This is a coverage policy for gene expression profile tests that assess risk
or predict therapeutic response in men who have an established diagnosis of
castration resistant or metastatic prostate cancer.

Such testing is considered reasonable and necessary to help guide treatment
decisions in men with prostate cancer and a life expectancy such that they are
candidates for prostate cancer treatment according to the most recent
nationally recognized guidelines at the time of testing or based on FDA
labelling of drugs and biologics available as potential treatment options.

The scope of this policy includes gene expression profile tests regardless of
methodology. It is exclusive of targeted and comprehensive genomic profiles
(CGP) by next generation sequencing (NGS) and single biomarker expression
analyses.

_**Coverage criteria:**_

  1. BOTH of the following criteria must be met:

    1. The beneficiary is being actively managed for castration resistant or metastatic (hormone sensitive or castration resistant) prostate cancer.
    2. The beneficiary is within the population and has the indication for which the test was developed and validated.
  2. At least 1 of the following criteria are met:

    1. The patient is a candidate for more than one management option, which could be considered to have varied, or increasing/decreasing levels of intensity based on a nationally recognized consensus guideline, and the physician and patient must decide among these treatments OR
    2. The patient is a candidate for more than one management option, and the test has shown that it predicts response to a specific therapy among accepted therapy options based on nationally recognized consensus guidelines and/or FDA labelling.
  3. The patient has not been tested with the same or similar test for prostate cancer.

  4. The patient has not received pelvic radiation or androgen deprivation therapy (ADT) prior to the biopsy or prostate resection specimen on which the test will be performed.

The only exception to this is for men who are naive to secondary systemic
therapies (that could be given after ADT monotherapy) AND at least 1 of the
following is true:

    1. They do not have other standard-of-care drug-targetable gene alterations to guide systemic therapy, as defined in nationally recognized guidelines OR
    2. They have other standard-of-care drug-targetable gene alterations to guide systemic therapy, as defined in nationally recognized guidelines but they are not eligible for those therapies for another reason.
  5. The test demonstrates analytical validity (AV), clinical validity (CV) and clinical utility (CU), establishing a clear and significant biological/ molecular basis for stratifying patients and subsequently selecting (either positively or negatively) a clinical management in a clearly defined population.

  6. Clinical validity of any analytes (or expression profiles) measured must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population.

  7. If the test relies on an algorithm, the algorithm must be validated in a cohort that is not a development cohort for the algorithm.

  8. Testing must be performed according to Clinical Laboratory Improvement Amendments (CLIA) and/or Food and Drug Administration (FDA) regulations in an accredited laboratory.

  9. The lab providing the test is responsible for clearly indicating to treating physicians the population and indication(s) for test use.

  10. The test successfully completes a Molecular Diagnostic Services Program (MolDX) Technical Assessment that ensures that AV, CV, and CU criteria set in this policy are met to establish the test as Reasonable and Necessary.

Genomic expression profile tests that demonstrate equivalent or superior
analytical and clinical validity to those covered by this contractor will be
considered reasonable and necessary for the same indications.

In the United States, prostate cancer (PC) is the most common cancer in men,
with an estimated 288,300 new cases projected in 2023 representing roughly 29%
of all new cancer cases in men.1 Men have a 12.6% chance of developing
prostate cancer during their lifetime.1 Prostate cancer is also the second
most common cause of cancer death in men with an estimated 34,700 deaths due
to prostate cancer in 2023, representing 11% of cancer-related deaths in men.1
Prostate cancer incidence and deaths have increased since 2014 after two
decades of decline; now, more than 30% of new cases are advanced cancers at
diagnosis.1 Reports of a shift toward higher grade and stage at initial
diagnosis have been attributed in large part to changes in prostate-specific
antigen (PSA) screening practices.1 Prostate cancer incidence in African
American men is 70% higher than in White men and prostate cancer mortality
rates in African American men are approximately two to four times higher than
those in every other racial and ethnic group.1 African American men may
benefit more from screening and from testing for genomic biomarkers because
they are more likely to harbor genomically aggressive cancer, even in
categorically lower risk tumors.2,3 Most cases of prostate cancer are
localized with excellent survival (>99%); however, the 5- year survival rate
is substantially lower (~30%) for patients with distant metastasis.1,4

