Campbell-Walsh Urology, 11th Edition

PART XIV

Prostate

121

Treatment of Castration-Resistant Prostate Cancer

Emmanuel S. Antonarakis; Michael A. Carducci; Mario A. Eisenberger

Questions

1. The term “castration-resistant disease” has replaced the older classification of “hormone-resistant disease” used to define all patients who demonstrate evidence of disease progression after initial androgen deprivation treatment because:
2. androgen deprivation treatment focusing on medical/surgical castration is the initial systemic approach for patients with metastatic prostate cancer.
3. in patients with castration-resistant disease, responses to subsequent androgen-receptor–targeted treatments continue to show a benefit.
4. current data indicate that the androgen receptor continues to play a major role in the control of prostate cancer growth even when serum levels of testosterone are in the castrate range (less than 50 ng/dL).
5. castration resistance does not equal hormone resistance.
6. all of the above adequately describe the castration-resistant state.
7. Patients eventually stop benefiting from primary and secondary hormonal treatments and become refractory. Which of the following statement (s) INCORRECTLY defines the “castration-resistant” paradigm?
8. Careful clinical monitoring of patients in clinical practice, including regular physical exams and sequential assessments of radiologic parameters and serum prostate-specific antigen (PSA) levels, facilitates early identification of patients who are becoming resistant to secondary hormonal manipulations.
9. The definition of castration resistance is based on well-defined clinical and pathologic criteria such as Gleason score and extent of disease.
10. Determination of castration resistance requires clinical evidence of disease progression to primary and secondary hormonal manipulations.
11. The vast majority of patients treated with endocrine manipulations will develop evidence of disease progression and eventually require chemotherapy.
12. Docetaxel remains the standard first-line chemotherapy treatment for patients with metastatic castration-resistant prostate cancer considered candidates for this modality. Which of the following statement(s) is NOT true?
13. Docetaxel infusion every 3 weeks (as many as 10 cycles) given in conjunction with daily oral prednisone is the standard schedule that has been shown to prolong survival and improve quality of life compared with mitoxantrone.
14. Significant clinical benefits are seen in patients regardless of their age, functional status, and presence or absence of pain.
15. Patients with metastatic castration-resistant disease who have favorable functional status (fully ambulatory, asymptomatic), no visceral involvement, and normal hemoglobin and serum lactate dehydrogenase (LDH) have survival outcomes frequently in excess of 2 years.
16. Frequent toxicities associated with docetaxel treatment include fatigue, myelosuppression, modest neuropathy, lacrimation, and nail changes, among others. Routine evaluation before each cycle is indicated.
17. Patients demonstrating rising serum PSAs during the first three cycles of treatment should be taken off treatment because it is not effective.
18. Cabazitaxel is another taxane approved for metastatic castration-resistant prostate cancer. In preclinical studies that used cancer cell lines and mouse xenograft models, cabazitaxel was shown to be active in docetaxel-sensitive tumors as well as those with primary or acquired docetaxel resistance. Which of the following statements adequately describes the clinical experience with this compound?
19. Cabazitaxel was shown to prolong survival compared with mitoxantrone in patients previously treated with docetaxel.
20. The toxicity pattern of cabazitaxel suggests a lower incidence of neuropathy, fatigue, lacrimation, and nail changes but has a higher incidence of neutropenic fever and diarrhea compared with docetaxel.
21. Data on the TROPIC trial suggest that patients who fail to respond or develop early evidence of disease progression after docetaxel may benefit from cabazitaxel.
22. Patients demonstrating disease progression after docetaxel can still survive longer than 1 year with cabazitaxel treatment.
23. All of the above are correct.
24. After initial gonadal suppression, androgen receptor (AR) signaling is upregulated in castration-resistant disease and continues to play a major role in tumor growth. Which of the following statement(s) adequately describes AR-targeted treatments?
25. CYP17 inhibitors target androgen synthesis both of adrenal and intracrine source and yield significant benefit in patients treated with first-line gonadal suppression who subsequently develop evidence of disease progression. This effect has been shown in patients with or without previous treatment with docetaxel.
26. The side effects with abiraterone acetate include a mineralocorticoid excess state (efficiently prevented by a concomitant administration of prednisone), fatigue, abnormal liver function tests, possible cardiac toxicity, and potential drug interactions.
