2022 Canadian Urological Association (CUA)- Canadian Uro Oncology Group (CUOG) guideline: Management of castration-resistant prostate cancer (CRPC)

Question 1

What is the definition of castration-resistant prostate cancer (CRPC)?

A. A continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases despite castrate levels of testosterone
B. A continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases despite high levels of testosterone
C. A reduction in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases despite castrate levels of testosterone
D. A continuous rise in serum prostate-specific antigen (PSA) levels, the reduction of pre-existing disease, and/or the disappearance of new metastases despite castrate levels of testosterone

Answer 1

A
Explanation: CRPC is defined by disease progression (rising PSA levels, progression of pre-existing disease, appearance of new metastases) despite castrate levels of testosterone.

Question 2

What factors go beyond PSA levels to associate with the prognosis of CRPC?

A. Performance status, presence of visceral metastases, presence of bone pain, extent of disease on bone scan, serum lactate dehydrogenase and alkaline phosphatase levels
B. Performance status, absence of visceral metastases, presence of bone pain, extent of disease on bone scan, serum lactate dehydrogenase and alkaline phosphatase levels
C. Performance status, presence of visceral metastases, absence of bone pain, extent of disease on bone scan, serum lactate dehydrogenase and alkaline phosphatase levels
D. Performance status, presence of visceral metastases, presence of bone pain, absence of disease on bone scan, serum lactate dehydrogenase and alkaline phosphatase levels

Answer 2

A
Explanation: The prognosis of CRPC is associated with factors such as performance status, presence of visceral metastases, presence of bone pain, extent of disease on bone scan, and serum lactate dehydrogenase and alkaline phosphatase levels. These factors go beyond just the PSA levels.

Question 3

Which of the following is NOT a common morbidity associated with bone metastases in men with CRPC?

A. Pain
B. Pathological fractures
C. Spinal cord compression
D. Bone marrow proliferation

Answer 3

D
Explanation: Bone metastases in men with CRPC can produce significant morbidity, including pain, pathological fractures, spinal cord compression, and bone marrow failure. Note the condition is bone marrow failure, not proliferation.

Question 4

What is the general recommendation regarding the continuation of ADT in patients with CRPC?

A. ADT should be discontinued as it is ineffective in CRPC
B. ADT should be continued for the remainder of a patient’s life
C. ADT should be replaced with first-generation androgen receptor antagonists
D. ADT should be continued only until first-generation androgen receptor antagonists are introduced

Answer 4

B
Explanation: Because the androgen receptor remains active in most patients who have developed castration-resistant disease, it is recommended that ADT be continued for the remainder of a patient’s life.

Question 5

How often should imaging be performed for patients with a rapid PSADT (<10 months) or elevated PSA levels (>20)?

A. Every 1-2 months
B. Every 3-6 months
C. Every 6-12 months
D. Once a year

Answer 5

B
Explanation: Patients with a rapid PSADT (<10 months) or elevated PSA levels (>20) are at high risk for developing metastases earlier. Imaging in these patients should be performed every 3–6 months.

Question 6

What should be done for patients who have undergone total androgen blockade (TAB) and develop CRPC?

A. The anti-androgen (AA) should be discontinued to test for an anti-androgen withdrawal response (AAWD)
B. The anti-androgen (AA) should be continued and first-generation androgen receptor antagonists should be added
C. The anti-androgen (AA) should be replaced with a second-generation androgen receptor antagonist
D. The anti-androgen (AA) should be replaced with a different type of AA

Answer 6

A
Explanation: For patients who have undergone total androgen blockade (TAB), the anti-androgen (AA) should be discontinued to test for an anti-androgen withdrawal response (AAWD).

Question 7

What is the recommendation for men with high-risk nmCRPC (PSADT of less than 10 months and estimated life expectancy of greater than five years)?

A. These patients should be offered apalutamide, enzalutamide, or darolutamide
B. These patients should be offered only apalutamide
C. These patients should be offered only enzalutamide
D. These patients should be offered only darolutamide

Answer 7

A
Explanation: Men with high-risk nmCRPC, defined as a PSA doubling time (PSADT) of less than 10 months, with an estimated life expectancy of greater than five years should be offered apalutamide, enzalutamide, or darolutamide.

Question 8

What is the impact of apalutamide on median Metastases-Free Survival (MFS) in patients with nmCRPC at high risk for progression?