A mainstay of therapy in prostate cancer is androgen deprivation therapy
(ADT). However, most castration sensitive prostate cancer (CSPC), also known
as hormone sensitive prostate cancer (HSPC) eventually becomes resistant to
ADT, a condition known as castration-resistant prostate cancer (CRPC).5 In
recent years, the evidence has shown that combining additional therapies with
ADT early during treatment for advanced and metastatic HSPC (mHSPC) prolongs
time to CRPC and improves overall survival (OS).6-10 For this reason,
combination therapy has become the standard of care in treating mHSPC.11-13
However, there are a number of options to use for combined therapy with ADT,
including androgen receptor signaling inhibitors (ARSIs), chemotherapy,
targeted therapy, immunotherapy, and combinations of these. Disease burden
(i.e. volume of disease) plays an important differential role in response to
therapy and is included in treatment guidelines.11,12 However, with the
exception of specific recommended triplet therapies currently recommended for
high volume mHSPC, the nationally recognized guidelines do not provide a
preferred approach for choosing among the various options when dual
combination therapy is appropriate.11-13 Further, some of the therapeutic
options include agents with significant toxicities and side effects. In
addition, prostate cancer is a heterogeneous disease with different underlying
genomic signatures and phenotypes that respond differentially to available
treatment options. As such, the use of molecular biomarkers to help guide the
choice of therapy is a welcome addition to the treatment arsenal for advanced
and metastatic prostate cancer.

Somatic and germline mutations in deoxyribonucleic acid (DNA) repair pathway
genes occur in approximately 20% of prostate tumors.14,15 Hereditary prostate
cancers are associated with hereditary breast and ovarian cancer (HBOC) and
Lynch syndromes, resulting from germline mutations in homologous recombination
repair (HRR) genes and DNA mismatch repair (MMR) genes, respectively.16,17
Patients with prostate cancer who have BRCA1/2 germline mutations in
particular have increased risk of progression and decreased overall survival
(OS).17,18 Patients with such HRR gene mutations respond to poly(adenosine
diphosphate-ribose) polymerase (PARP) inhibition.19 Similarly, patients with
MMR gene mutations, microsatellite instability and high tumor mutational
burden may respond to pembrolizumab.20 An estimated 89% of mCRPC tumors
contain a potentially actionable mutation; many of these are in the androgen
receptor (AR) gene and AR-signaling pathways with germline mutations reported
in approximately 12% of patients.15,21 For this reason, multigene tumor
testing for somatic and/or germline mutations is recommended for patients with
prostate cancer and is a covered service. Additionally, gene expression
profile tests (GEPs) also take advantage of prostate cancer heterogeneity to
further refine the risk for recurrence and metastasis and guide therapy
selection for patients with prostate cancer.

**Gene Expression Profile Tests**

NCCN guidelines recommend the Decipher Prostate (Veracyte) genomic risk
classifier, a GEP, to inform adjuvant treatment if adverse features are found
post-radical prostatectomy (RP) and to risk stratify patients with PSA
resistance/recurrence after RP.11 Decipher Prostate is a 22 RNA biomarker
test that was developed using a whole-transcriptome based approach.22-24 The
assay is performed on FFPE prostate cancer tumor tissue from the diagnostic
biopsy or prostate resection tissue. Results are reported as a genomic
classifier score (GC) between 0 and 1 (with higher scores indicating greater
risk of metastasis) based on gene expression using a machine-learning
algorithm. The molecular pathways represented include cell proliferation, cell
death, invasion and metastasis, androgen signaling, immune activity and
response, growth and differentiation, angiogenesis and metabolism functions.
It has been clinically validated to predict the risk of prostate cancer
metastasis at initial diagnosis or after radical prostatectomy.23,24

The Prediction Analysis of Microarray 50 gene expression profile (PAM50) is a
well-studied primary tumor classification system initially developed from
large-scale transcriptomic analyses of breast carcinoma.25-27 It is used to
partition breast carcinomas into multiple intrinsic subtypes, including
luminal A, luminal B, basal, HER2, and Normal-types. The classifier has
subsequently demonstrated the ability to subtype other solid tumors, including
urothelial and prostate cancers.28-30 In localized prostate cancer, a
PAM50-based analysis of samples from seven cohort studies found that luminal B
cancers displayed poor clinical outcomes following primary therapy but
outcomes were improved with the use of ADT; further, luminal B tumors
responded better than non-luminal B tumors to postoperative ADT.29
Additionally, prostate cancers classified by PAM50 as basal-like have been
found to be highly enriched for low AR signaling, with features resembling
mCRPC and high recurrence rates following primary treatment.31