27. Enzalutamide is a more recent nonsteroidal antiandrogen that differs from the first-generation compounds (flutamide, bicalutamide, and nilutamide) based on a greater AR affinity, AR nuclear translocation, and DNA binding. Most patients with castration-resistant disease benefit from treatment, which was shown to be significantly superior to placebo in prospective randomized trials.
28. The benefits from CYP17 inhibitors (abiraterone) and AR antagonists (enzalutamide) are most likely more pronounced in patients who have not received prior docetaxel treatment.
29. All of the above are correct.
30. Which of the following statements is correct regarding patients with widely metastatic prostate cancer who present with back pain?
31. Administration of narcotic analgesics is the appropriate management, and if pain management becomes more challenging, patients should be referred to hospice.
32. All patients with known bone metastasis should be carefully assessed clinically for the possibility of epidural cord or nerve root compression. Administration of high-dose dexamethasone and early magnetic resonance imaging (MRI) should be used, and more definitive treatment with radiation or neurosurgical decompression should be considered.
33. Patients with back pain and stable skeletal radiographs should be treated with narcotic analgesics and corticosteroids. If improvement occurs, no further evaluation is necessary.
34. If the PSA is not rising and the workup with a bone scan and CT scans reveal stable disease, it can be assumed that cord compression or other complex neurologic involvement is unlikely.
35. Most current systemic treatments are effective for managing extensive bone metastasis even if there is evidence of nerve root or cord compression.
36. A small proportion of patients with advanced-stage disease develop a syndrome of rapid and dramatic development of severe symptoms (pain, obstruction, weight loss) and clinical evidence of rapidly growing disease with soft tissue and organ involvement. In these patients, typically serum PSA levels are either below detectable levels or grossly disproportionate to the other extent of disease parameters. Which statement is correct regarding this rare event in castration-resistant prostate cancer?
37. These patients usually benefit from hormonal therapy including all AR-targeted compounds
38. Serum PSA is low or undetectable and the PSA stains in tumor biopsies are usually negative. These tumors do not express androgen receptors.
39. A small proportion of patients demonstrate evidence of a rapidly progressing disease predominantly involving visceral sites, with low or no PSA expression. Biopsy is indicated because it will affect treatment decisions.
40. Patients with this clinical syndrome often demonstrate anaplastic tumors at biopsy, some with small-cell features, and most stain positive for neuroendocrine markers. Platinum-based chemotherapy has been show to offer some benefits for patients with the small-cell variety, whereas those with anaplastic tumors that are not of the small-cell subtype should be treated with taxane-based chemotherapy.
41. All statements are correct except a.
42. The radium-223 radiopharmaceutical was approved for the treatment of patients with metastatic castration-resistant disease. Which statement regarding ²²³Ra is FALSE?
43. Radium-223 is an alpha-emitting radiopharmaceutical that has recently shown to be associated with a survival advantage compared to symptomatic/palliative care.
44. Alpha particles are approximately 7000 times heavier than beta particles, and as few as one or two hits can be sufficient to cause cell death, in comparison with hundreds or thousands of hits required from beta particles. In addition, alpha particles have a very short path length (less than 100 μm), which may spare surrounding healthy bone marrow, thereby limiting hematologic toxicities.
45. Radium-223 infusion has shown a very favorable toxicity spectrum with low hematological toxicity rates.
46. It is indicated for patients with bone metastasis, hemoglobin greater than 10 g/L and lymph-node metastasis smaller than 3 cm.
47. It was approved only for patients who have received prior docetaxel treatment.
48. Sipuleucel-T is a personalized vaccine derived from autologous CD54 + dendritic cells, the major class of antigen-presenting cells, which are apheresed from individuals and processed with a recombinant fusion protein made up of PAP and GM-CSF. Which statement is TRUE regarding this treatment?
49. Sipuleucel-T is approved for all patients with castration-resistant disease as long as they are symptomatic.
50. Sipuleucel-T treatment results in PSA declines and prolongation of progression-free survival, but no survival improvements.
51. Sipuleucel-T should be offered to patients with no evidence of metastasis as long as their disease is castration resistant.
52. Sipuleucel-T is a treatment option for patients with minimally or asymptomatic metastatic prostate cancer. Treatment is generally very safe. There is no evidence that sipuleucel-T treatment causes symptomatic relief, any clinically meaningful PSA declines, or delay in disease progression. The drug was approved based on a survival benefit compared to placebo.

