to high cure
rates for early stage prostate cancer, yet it is widely accepted that many men
are over-treated to achieve this cure rate. In the Prostate Cancer
Intervention Versus Observation (PIVOT) trial4, men with early prostate
cancer, initially randomized to RP or observation, showed that over 12 years
there was no difference in absolute mortality between the groups. However,
this study was hampered by several factors including:

  * Only 731 of 5,023 eligible patients chose to participate in the study based on randomization criteria.
  * In the group randomized to RP: only 85% of the men received definitive therapy (79% surgery; 6% other).
  * In the observational group: 10% of the observation group received RP initially and additional 20% eventual received definitive treatment.
  * Despite broad inclusion criteria, > 50% of patients had a PSA of <10 (median PSA of 7) and had biopsy proven T1c disease. Although there were a significant number of patients with Gleason score 7 (25%), 40% of men were classified initially as being low risk; and 30% were intermediate.

Although subgroups were small, it appears that high risk groups (including
those with PSA > 10) benefitted from RP. Furthermore, there was a trend for
the intermediate risk patients to benefit from RP as well. The small number of
patients willing to enter the study, and the high rate of crossover (both
initially and subsequently) demonstrates the difficulty of doing observation
trials in the U.S.

Recent results from the Prostate Testing for Cancer and Treatment (ProtecT)
trial of men with primarily low risk prostate cancer randomized to active
surveillance or intervention with local therapy also highlight risks for men
deferring initial therapy. At a median of 10 years, death from prostate cancer
was low irrespective of the treatment assigned. However, roughly 20% of men
randomized to active surveillance experienced disease progression to an
incurable state (including metastatic disease, locally advanced prostate
cancer and need for long term chemical castration), a two-fold increase
compared to men treated with local therapy.5 In spite of the fact that a
sizeable portion of men managed with active surveillance will experience
disease progression to an incurable state, evidence also suggests that active
surveillance is under used. Data from the U.S. National Cancer Data Base and
the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE)
summarized prostate cancer diagnosis and management in the U.S., including
changes over time. Although the use of active surveillance for men with low
risk prostate cancer increased over time, it was utilized in only 18.4-40% of
patients despite societal guidelines supporting its use in this population. In
the intermediate risk group, active surveillance was pursued in only 4-8% of
patients.6,7

In summary, research shows refinement of the current risk stratification
techniques, techniques based on clinical and pathologic variables, could
potentially allow for a better assessment of a patient's risk of a poor
outcome in the absence of treatment, thereby avoiding unnecessary treatment in
men who are at a lower risk of disease progression to an incurable state. The
availability of molecular diagnostic tests that provide a more accurate
prediction of oncologic endpoints like 10-year disease specific mortality,
compared to standard clinical and pathologic features, provides an opportunity
to refine risk stratification and may identify men who may safely pursue
active surveillance and increase physician/patient confidence in that choice
or pursue treatment intensification for those identified at elevated risk for
disease progression. The benefits associated with active surveillance and
foregoing immediate intervention for appropriate men include a reduction in
treatment related complications and avoidance of adverse events.

For men that progress beyond biochemically recurrent prostate cancer to non-
metastatic castrate-resistant, there are multiple treatment options including
standard ADT versus intensified next-generation ADT with enzalutamide or
apalutamide with minimal guidance on who needs these expensive therapies.
Finally, for men with castration naive metastatic prostate cancer, treatment
options include observation, endocrine therapies, or orchiectomy.2 While,
consideration of the adverse effects associated with each of these therapies
is a recommended consideration, there is limited data in existing guidelines
to support a particular risk stratification approach based on clinical and
pathological features. However, risk of metastatic progression or death from
disease remain important considerations in decisions on treatment intensity.2

**Decipher** **** **Prostate Cancer Classifier Assay**

**Test Description**

Decipher Prostate is a 22 gene genomic classifier microarray assay, measuring
the expression of over 1.4 million RNAs (from coding and non-coding genes).
The assay is performed on FFPE prostate cancer tumor tissue from diagnostic
biopsy needle cores or prostate resection tissue (Transurethral resection
(TUR) or prostatectomy). The assay results are reported as a genomic
classifier (GC) score based on gene expression using a machine-learning
algorithm. The molecular pathways represented include proliferation/cell
death, invasion & metastasis, androgen signaling, immune activity & response,
growth & differentiation, angiogenesis and metabolism functions.