More recently, the Decipher GC, PAM50 classifier and other gene expression
profile (transcriptomic) tests have been used to prognosticate and predict
response to therapy in advanced and metastatic prostate cancers. The
Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive
Disease in Prostate Cancer (CHAARTED) and the Systemic Therapy in Advancing or
Metastatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) trials
demonstrated a survival benefit of ADT in combination with docetaxel compared
to ADT monotherapy, particularly in the subgroup with high-volume
disease.6,7,32 A subanalysis evaluated the association of three different
transcriptomic signatures (Decipher GC, PAM50, and Androgen Receptor Activity
(AR-A)) with the response to therapy in men with mHSPC from the CHAARTED
trial.33 Expression profiling was performed on primary prostate cancer tissue.
The study found a nearly even split between luminal B and basal tumor
signatures; luminal A tumors were lacking, the rationale being that these tend
to be enriched in localized prostate cancer. Additionally, prognostic
information was found to vary according to transcriptomic subtype; for
example, higher GCs were associated with lower OS and ttCRPC. Moreover, a
positive effect of chemohormonal therapy on OS was observed across all GC
(risk score) groups; however the relative benefit varied by GC group and was
significantly greater in those with the highest GCs, termed Quartile 4 (Q4)
[Q4: hazard ratio (HR) 0.41 [95% confidence interval (CI) 0.19-0.84], p=0.01],
compared to those with the lowest GCs, termed Quartile 1 (Q1) [Q1: HR 0.72
[95% CI 0.29-1.73], p=0.46].33 Similarly, OS significantly improved in the
PAM50 Luminal B subgroup that was treated with docetaxel (median OS: 29.8 vs
52.1 months, HR 0.45 (95%CI 0.25-0.81), p=0.007).33 Though this effect was not
seen in the basal subgroup (even in those with high volume disease), patients
with both luminal B and basal subtypes showed an improved time to CRPC
(ttCRPC) with the addition of docetaxel. Finally, the addition of docetaxel
improved both OS and ttCRPC in all AR-A subtypes.33 Therefore, though the
benefit of combination therapy was seen across all subgroups, the magnitude of
benefit was greatest in patients with specific transcriptomic signatures,
particularly those with high GC score and luminal B subtype. This information
can serve as a guide when counseling patients regarding choice of one specific
therapeutic option over another.

Similar findings have been reported in men with CRPC. The Selective Prostate
Androgen Receptor Targeting with ARN-509 (SPARTAN) trial found that the
addition of apalutamide (APA), a second-generation ARSI, to ADT significantly
improved metastasis-free survival (MFS), time to second progression (also
referred to as time to progression-free survival 2 (PFS2), and OS in men with
nonmetastatic CRPC (nmCRPC).34 A subanalysis evaluated the association of the
Decipher GC and the PAM50 signatures with the response to therapy in men from
the SPARTAN trial.35 The study found that although all patients had improved
outcomes with the addition of APA to ADT vs. placebo + ADT, those with higher
GC scores showed the greatest improvements in MFS (HR 0.21; 95% CI, 0.11-0.40;
P < .001), OS (HR, 0.52; 95% CI, 0.29-0.94; P = .03), and PFS2 (HR, 0.39; 95%
CI, 0.23-0.67; P = .001).35 In the placebo + ADT arm, patients with higher-
risk GC scores showed significantly shorter MFS than those with lower-risk GC
scores. However, when patients received combination therapy with APA + ADT,
there was a substantial improvement in MFS outcomes for the GC-high patients
such that the GC high- and low-risk scores showed similar and overlapping MFS,
suggesting that the addition of APA overcame the poor prognosis associated
with a high-risk GC score.35 Finally, patients with the luminal subtype in the
APA + ADT arm had a significantly longer MFS (APA + ADT: HR, 0.40; 95% CI,
0.18-0.91; P = .03; placebo + ADT: HR, 0.66; 95% CI, 0.33-1.31; P = .23)
compared with patients with basal subtype; similar trends were observed for OS
and PFS2.35

