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 This is an original JCO publication from 2017. Please visit the JCO website to access the full article.


Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion

 

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titleAuthors

Katherine S. Virgo, Ethan Basch, D. Andrew Loblaw, Tom Oliver, R. Bryan Rumble, Michael A. Carducci, Luke Nordquist, Mary-Ellen Taplin, Eric Winquist, and Eric A. Singer


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THE BOTTOM LINE


Second-Line Hormonal Therapy for Men With Chemotherapy-Naïve, Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion

Research Question

Do second-line hormonal therapies play a role in the treatment of chemotherapy-naïve men with castration-resistant prostate cancer (CRPC)?

Target Population

Chemotherapy-naïve men with CRPC maintained in a continuous or intermittent castrate state through orchiectomy or pharmacologic castration. The primary target population is asymptomatic men but also includes those with minimal symptoms.

Target Audience

Urologists, radiation, and medical oncologists.

Methods

Systematic review of the medical literature along with a formal consensus process (modified Delphi) performed using previously published ASCO methods.17

Key Points

Except where noted, the following provisional clinical opinions (PCOs) are based on formal consensus of Expert and Consensus Panel members:

  • Men who develop CRPC despite castrate levels of testosterone should be maintained in a castrate state indefinitely.
  • No data support the use of second-line hormonal therapies for chemotherapy-naïve men with M0 CRPC who are at low risk of developing metastases (low risk is defined as low prostate-specific antigen [PSA] and slow PSA doubling time).18,19
  • For chemotherapy-naïve patients at high risk of developing metastases (rapid PSA doubling time or velocity), second-line hormonal therapies that lower PSA values or slow the rate of rise may be offered, preferably in a clinical trial setting where available, after a discussion with the patient about limited scientific evidence, potential harms, benefits, costs, and patient preferences.
  • Abiraterone acetate plus prednisone or enzalutamide should be offered for second-line hormonal treatment after first-line hormonal treatment failure for chemotherapy-naïve men who develop CRPC and have radiographic evidence of metastases (M1a/M1s CRPC) because these agents have been shown to significantly increase radiographic progression-free survival and overall survival (PCO type: evidence based [three randomized controlled trials]; Strength of PCO: strong)
  • A PSA evaluation every 4 to 6 months should be performed for men who develop CRPC and have no radiographic evidence of metastases (M0 CRPC) and a slow PSA doubling time or velocity. If PSA levels are rising, checking serum testosterone levels should be considered.
  • A PSA evaluation every 3 months is recommended for men who develop CRPC with a rapid PSA doubling time, velocity, or radiographic evidence of metastases (M1 CRPC).
  • When imaging is performed for men with CRPC, a bone scan and either computed tomography or magnetic resonance imaging of the abdomen and pelvis should be offered. Of note is that sodium fluoride positron emission tomography (18F-labeled positron emission tomography) imaging is only approved in the United States for the diagnosis of recurrent prostate cancer among men with elevated PSA after treatment. The use of this technique is otherwise limited to patients who participate in clinical trials and prospective registries. Whole-body magnetic resonance imaging to detect oligometastatic disease and radiotracers and imaging agents such as c-11 choline, prostate-specific membrane antigen, and 18F-flucicovine currently are considered investigational for chemotherapy-naïve patients with CRPC.
  • Radiographic imaging is not indicated for men with CRPC and a rising PSA unless treatment selection would be altered on the basis of radiographic findings or if symptoms potentially attributable to prostate cancer develop or worsen (eg, bone pain). Routine surveillance radiographic restaging also is not indicated, with the exception of patients for whom PSA is not a reliable marker of disease.
  • Palliative care should be offered to all chemotherapy-na¨ıve men with M1 CRPC, particularly those who exhibit symptoms or decreased quality of life.20

The Literature Review and Analysis sections provide more detail about the PCOs.

Appendix Figure A1 shows an algorithm for second-line hormonal CRPC treatment.

Additional resources: More information, including a Data Supplement with additional evidence tables, a Methodology Supplement with information about evidence quality and strength of PCOs, slide sets, and clinical tools and resources, is available at www.asco.org/genitourinary-cancer-guidelines. Patient information is available at www.cancer.net.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate.

Note: Opinions expressed in this article should not be interpreted as the official positions of any US or Canadian governmental agency, including the National Cancer Institute, National Institutes of Health, the Food and Drug Administration, or the US Department of Health and Human Services.


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SUMMARY OF RECOMMENDATIONS


Research QuestionProvisional Clinical Opinion
Should a castrate state be maintained in patients who develop CRPC?For men who develop CRPC despite castrate levels of testosterone:

Patients should be maintained in a castrate state indefinitely. This PCO is based on indirect scientific evidence and current understandings of disease progression mechanisms in prostate cancer. A discussion with patients about the limited nature of available scientific evidence and the balance among potential harms, benefits, costs, and patient preferences is essential when planning treatment.