The test can be used to further risk stratify patients providing both a
continuous score and a categorization of that score into low, average or high-
risk with associated probabilities of high-grade disease, 5-year metastatic
risk and 10-year prostate cancer specific mortality.

**Test Performance**

Several clinical studies of patients with NCCN very low, low, or intermediate
risk prostate cancer who were potential candidates for active surveillance
demonstrate:

  * Decipher is an independent and significant predictor of prostate cancer tumor aggressiveness. The assay was clinically validated as a biopsy-based predictor of adverse pathology at RP (high-grade disease, pT3b or higher, or lymph node invasion), metastasis, and prostate cancer-specific mortality.
  * Decipher outperforms clinical and pathological risk factors currently used in standard practice (including pre-treatment PSA, clinical stage, Gleason Score/grade group or nomograms) and assesses underlying biology from very small biopsy tumor volumes, while also addressing issues of biopsy under-sampling, to predict disease aggressiveness.
  * In men with NCCN intermediate risk prostate cancer, Decipher classified low-risk patients had a low rate of adverse pathology, similar to NCCN very low or low-risk. Decipher high-risk patients, however, had a significantly higher rate of adverse pathology as compared to NCCN very low or low-risk.
  * In addition, men with NCCN intermediate or high-risk prostate cancer and a Decipher score of <0.45 have a low-risk of developing metastases and/or prostate cancer specific death at 10 years.
  * Decipher enables physicians to determine a) which patients with prostate cancer are candidates for active surveillance and are more likely to have a good outcome without immediate definitive treatment and b) which patients may receive the oncologic benefits of immediate or intensified treatment modalities.

**Clinical Validation for Adverse Pathology**

Three validation studies prospectively validated Decipher as a significant
predictor of adverse pathology at RP in men who were candidates for active
surveillance. Patients with adverse pathology such as high grade disease, pT3b
or higher or lymph node invasion are at increased recurrence and metastasis
risk, and not suitable for active surveillance candidates.

Kim et al.8 examined the ability of Decipher to predict adverse pathology in
266 men with NCCN very low, low and favorable intermediate risk patients.8
Decipher was an independent predictor of adverse pathology (OR, 1.29; 95%
confidence interval [CI], 1.03-1.61; p=0.025) in multivariable analysis (MVA).
Decipher risk group was associated with adverse pathology rate; 10.5% in
Decipher low risk men and 19.1% in Decipher intermediate/high risk men. The
authors also showed that a Decipher score below the threshold of 0.45 (upper-
bound of the Decipher low risk) had a negative predictive value (NPV) of 91%,
and a Decipher score below the threshold of 0.2 had an NPV of 96%.

Klein et al.9 clinically validated Decipher as a significant predictor of
adverse pathology at RP (OR, 1.52; 95% CI, 1.06-2.32; p=0.02) in a cohort
(n=57) balanced for NCCN low risk (40%), intermediate risk (47%) and
high/unknown risk (13%) patients.9 The study also showed that Decipher has a
c-index of 0.71 (95% CI, 0.56-0.86) for predicting adverse pathology at RP.

**Clinical Validation for Metastasis**

Several clinical validation studies demonstrated the high discrimination of
Decipher for predicting lymph node involvement or metastasis. Recently, a
study led by investigators at the University of California San Francisco Xu et
al10 confirmed the ability of Decipher to predict metastatic lymph node
involvement in a cohort of 91 NCCN intermediate and high risk disease
patients. In MVA adjusting for clinical risk factors, the study showed that
for every 10% increase in Decipher score was associated with an approximate
33-35% increase in the odds of harboring lymph node involvement as assessed on
subsequent 68 Ga-Prostate Specific Membrane Antigen (PSMA)-11 PET scan.10

Berlin et al11 investigated Decipher in an intermediate risk prostate cancer
cohort (n=121) treated uniformly with 78 Gy image-guided intensity-modulated
radiotherapy but without use of any neoadjuvant or adjuvant hormone therapy or
brachytherapy boost. The cohort consisted primarily of NCCN favorable (27%)
and unfavorable (72%) intermediate risk disease patients. Decipher
reclassified 72% of the cohort as low genomic risk. Berlin et al11 reported
that Decipher was a significant predictor of 5-year metastasis (HR, 2.05; 95%
CI, 1.24-4.24; p=0.004) in multivariable models adjusting for NCCN risk
groups. Also, the authors demonstrated that Decipher was significantly more
accurate than existing NCCN clinical criteria to predict metastasis (Decipher
AUC 0.86 vs NCCN AUC 0.54). Finally, the study showed a 0% 5-year cumulative
incidence of metastasis in Decipher low risk men but 14.3% in Decipher high
risk men.11