Answers

1. e. All of the above adequately describe the castration-resistant state.
2. b. The definition of hormone resistance is based on well-defined clinical and pathologic criteria such as Gleason score and extent of disease.
3. e. Patients demonstrating rising serum PSAs during the first three cycles of treatment should be taken off treatment because it is not effective.
4. e. All of the above are correct.
5. e. All of the above are correct.
6. b. All patients with known bone metastasis should be carefully assessed clinically for the possibility of epidural cord or nerve root compression. Administration of high-dose dexamethasone and early magnetic resonance imaging (MRI) should be used, and more definitive treatment with radiation or neurosurgical decompression should be considered.
7. e. All statements are correct except a.
8. e. It was approved only for patients who have received prior docetaxel treatment.
9. d. Sipuleucel-T is a treatment option for patients with minimally or asymptomatic metastatic prostate cancer. Treatment is generally very safe. There is no evidence that sipuleucel-T treatment causes symptomatic relief, any clinically meaningful PSA declines, or delay in disease progression. The drug was approved based on a survival benefit compared to placebo.

Chapter review

1. Androgen ablation induces apoptosis.
2. The androgen receptor may be stimulated by hormones other than androgens, including estrogens and progestins as well as growth factors and cytokines.
3. Patients with castration-resistant disease are not androgen independent and should be maintained on ablative hormonal therapy.
4. PSA doubling time (PSADT) may be used to predict bone scan progression and survival; a PSADT of less than 3 months is associated with a rapid clinical course.
5. When evaluating therapeutic agents, progression-free survival is a better end point than response rate.
6. PSA may or may not be affected by drugs that are efficacious, and therefore it is not a good marker to evaluate new drugs—perhaps circulating tumor cells will become a better marker.
7. Docetaxel is the first-line chemotherapeutic agent for metastatic castration-resistant prostate cancer.
8. Abiraterone inhibits enzymes involved in androgen synthesis. It does result in secondary mineralocorticoid excess with resultant hypertension and hypokalemia, and as such it is commonly given with prednisone. Occasionally, when secondary mineralocorticoid excess causes significant abnormalities, a mineralocorticoid antagonist may be necessary.
9. Bone metastases in prostate cancer are usually blastic; hypercalcemia is rare.
10. Suspected spinal cord compression from prostate metastases may be diagnosed with a spinal MRI. Those with compression or impending compression, if they are not androgen suppressed, should have an immediate orchiectomy or be given aminoglutethimide or ketoconazole and high-dose corticosteroids. A decompression laminectomy and radiation therapy should be considered.
11. Bisphosphonates are used to limit skeletal events. Oral calcium supplements as well as vitamin D may be necessary.
12. Radiopharmaceuticals used to treat bone pain due to prostate metastases include the beta-emitters strontium-89 and samarium-153. These agents may cause severe myelotoxicity. The alpha-emitter radium-223 shows promise in palliating bone pain without the myelosuppressive effects of the beta-emitters.
13. Rarely, patients with advanced prostate cancer may have a transformation of their tumor to a neuroendocrine/anaplastic variant. These tumors are endocrine resistant, frequently involve the viscera and brain, have little impact on PSA, and are treated with platinum-based chemotherapy.
14. After initial gonadal suppression, AR signaling is upregulated in castration-resistant disease and continues to play a major role in tumor growth.
15. Sipuleucel-T is a treatment option for patients with minimally or asymptomatic metastatic prostate cancer. Treatment is generally very safe. There is no evidence that sipuleucel-T treatment causes symptomatic relief, any clinically meaningful PSA declines, or delay in disease progression. The drug was approved based on a survival benefit compared with placebo.