A castrate state should be maintained through orchiectomy or pharmacologic castration (e.g., luteinizing hormone–releasing hormone [LHRH] agonists/antagonists, antiandrogens).

In chemotherapy-naïve patients who develop CRPC but have no radiographic evidence of metastases (M0 CRPC), should second-line hormonal therapies be used? If so, what agents or specific sequence of agents should be offered?For chemotherapy-naïve patients believed to be at low risk for metastases (low PSA and slow PSA doubling time),1,2 second-line hormonal therapies are not suggested.
For chemotherapy-naïve patients at high risk of developing metastases (rapid PSA doubling time or velocity), second-line hormonal therapies that lower PSA values or slow the rate of PSA rise may be offered (preferably in a clinical trial setting where available) after discussion with the patient about limited scientific evidence, potential harms, benefits, costs, and patient preferences.
Alternative treatment options include observation (with maintenance of a castrate state) or participation in a clinical trial.
Chemotherapy or immunotherapy is not suggested except in a clinical trial.
No evidence provides guidance about the optimal order of hormonal therapies after second-line hormonal therapy for high-risk chemotherapy-naïve patients with M0 CRPC. The panel was unable to come to consensus about sequencing.
In chemotherapy-naïve patients who develop CRPC and have radiographic evidence of metastases but minimal symptoms (M1a/M1s CRPC), should second-line hormonal therapies be used? If so, what agents are recommended?After first-line hormonal treatment failure and a discussion with chemotherapy-naïve patients about potential harms, benefits, costs, and patient preferences:

Abiraterone acetate plus prednisone should be offered because they significantly improved rPFS and OS as well as secondary end points, including median time to opiate use, chemotherapy initiation, performance status deterioration, and PSA progression (v prednisone alone). The drugs are also well tolerated.

Enzalutamide should be offered because it significantly improves rPFS and OS. Secondary end points are also improved, including time to initiation of cytotoxic chemotherapy, risk of a first skeletal-related event, complete or partial soft tissue response, time to PSA progression, time to deterioration in quality of life, and decline in PSA of ≥ 50% from baseline (v placebo). The drug is also well tolerated.

Alternative treatment options include immunotherapy (sipuleucel-T),3 chemotherapy (docetaxel and prednisone),4 and radium-223.

If none of these therapies can be obtained or tolerated by the patient, other antiandrogens, prednisone, and ketoconazole/hydrocortisone may be offered because they provide modest clinical benefits in this population, but no survival benefits have been established.

Other alternative treatment options include enrollment in a clinical trial and observation.

No evidence provides guidance about the optimal order of hormonal therapies after second-line hormonal therapy for patients with M1 CRPC. The panel was unable to come to a consensus about sequencing.

Other second-line hormonal therapy options where results from phase III trials are pending are not suggested.

Palliative care should be offered to all chemotherapy-naïve men with M1 CRPC, particularly to those who exhibit symptoms or decreased quality of life.5

How often should patients with CRPC undergo PSA monitoring?No evidence provides guidance about the optimal frequency of PSA monitoring before starting second-line hormonal therapy or after treatment has begun.

For patients with no radiographic evidence of metastases and a slow PSA doubling time1,2 or velocity, a PSA evaluation every 4 to 6 months is reasonable. If PSA levels rise, checking serum testosterone levels should be considered.

For patients with a rapid PSA doubling time, velocity, or radiographic evidence of metastases, a PSA evaluation every 3 months is reasonable.

What imaging modalities are appropriate for patients with CRPC?When imaging is considered for patients both before and while receiving treatment, a bone scan and either computed tomography or magnetic resonance imaging of the abdomen and pelvis are reasonable.
Imaging with 18F-labeled positron emission tomography (18F PET) generally is not recommended because it is currently only approved in the United States for the diagnosis of recurrent prostate cancer among men with elevated PSA after treatment. The use of this technique is otherwise limited to patients who participate in clinical trials and prospective registries.
How often should patients with CRPC undergo radiographic imaging or routine radiographic restaging?Radiographic imaging is not indicated for men with rising PSA unless treatment selection would be altered on the basis of radiographic findings or if symptoms potentially attributed to prostate cancer develop or worsen (e.g., bone pain).
Routine radiographic restaging generally is not recommended, except among patients in whom PSA is not a reliable marker of disease.

References

1. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 281:1591-1597, 1999

2. Scher HI, Morris MJ, Stadler WM, et al: Trial design and objectives for castration-resistant prostate cancer: Updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 34:1402-1418, 2016

3. Kantoff PW, Higano CS, Shore ND, et al: Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 363:411-422, 2010

4. Basch E, Loblaw DA, Oliver TK, et al: Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol 32:3436-3448, 2014

5. Ferrell BR, Temel JS, Temin S, et al: Integration of palliative care into standard oncology care: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 35:96-112, 2017


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