Spratt et al.12 demonstrated how the combination of NCCN and Decipher risk
groups using a simple summation method to create a novel clinical-genomic risk
system can dramatically improve risk stratification for clinically localized
prostate cancer patients. In the biopsy cohort (n=235) consisting primarily of
unfavorable intermediate (40%) and high (35%) risk patients, the clinical-
genomic model had an AUC of 0.84 (95% CI, 0.61-0.93) compared to 0.74 (95% CI,
0.65-0.84) with CAPRA alone for prediction of metastasis at 10 years post
definitive treatment. Compared with clinical-genomic low risk group, the
hazard ratio for metastasis was 21.3 (95% CI, 2.8-2728; p<0.001) and 62.5 (95%
CI, 8.5-7970; p<0.001) for clinical-genomic intermediate and high risk groups,
respectively. In combination with NCCN, men with low clinical-genomic risk had
10-year cumulative incidence of metastasis of 0% compared to 25.9% and 55.2%
for clinical-genomic intermediate and high risk groups, respectively
(p<0.001). Further in a subset analysis, men with both Decipher low and NCCN
low or favorable intermediate risk disease had 100% metastasis free survival
at 10 years.12

Nguyen et al.13 studied the validity of Decipher for predicting metastasis
for men treated with definitive radiation ( i.e., external beam radiation
therapy and/or brachytherapy with neoadjuvant ADT). The cohort (n=100)
consisted of NCCN intermediate (55%) and high (45%) risk group patients. In
MVA, each 0.1 unit increase in Decipher score was significantly associated
with time to distant metastasis (HR, 1.37; 95% CI, 1.06-1.78, p=0.014).
Decipher had a c-index of 0.76 (95% CI, 0.57-0.89) for predicting metastasis
at 5 years post definitive radiation, greater than NCCN risk groups and CAPRA
clinical risk model alone. Finally, the authors performed a sensitivity
analysis and found in survival analysis that for patients with a Decipher
score <0.2, there were no metastatic events at 10 years post definitive
radiation and suggested that these men may be candidates for de-
intensification of therapy. Furthermore, the study showed Decipher classified
26% of NCCN intermediate and high-risk men to Decipher high-risk with a
resulting 19.5% 5-year cumulative incidence of metastasis compared to 6.3% for
Decipher low-risk patients. The authors concluded that the Decipher high-
risk men would be good candidates for more potent systemic therapies and
further that a significant portion of men in this cohort perhaps were over
treated with hormone therapy.13

In a follow-on study led by the Dana-Farber group, Nguyen et al14 further
demonstrated the ability of Decipher to predict metastasis after definitive
therapy. The cohort consisted primarily of 54% NCCN intermediate and 32% NCCN
high risk treated with either definitive surgery (n=105) or radiation (n=130).
Decipher reclassified 60% of these patients to low genomic risk, 18% as
intermediate and 23% classified as high risk. In MVA, Decipher was a
significant predictor of metastasis (HR, 1.39; 95% CI, 1.15-1.69; p=0.001)
after adjusting for NCCN risk groups. The c-index for predicting 5-year
metastasis was 0.74 (95% CI, 0.63-0.83) for Decipher, which was substantially
better than 0.60 (95% CI, 0.50-0.69) for the CAPRA clinical risk model and
0.66 (95% CI, 0.53-0.77) for NCCN risk groups. In this study, the Decipher
low risk group had favorable outcomes with 5-year metastasis rate of only 4.1%
compared to 21.0% in those with Decipher high risk.14

Klein et al. 9 found similar performance of Decipher for predicting short and
long-term oncological outcomes when measured in tumor tissue from diagnostic
biopsy as compared to their original study in RP tissue. In MVA, Decipher was
shown to be a significant predictor of metastasis (HR, 1.66; 95% CI,
1.09-2.55; p=0.01) after adjusting for NCCN risk groups. Decipher alone had
an improved c-index for 10-year metastasis risk post RP of 0.80 (95% CI,
0.63-0.94) compared to NCCN model alone (c-index, 0.75; 95% CI, 0.64-0.87).
The c-index for Decipher plus NCCN model was much higher at 0.88 (95% CI,
0.77-0.96). Additionally, Decipher was a significant predictor of 5-year
metastasis post RP with c-index of 0.87 (95% CI, 0.76-0.97). Decipher
reclassified 48% of NCCN intermediate clinical risk men as low genomic risk
and none of these patients developed metastasis on study follow-up.9