The gene expression association studies described above were conducted in
primary tissue from prospective, double-blind, randomized trials, though the
transcriptomic analysis was performed retrospectively. Both of the studies
(one evaluating mHSPC and the other evaluating nmCRPC) found that although all
patients seemed to benefit from combination therapy with ADT, the greatest
benefit of combination therapy (with docetaxel or APA) was seen in patients
with high Decipher scores and in those with the luminal B subtype of prostate
cancer.33,35 Similarly, a retrospective analysis of 634 tissue biopsy samples
from four cohorts of men with mCRPC found that patients with luminal tumors
(found to be enriched with genes associated with androgen signaling) had
significantly better survival (HR, 0.27; 95% CI, 0.14-0.53; P < .001) than
patients with basal tumors (HR, 0.62; 95% CI, 0.36-1.04, P = .07) when treated
with ARSI combination therapy; this study also noted that the basal signature
was also seen almost exclusively in the small cell/ neuroendocrine subtype
tumors.36 Importantly, in this study, when they examined patients who received
prior ARSI therapy, the difference between luminal and basal tumors
disappeared.36

Studies have also evaluated the transcriptome of metastatic prostate tissue
samples. A recent study of men with mCRPC who progressed on ADT evaluated
whether genomic and transcriptomic features from metastatic biopsies prior to
treatment (with enzalutamide, abiraterone, or docetaxel) would be predictive
of de novo treatment resistance to enzalutamide, which occurs in approximately
one-third of men.37 The transcriptional findings demonstrated that gene sets
linked to low AR expression and a basal/stem cell signature were activated in
nonresponders and were associated with a more aggressive phenotype and worse
outcomes, as has been reported by others.36-38 Lower AR transcriptional
activity was associated with enzalutamide resistance; however, levels of AR
mRNA and protein expression were similar between nonresponders and responders,
suggesting that AR changes may not be good predictors of enzalutamide
response.37 Notably, only a single metastatic site was biopsied prior to
treatment; despite this, these biopsies did show features strongly associated
with de novo enzalutamide resistance, suggesting that single-site biopsy may
be adequate.37 Another retrospective study evaluated archived biopsies of
mCRPC samples from men who had died of prostate cancer to look for whether the
PAM50 classification can partition mCRPC into subtypes reflecting cell of
origin and whether these correlate with specific genomic aberrations or
cellular phenotypes.39 Basal tumors were found to be largely resistant to ADT
plus docetaxel and, as noted in prior studies,37,38 the neuroendocrine (NE)
tumors in the cohort were found to almost exclusively classify as basal.39
Importantly, these cells with small cell NE differentiation are generally AR-
null.40,41 This is unlike the mCRPC adenocarcinomas that have retained AR
signaling but still express luminal or basal signatures in near-equal
proportions, indicating that there are multiple drivers of the mCRPC
phenotype, an observation that also been documented in other reports.39,40
Finally, though phenotypes of most primary tumors and their metastases
remained intact despite therapy with ADT, docetaxel and ARSIs, there were
observed instances of discordance in cases where multiple metastatic tumors
were acquired. This occurred in 40% of men (n = 23) for who at least one tumor
received a discordant classification from other tumors; for a subset of these,
the assignment to a particular phenotype lacked confidence.39 Excluding tumors
with lower confidence PAM50 classification (<0.75) resulted in a 78%
concordance across tumors within an individual.39 Multiple additional studies
have also found (using a number of different genomic test methodologies) a
high degree of homogeneity between metastatic lesions within an
individual.42-44 Further research is needed to better define intra-individual
genomic tumor heterogeneity and divergence as well as phenotypic plasticity
that may occur as a result of pressures from systemic therapies.