A. The median MFS was 40.5 months with apalutamide and 16.2 months with placebo
B. The median MFS was 16.2 months with apalutamide and 40.5 months with placebo
C. The median MFS was 30 months with apalutamide and 20 months with placebo
D. The median MFS was 20 months with apalutamide and 30 months with placebo

Answer 8

A
Explanation: The median MFS was 40.5 months with apalutamide and 16.2 months with placebo (hazard ratio [HR] for metastasis or death 0.28; 95% confidence interval [CI] 0.23–0.35; p<0.001).

Question 9

What were the results of the final analysis of the impact of darolutamide on survival rate in patients with nmCRPC at high risk for progression?

A. After a median followup time of 29 months, the median survival rate at three years was 83% in the darolutamide cohort and 77% in the placebo group
B. After a median followup time of 29 months, the median survival rate at three years was 77% in the darolutamide cohort and 83% in the placebo group
C. After a median followup time of 29 months, the median survival rate at three years was 70% in the darolutamide cohort and 80% in the placebo group
D. After a median followup time of 29 months, the median survival rate at three years was 80% in the darolutamide cohort and 70% in the placebo group

Answer 9

A
Explanation: After a median followup time of 29 months, the median survival rate at three years was 83% in the darolutamide cohort and 77% in the placebo group (HR 0.69; 95% CI 0.53–0.88; p=0.003).

Question 10

What is the recommendation for maintaining ADT in the nmCRPC state?

A. ADT should be maintained and first-generation androgen receptor antagonists should be discontinued if patients are receiving these agents
B. ADT should be discontinued and first-generation androgen receptor antagonists should be continued if patients are receiving these agents
C. Both ADT and first-generation androgen receptor antagonists should be maintained
D. Both ADT and first-generation androgen receptor antagonists should be discontinued

Answer 10

A
Explanation: ADT should be maintained in the nmCRPC state. First-generation androgen receptor antagonists (i.e., bicalutamide, flutamide, etc.) should be discontinued if patients are receiving these agents.

Question 11

How often should patients who are untreated for nmCRPC be followed with regular imaging?

A. Every 1-3 months
B. Every 3-6 months
C. Every 6-12 months
D. Once a year

Answer 11

C
Explanation: Patients who are untreated for nmCRPC should be followed with regular imaging every 6–12 months depending on PSADT.

Question 12

What is the recommendation for men with high-risk nmCRPC who are felt to be unsuitable or refuse approved therapies?

A. Observation or use of first-generation androgen receptor antagonists may be attempted
B. These patients should be offered apalutamide, enzalutamide, or darolutamide regardless of their suitability or willingness
C. These patients should be offered only apalutamide
D. These patients should be offered only enzalutamide

Answer 12

A
Explanation: In men with high-risk nmCRPC who are felt to be unsuitable or refuse approved therapies, observation or use of first-generation androgen receptor antagonists may be attempted.

Question 13

In the chemo-naive setting, is abiraterone acetate recommended for asymptomatic or minimally symptomatic mCRPC?
a) Yes, it is recommended as a first-line therapy
b) No, it is not recommended
c) It is only recommended for symptomatic mCRPC
d) The recommendation depends on the individual patient’s condition

Answer 13

a) Yes, it is recommended as a first-line therapy
Explanation: Abiraterone acetate 1000 mg/day plus prednisone 5 mg twice daily is recommended for first-line therapy for asymptomatic or minimally symptomatic mCRPC.

Question 14

What is the role of enzalutamide in the chemo-naive setting for asymptomatic or minimally symptomatic mCRPC?
a) It is not recommended
b) It is recommended as a first-line therapy
c) It is only recommended after other therapies have failed
d) It is recommended as a second-line therapy after abiraterone acetate

Answer 14

b) It is recommended as a first-line therapy
Explanation: Enzalutamide 160 mg per day is recommended as first-line therapy for asymptomatic or minimally symptomatic mCRPC.

Question 15

In the post-docetaxel setting, how is abiraterone acetate used?
a) It is not recommended
b) It is recommended in patients progressing on or after docetaxel-based chemotherapy
c) It is recommended as a first-line therapy
d) It is recommended only for patients who have not responded to enzalutamide

Answer 15

b) It is recommended in patients progressing on or after docetaxel-based chemotherapy
Explanation: Abiraterone acetate 1000 mg per day plus prednisone 5 mg twice daily is recommended in patients progressing on or after docetaxel-based chemotherapy.