**Clinical Validation for Prostate Cancer-Specific Mortality**

Decipher was also validated as a significant predictor of prostate cancer-
specific mortality. Using univariable analysis, Nguyen et al14 showed that
Decipher was a significant predictor of prostate cancer-specific mortality
(HR, 1.57; 95% CI, 1.03-2.48; p=0.037). Decipher risk group was associated
with 10-year cumulative incidence of prostate cancer-specific mortality--0% in
men with Decipher low risk vs. 9.4% in those with Decipher high risk.14





**End Point**

|





**Description**

|

**Results**  
  
---|---|---  
  
**MVA Effect Size**

**(95% CI, p** **-** **value)**

|

**AUC (95% CI) a**  
  
Decipher **b**

|

**Clinical Risk c**

|

Decipher

|

**Clinical Risk c \+ Decipher**  
  




Adverse pathologyd

|

Kim et al8

_Prostate Cancer Prostatic Disease_

N=266

|

OR 1.29

(1.03-1.61, p=0.025)

|

0.57

(0.47-0.68) [CAPRA]

|

0.65

(0.56-0.74)

|

0.65

(0.58-0.70)e  
  
Klein et al9

_Urology_

N=57

|

OR 1.52

(1.06-2.32, p=0.02)

|

NR

|

0.71

(0.56-0.86)

|

NR  
  


Biochemical Failure

|

Berlin et al11

_Int J Radiat Oncol Biol Phys_

N=121

|

HR 1.36

(1.09-1.71, p=0.007)

|

0.56

(0.43-0.66)

[NCCN, 5yr]

|

0.78

(0.59-0.91)

[5yr]

|

0.85

(0.73-1.00)f

[5yr.]  
  
















Metastasis

|

Xu et al10

_Eur Urol Oncol h_

|

OR 1.33

(1.04-1.71, p=0.02)

|

NR

|

NR

|

NR  
  
Berlin et al11

_Int J Radiat Oncol Biol Phys_

N=121

|

HR 2.05

(1.24-4.24, p=0.004)

|

0.54

(0.32-0.67)

[NCCN, 5yr]

|

0.86

(0.79-0.94)

[5yr]

|

0.89

(0.68-1.00)

[5yr.]  
  
Spratt et al12

_J Clin Onc_

N= 235

|

HR 21.3

(2.8-2728, p<0.001)

62.5

(8.5-7970, p<0.001)j

[CGRG Int, High ref: Low]

|

0.74

(0.65-0.84)

[CAPRA, 10yr]

|



NR

|

0.84

(0.61-0.93)i

[10yr]  
  
Nguyen et al13

_Prostate Cancer Prostatic Disease_

N=100

|

HR 1.37

(1.06-1.78, p=0.014)

|

0.63

(0.40-0.78)

[NCCN, 5yr]

|

0.76

(0.57-0.89)

[5yr]

|

NR  
  
Nguyen et al14

_Eur Urol_

N=235

|

HR 1.39

(1.15-1.69, p=0.001)

|

0.66

(0.53-0.77) [NCCN, 5yr]

|

0.74

(0.63- 0.83)

[5yr]

|

0.74

(0.66-0.82)f

[5yr]  
  
Klein et al9

_Urology_

N=57

|

HR 1.66

(1.09-2.55, p=0.01)

|

0.75

(0.64-0.87)

[NCCN, 10yr]

|

0.80

(0.63-0.94)

[10yr]

|

0.88

(0.77-0.96)

[10yr]  
  
Klein et al9

_Urology_ j

N=57

|

OR 1.93

(1.10-3.91, p=0.02)

|

NR

|

0.87

(0.76-0.97)

[5 yr]

|

NR  
  
Prostate Cancer- Specific Mortality

|

Nguyen et al14

_Eur Urol_

N=235

|

HR 1.57

(1.03-2.48, p=0.037)l

|

NR

|

 0.73

(0.54-0.85)g

[10 yr]

|

NR  
  
_MVA = multivariable analysis; CI = confidence interval; HR = hazard ratio; OR
= odds ratio; ref = reference group; NR = not reported; CGRG = Clinical
Genomic Risk Groups._

