Page 2 - Castration-resistant prostate cancer (CRPC): CUA/CUOG

Saad et al

In patients who develop CRPC, the addition or change with standard ADT in patients with nmCRPC at high risk
5
of first-generation androgen receptor antagonists may be for progression (PSADT of ≤10 months). The median MFS
considered (Level 3, Weak recommendation). was 40.5 months with apalutamide and 16.2 months with
To date, no study using first-generation androgen recep- placebo (hazard ratio [HR] for metastasis or death 0.28; 95%
tor antagonists, when introduced in the CRPC setting, has confidence interval [CI] 0.23–0.35; p<0.001). Secondary
shown survival benefits; most trials have been small, were endpoints analyzed, including progression-free survival
not designed to evaluate overall survival (OS), and were (PFS) (local and distant), time to PSA progression, and time
heavily confounded by future treatments used. In patients to subsequent therapy, were all statistically significantly
5
treated with luteinizing hormone-releasing hormone (LHRH) improved. Although more adverse events were reported in
agonist/antagonist monotherapy or those who have had an patients receiving ADT + apalutamide vs. ADT + placebo,
orchidectomy, the addition of androgen receptor antagonists, patient-reported health-related quality of life was similar
such as bicalutamide, can offer modest PSA responses that between both groups. 8
are short-lived in 30–35% of patients. 4
For patients who have undergone total androgen block- Enzalutamide
ade (TAB), the anti-androgen (AA) should be discontinued Enzalutamide is a second-generation AR ligand-binding
to test for an anti-androgen withdrawal response (AAWD). domain inhibitor. This agent was tested in combination
Changing AA or using corticosteroids with or without keto- with standard ADT in patients with nmCRPC at high risk
conazole have been noted to cause transient PSA reduc- for progression (PSADT of ≤10 months). The median MFS
6
tions in about 30% of patients but have not been shown to was 36.6 months with enzalutamide and 14.7 months with
improve any of the clinically meaningful outcome measures. placebo (HR for metastasis or death 0.29; 95% CI 0.24–
0.35; p<0.001). Secondary endpoints analyzed, including
Non-metastatic CRPC (nmCRPC) PFS (local and distant), time to PSA progression, and time
to subsequent therapy, were all statistically significantly
For men with high-risk nmCRPC, defined as a PSA doubling improved. Although more adverse events were reported in
time (PSADT) of less than 10 months, with an estimated life patients receiving ADT + enzalutamide vs. ADT + placebo,
expectancy of greater than five years should be offered apalu- patient-reported health-related quality of life was similar
tamide or enzalutamide (Level 1, Strong recommendation). between both groups. 9
Until 2018, there was no standard of care and no approved Both apalutamide and enzalutamide have received Health
regimen for the nmCRPC state. The risk of progression to Canada approval for use in high-risk nmCRPC.
clinical metastases or death is linked to PSADT. PSADT of
less than 10 months has been correlated to worse outcome Detection of metastases and imaging in untreated patients
and has been used in recent clinical trials as the definition For patients who progress on ADT without evidence of distant
for high-risk nmCRPC. Patients in these studies were ran- metastases, it is suggested to screen for bone metastases with
domized to treatment + ADT vs. placebo + ADT until the bone scans and monitor for lymph node and visceral metasta-
appearance of metastases on conventional imaging (bone ses/progression with imaging of the abdomen/pelvis and chest.
scan and computed tomography [CT]/magnetic resonance Patients with a rapid PSADT (<10 months) or elevated PSA
imaging [MRI] of the abdomen/chest). To date, two phase 3 levels (>20) are at high risk for developing metastases ear-
3
studies have led to Health Canada approvals for the treatment lier. Imaging in these patients should be performed every 3–6
of nmCRPC in Canada. Both studies used second-generation months. Patients with a slower PSADT (>10 months) should
androgen receptor (AR)-targeted therapies (apalutamide and be screened every 6–12 months (Expert opinion). Imaging
enzalutamide) and reported similar results in significantly techniques most commonly used include nuclear bone scans
improving the primary endpoint of metastases-free survival and abdominal/pelvic CT and chest X-ray. The role of positron-
(MFS). Median OS, a secondary endpoint, was not reached emission tomography (PET), such as prostate specific membrane
but at interim analysis showed a non-significant improve- antigen (PSMA)-PET are still unclear and the benefits unknown.
5,6
ment in both studies. Recently, darolutamide was tested in a If and when metastases are detected, patients should
similar patient population of high-risk nmCRPC with positive be treated according to guidelines for metastatic CRPC
results. At this time, this agent is not approved in Canada. 7 (mCRPC). How patients are treated in the mCRPC state will
depend on what they received prior to becoming mCRPC.
Summary of results
Treatment of mCRPC
Apalutamide
Apalutamide is a second-generation AR ligand-binding Since mCRPC is generally associated with a high risk of mor-
domain inhibitor. This agent was tested in combination bidity and cancer-related mortality, patients with mCRPC

308 CUAJ • October 2019 • Volume 13, Issue 10