Question 16

What is the recommended first-line systemic chemotherapy for patients with metastatic castration-resistant prostate cancer (mCRPC)?

Answer 16

Docetaxel 75 mg/m2 intravenous (IV) every three weeks with 5 mg oral prednisone twice daily.

Question 17

What were the three treatment arms in the TAX-327 study?

Answer 17

1) Docetaxel 75 mg/m2 IV every three weeks; 2) Docetaxel 30 mg/m2 weekly for five of six weeks; 3) Control therapy with mitoxantrone.

Question 18

What survival advantage did docetaxel (every three weeks) show compared to mitoxantrone-prednisone in the TAX-327 study?

Answer 18

Median survival was 18.9 months with docetaxel compared to 16.5 months with mitoxantrone-prednisone.

Question 19

Median survival was 18.9 months with docetaxel compared to 16.5 months with mitoxantrone-prednisone.

Answer 19

Quality of life response was defined as a sustained 16-point or greater improvement from baseline on two consecutive measurements. It was higher with docetaxel given every three weeks (22% vs. 13%) or weekly (23% vs. 13%) compared with mitoxantrone.

Question 20

What is recommended for patients who do not respond to first-line ADT or who progress clinically or radiologically without significant PSA elevations?

Answer 20

These patients may have neuroendocrine differentiation. A biopsy of accessible lesions should be considered. If confirmed, these patients should be treated with combination chemotherapy, such as cisplatin/etoposide or carboplatin/etoposide.

Question 21

What is the recommended second-line systemic chemotherapy for mCRPC patients progressing on or following docetaxel?

Answer 21

Cabazitaxel.

Question 22

What were the results of a phase 3 study comparing cabazitaxel to mitoxantrone in patients previously treated with docetaxel?

Answer 22

The study showed a statistically significant survival advantage for the cabazitaxel group, with a median survival of 15.1 months compared with 12.7 months in the mitoxantrone group.

Question 23

What can be considered for patients who have had a good response to first-line docetaxel?

Answer 23

Re-treatment with docetaxel can be considered.

Question 24

When is Radium-223 recommended for patients with mCRPC?

Answer 24

Radium-223 is recommended for bone symptomatic mCRPC patients who have progressed following taxane chemotherapy or are unfit for chemotherapy and do not have visceral metastases.

Question 25

What is the mechanism of action of Radium-223 and its impact on patient survival?

Answer 25

Radium-223, an intravenous alpha-emitting agent, mimics calcium and preferentially targets bone metastases. It improves overall survival by 3.6 months and delays symptomatic skeletal-related events by 5.8 months.

Question 26

Why can’t PSA measurements be used to evaluate the effectiveness of Radium-223?

Answer 26

PSA measurements are not a good indicator of the effectiveness of Radium-223, given the drug’s mechanism of action. Alkaline phosphatase appears to be a better marker of activity.

Question 27

Which agent should always be used when using Radium-223 and why?

Answer 27

A bone-supportive agent (denosumab or zoledronic acid) should always be used when using Radium-223 to prevent an increased risk of fractures.

Question 28

When is 177Lu-PSMA-617 recommended for use in patients with mCRPC?

Answer 28

177Lu-PSMA-617 is recommended for patients with mCRPC and PSMA-expressing metastatic lesions who have progressed on at least one previous taxane chemotherapy and an androgen receptor-axis-targeted therapy (ARAT).

Question 29

When is Radium-223 recommended for patients with mCRPC?

Answer 29

Radium-223 is recommended for bone symptomatic mCRPC patients who have progressed following taxane chemotherapy or are unfit for chemotherapy and do not have visceral metastases.

Question 29

177Lu-PSMA-617 is recommended for patients with mCRPC and PSMA-expressing metastatic lesions who have progressed on at least one previous taxane chemotherapy and an androgen receptor-axis-targeted therapy (ARAT).

Question 30

What are the benefits of 177Lu-PSMA-617 over cabazitaxel, according to the TheraP study?

Answer 30

The TheraP study showed that a significantly higher proportion of patients (66% vs. 37%) in the Lu-PSMA-617 arm had at least a 50% reduction in PSA from baseline. Grade 3–4 adverse events occurred less frequently in the 177Lu-PSMA-617 treatment group (33% vs. 53% in the cabazitaxel group).

Question 31

When is Radium-223 recommended for patients with mCRPC?