_a._ _Time is specified in square bracket if time_ _-_ _dependent AUC is
reported._

_b._ _Hazard ratios or odds ratios of Decipher  were reported per 10%
increase in score._

_c._ _Clinical risk model (indicated in square bracket) selected was the best
reported comparator (highest AUC)._

_d._ _Klein et al 9 Urology: primary Gleason pattern 4 or 5 (high grade
disease); Kim et al8 Prostate Cancer Prostatic Disease: primary Gleason
pattern 4 or 5, pT3b or higher, or LNI._

_e._ _The result reported is based on the OR of NCCN favorable intermediate
and Decipher  high risk group compared to NCCN very low/low. _

_f. AUCs of MVA models were corrected for optimism._

_g. 10 year mortality prediction_.

_h._ _The end point reported was lymph node involvement defined as PSMA_ _-_
_avid pelvic nodal involvement._

_i._ _The results reported are based on a clinical genomic point_ _-_ _based
system that combines NCCN and Decipher  risk groups._

_j. The end point reported was metastasis within 5 years._

**Guideline Review**

The NCCN Clinical Practice Guideline in Oncology for Prostate Cancer notes
that molecular assays may be able to reduce the uncertainty about the risk of
disease progression, but no tests have been studied with randomized controlled
trials.

Numerous prior Medicare coverage decisions have considered the evidence in the
hierarchical framework of Fryback and Thornbury15 where Level 2 addresses
diagnostic accuracy, sensitivity, and specificity of the test; Level 3 focuses
on whether the information produces change in the physician's diagnostic
thinking; Level 4 concerns the effect on the patient management plan and Level
5 measures the effect of the diagnostic information on patient outcomes. To
apply this same hierarchical framework to analyze an in vitro diagnostic test,
we utilized the ACCE Model Process for Evaluating Genetic Tests.16 The
practical value of a diagnostic test can only be assessed by taking into
account subsequent health outcomes. When a proven, well established
association or pathway is available, intermediate health outcomes may also be
considered. For example, if a particular diagnostic test result can be shown
to change patient management and other evidence has demonstrated that those
patient management changes improve health outcomes, then those separate
sources of evidence may be sufficient to demonstrate positive health outcomes
from the diagnostic test.

In the treatment of prostate cancer, a number of treatment approaches have
shown potential benefits for survival, but also significant adverse events.
Therefore, the risk of a patient having an unfavorable outcome due to prostate
cancer within the patient's expected lifetime is at the core of the management
of prostate cancer. Patients at a higher risk are recommended to have a
greater intensity of treatment. For the treatment of localized prostate cancer
there is a well-established risk stratification scheme based on clinical and
pathological factors, though even within a single risk stratum there is
significant variability, which Decipher has shown the ability to further
stratify. There are also numerous potential treatment options of varying
levels of intensity with varying severities of side effects, so the potential
benefit of treatment, which is heavily driven by risk stratum, must be weighed
against the downsides of therapy. For patients with recurrent or metastatic
disease there are also a number of effective treatment options of varying
intensity, also associated with varying severities of adverse events. While
there are no randomized controlled trials of outcomes using the Decipher
test, numerous studies from different institutions have all had similar and
consistent findings, providing evidence that this test accurately risk
stratifies patients based on genetic information and accurately predicts risk
of biochemical recurrence, metastatic disease, or prostate-cancer specific
mortality. Given that existing treatment paradigms are heavily reliant upon
risk assessment, the ability to accurately risk stratify has potential utility
in the management of prostate cancer. As such, this test provides clinically
actionable incremental information that fits into existing evidence-based or
consensus-recommended prostate cancer treatment paradigms.

Since this test helps inform clinicians at a decision point regarding the need
for treatment in the existing consensus treatment guidelines, the clinical
utility of this test hinges on both the framework's treatment recommendations,
and a certain level of decision uncertainty that accompanies treatment
decisions within this framework. As such, this contractor will continue to
monitor evidence and consensus recommendations regarding optimal selection of
treatment intensity, and coverage may be re-evaluated following any
substantial new evidentiary developments or guideline changes regarding the
treatment of patients who are currently considered to have unfavorable
intermediate risk prostate cancer. Such changes may include a new treatment
paradigm or the development of a risk-stratification tool for which high
quality, strength, and weight evidence shows improved outcomes and obviates
the need for previously developed tests.