Treatment approaches that utilize a patient's genomic signatures for the
selection of optimal therapeutics have become a standard of care for many
disorders. Comprehensive genomic profiling using NGS and select biomarker
testing are already considered to be standard-of-care and covered services for
Medicare beneficiaries with prostate cancer. Additionally, the Decipher GC has
been a covered service for Medicare beneficiaries with localized prostate
cancer. There is now evidence to support its use (and that of other gene
expression profiles) in the advanced and metastatic prostate cancer setting.
It is still expected that a patient will only require one such test for his
prostate cancer indication, preferably on a primary tumor sample. However, not
all men initially present with localized disease. Therefore, men who were not
previously tested using a GEP for localized cancer (because they initially
present with advanced or metastatic disease or because they were not
previously tested for their localized cancer for some other reason) may still
benefit from GEP testing of their tumor.

For castration resistant and metastatic prostate cancers, combination therapy
with more than one systemic and/or radiation/radioisotope-based modality is a
mainstay of treatment. However, there are multiple therapeutic options
available and guidelines do not necessarily recommend the use of these agents
in any other particular combination or in any particular series, particularly
for low-volume advanced and metastatic disease.11,12 For some of these men,
the choice may involve time and sequence -i.e. earlier combination therapy
with a preferred (for multiple possible reasons) choice of drug if the results
of a genomic expression profile suggest a benefit. For others, the choice may
be whether to begin a therapy that they would otherwise have been unwilling to
consider, if their genomic signature is found to respond particularly well to
that therapy. Here we underscore the significant adverse events reported with
some of the treatment options. The CHAARTED trial reported severe (Grade 3 and
4) adverse events with the use of docetaxel in approximately 30% of men.6
Additionally, a Cochrane review found that the addition of taxane-based
chemotherapy to ADT increases the incidence of Grade III to V adverse events
compared to ADT alone (risk ratio (RR) 2.98, 95% CI 2.19 to 4.04; low-
certainty evidence); this would result in 405 more Grade III to V adverse
events per 1,000 men (95% CI 243 to 621 more events).45 Antiandrogens have
their own array of side effects.46 Therefore, though the choice of therapy is
influenced by multiple clinical factors, including volume of disease and
eligibility for chemotherapy, if a patient's transcriptomic signature shows a
differential positive benefit with a particular treatment option (a non-
chemotherapy based option, for example) that information may facilitate choice
of treatment, given the array of available options with their varying side
effect profiles. Importantly, the differential responses to specific therapies
based on transcriptomic signatures have been shown to impact survival outcomes
and as such, these tests have demonstrated clinical value.

There remain unmet needs in this space, including the continued lack of
evidence for the most appropriate sequencing of available treatments and for
the most optimal approaches for treatment combinations and intensification of
therapy. Moreover, the data to-date do not clearly demonstrate a differential
benefit between the various dual combination treatment options, as there are
not head-to-head studies directly comparing outcomes with ADT plus docetaxel
versus ADT plus an ARSI in men with different transcriptomic profiles.
Nevertheless, it has become clear that even within a single risk stratum there
is significant heterogeneity in the underlying biology of prostate cancer that
can be further stratified. It is also clear that genomic expression profiles
have defined subtypes of tumors that show a greater or lesser magnitude of
response to specific therapies that can impact survival. Finally, it is
important to remember that even the currently recommended triple therapy
combinations for men with high volume metastatic disease are based on the
trials that were performed and showed a survival benefit.47,48 Importantly,
these did not include head-to-head comparisons with all possible combinations
of available ARSI options. Systematic reviews and meta-analyses have reported
that, even among these patients, certain dual combinations may result in
similar outcomes to those afforded by the triple combination therapies.49,50
The literature in this space is progressing rapidly and it is possible that
gene expression signatures may help inform therapy for this group of men as
well.

Genomic expression profiling in the guidance of prostate cancer therapy
remains an actively evolving area of medicine. There are abstracts and
preprints of journal articles we could not consider, as they were not fully
reviewed peer-reviewed publications at the time of drafting this local
coverage determination. There is also active ongoing research on the
relationship between tumor volume and cancer biology and aggressiveness.51
Additionally, research on the biology and potential therapeutic value of the
genomics of the metastatic lesions themselves continues to evolve.52 Further,
genomic studies are being performed to help guide not only the choice of
additional systemic therapies but also precision radiotherapy options in
prostate cancer.53 As such, this contractor will continue to monitor the
evidence, and new developments may impact this coverage decision.

**Finally, the mention of specific tests in this policy as part of the
literature review does not automatically imply coverage by this contractor.**