Answer 31

Radium-223 is recommended for bone symptomatic mCRPC patients who have progressed following taxane chemotherapy or are unfit for chemotherapy and do not have visceral metastases.

Question 32

What were the clinical benefits of 177Lu vipivotide tetraxetan + SoC over SoC alone, according to the VISION trial?

Answer 32

The VISION trial demonstrated that 177Lu vipivotide tetraxetan + SoC prolonged median overall survival by 4 months, reduced risk of death by 38%, prolonged radiographic progression-free survival by 5.3 months, reduced risk of disease progression by 60%, and prolonged median time to first symptomatic skeletal event (SSE) or death by 4.7 months.

Question 33

What adverse events were noted in the Lu-PSMA-617 arm of the VISION trial?

Answer 33

Myelosuppression was noted in 47.4% (grade 3–5 in 23.4%) of patients in the Lu-PSMA-617 arm. Additional concerning adverse events included fatigue, xerostomia due to expression of PSMA in salivary glands, and nausea-vomiting.

Question 34

What is the recommended dosage of olaparib for patients with metastatic castration-resistant prostate cancer (mCPRC) and HRR mutation who have progressed on a previous androgen receptor-axis targeted therapy (ARAT)?

Answer 34

The recommended dosage of olaparib for such patients is 300 mg twice daily.

Question 35

Approximately what percentage of prostate cancers from patients with metastatic disease carry HRR gene mutations?

Answer 35

HRR gene mutations occur in approximately 20–30% of prostate cancers from patients with metastatic disease.

Question 36

What is the most commonly altered gene in prostate cancers with HRR mutations?

Answer 36

The most commonly altered gene is BRCA2.

Question 37

What renders a cancer susceptible to poly (ADP-ribose) polymerase (PARP) inhibition in a form of synthetic lethality?

Answer 37

Defective homologous recombination repair (HRR) renders a cancer susceptible to PARP inhibition.

Question 38

What were the radiographic progression-free survival (PFS) results for patients with BRCA1/2 or ATM mutations in the PROfound trial?

Answer 38

The radiographic PFS was significantly improved in the olaparib arm, with results favoring olaparib (7.39 months) versus the physician’s choice of enzalutamide/abiraterone (3.44 months), with a hazard ratio (HR) of 0.34.

Question 39

The radiographic PFS was significantly improved in the olaparib arm, with results favoring olaparib (7.39 months) versus the physician’s choice of enzalutamide/abiraterone (3.44 months), with a hazard ratio (HR) of 0.34.

Answer 39

The overall survival was significantly improved in the olaparib arm, with a median OS of 19.1 months versus 14.7 months in the physician’s choice arm. The hazard ratio was 0.69.

Question 40

What were the common adverse events reported in the olaparib arm of the PROfound study?

Answer 40

The common adverse events were anemia, fatigue, nausea, and diarrhea.

Question 41

What is the scope of approval for olaparib by Health Canada, the US Food and Drug Administration, and the European regulatory authority?

Answer 41

Health Canada approved olaparib for patients with deleterious or suspected deleterious germline or somatic BRCA1/2 or ATM mutations who have progressed following prior treatment with an NHT (i.e., abiraterone, enzalutamide, apalutamide, darolutamide). The U.S. FDA approved olaparib for prostate cancers harboring a broader spectrum of 11 additional genes directly or indirectly involved in HRR. The European authority approved olaparib only for BRCA1/2 alterations.

Question 42

Figure 1

Answer 42

Management of CRPC

Question 43

What are the key points about Bone-supportive agents in the management of CRPC according to the 2022 CUA-CUOG guidelines?

Answer 43

Denosumab (120 mg SC) and zoledronic acid (4 mg IV) are recommended every four weeks to prevent disease-related skeletal-related events (SREs) in men with CRPC and bone metastases.

Question 44

What are the key points about Bone loss and ADT in the management of CRPC according to the 2022 CUA-CUOG guidelines?

Answer 44

Bone loss associated with androgen deprivation therapy (ADT) increases the risk of fracture. About 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) will develop bone metastases, leading to local decreases in bone integrity and significant risk of SREs.

Question 45

What are the key points about Zoledronic acid in the management of CRPC according to the 2022 CUA-CUOG guidelines?

Answer 45

Zoledronic acid is a third-generation nitrogen-containing bisphosphonate. It reduced the rate of SREs by 36% in treated patients compared to placebo. It also increased the median time to first SRE. However, it should not be used in men with baseline creatinine clearance <30 mL/min.

Question 46

What are the key points about Denosumab in the management of CRPC according to the 2022 CUA-CUOG guidelines?

Answer 46

Denosumab is a fully humanized monoclonal antibody against RANK ligand. It has been shown to be effective in preventing bone loss and new vertebral fractures due to ADT. In mCRPC, denosumab has shown significant improvement in the time to the first SRE compared to zoledronic acid. No dose modification for renal function is necessary, but the risk of hypocalcemia is increased.

Question 47

What are the key points about Oral hygiene and dental evaluation in the management of CRPC according to the 2022 CUA-CUOG guidelines?

Answer 47

Good oral hygiene, baseline dental evaluation for high-risk individuals, and avoidance of invasive dental surgery during therapy are recommended to reduce the risk of osteonecrosis of the jaw (ONJ) for patients treated with bone-targeted therapies.

Question 48

What are the key points about Optimal duration in the management of CRPC according to the 2022 CUA-CUOG guidelines?

Answer 48

The optimal duration of zoledronic acid and denosumab in men with CRPC and bone metastases is undefined. The risk of ONJ appears to be related to time on bone-targeted therapy, so caution should be taken in using these agents beyond two years.

Question 49

What are the key points about Indications in the management of CRPC according to the 2022 CUA-CUOG guidelines?

Answer 49

Denosumab and zoledronic acid are not approved and not indicated for SRE prevention in the treatment of metastatic castration-sensitive prostate cancer or for bone metastases prevention.

Question 50

What are the potential benefits of systemic corticosteroid therapy in managing castration-resistant prostate cancer (CRPC)?

Answer 50

Corticosteroid therapy with low-dose prednisone or dexamethasone may offer improvements in PSA values and/or palliative outcomes in up to 30% of patients. This therapy is effective in both symptomatic and asymptomatic men. Steroids may also exert an anti-neoplastic effect on prostate cancer.

Question 51

When is Radium-223 recommended for patients with mCRPC?

Answer 51

Radium-223 is recommended for bone symptomatic mCRPC patients who have progressed following taxane chemotherapy or are unfit for chemotherapy and do not have visceral metastases.

Question 52

What level and strength of recommendation is given to the use of corticosteroid therapy in CRPC according to the 2022 CUA-CUOG guidelines?

Answer 52

Level 3, Weak recommendation.

Question 53

How effective is palliative radiation in treating bone metastases from prostate cancer?

Answer 53

Most men will experience partial or complete pain relief from external beam radiation to a specific lesion. Bone metastases from prostate cancer are often radiosensitive.

Question 54

What are the comparative benefits of single fraction versus multiple fraction standard palliative radiotherapy (RT) for prostate cancer?

Answer 54

A single fraction of standard palliative RT is as effective as five or more fractions in providing palliation. However, more patients require retreatment for pain recurrence with single fraction radiation.

Question 55

What is Stereotactic body RT (SBRT) and when can it be considered in the management of CRPC?

Answer 55

SBRT is a more precise form of palliation delivered in five or fewer treatments. It can be considered particularly for oligometastatic disease where high-dose RT is currently being studied for improved oncological outcomes.

Question 56

What is the management approach for malignant spinal cord compression in the context of CRPC?

Answer 56

Malignant spinal cord compression is an oncological emergency that requires immediate diagnosis with an MRI. Options for treatment are debulking surgery + RT, vertebrectomy with stabilization and RT, or RT + steroids.

Question 57

What level and strength of recommendation is given to the immediate diagnosis and treatment of malignant spinal cord compression in CRPC according to the 2022 CUA-CUOG guidelines?

Answer 57

Level 1, Strong recommendation.

Question 58

When is Radium-223 recommended for patients with mCRPC?

Answer 58

Radium-223 is recommended for bone symptomatic mCRPC patients who have progressed following taxane chemotherapy or are unfit for chemotherapy and do not have visceral metastases.

Question 59

When is Radium-223 recommended for patients with mCRPC?

Answer 59

Radium-223 is recommended for bone symptomatic mCRPC patients who have progressed following taxane chemotherapy or are unfit for chemotherapy and do not have visceral metastases.

Question 60

When is Radium-223 recommended for patients with mCRPC?

Answer 60

Radium-223 is recommended for bone symptomatic mCRPC patients who have progressed following taxane chemotherapy or are unfit for chemotherapy and do not have visceral metastases.