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Non Metastatic Castration Resistant Prostate Cancer

Active Surveillance And Watchful Waiting

Understanding non metastatic castration resistant prostate cancer with Dr. Hamilton

If prostate cancer is in an early stage, is growing slowly, and treating the cancer would cause more problems than the disease itself, a doctor may recommend active surveillance or watchful waiting.

Active surveillance. Prostate cancer treatments may seriously affect a person’s quality of life. These treatments can cause side effects, such as erectile dysfunction, which is when someone is unable to get and maintain an erection, and incontinence, which is when a person cannot control their urine flow or bowel function. In addition, many prostate cancers grow slowly and cause no symptoms or problems. For this reason, many people may consider delaying cancer treatment rather than starting treatment right away. This is called active surveillance. During active surveillance, the cancer is closely monitored for signs that it is worsening. If the cancer is found to be worsening, treatment will begin.

ASCO encourages the following testing schedule for active surveillance:

  • A PSA test every 3 to 6 months

  • A DRE at least once every year

  • Another prostate biopsy within 6 to 12 months, then a biopsy at least every 2 to 5 years

Treatment should begin if the results of the tests done during active surveillance show signs of the cancer becoming more aggressive or spreading, if the cancer causes pain, or if the cancer blocks the urinary tract.

Index Patient : Asymptomatic Non

One of the first clinical presentations of CRPC occurs in a patient with a rising PSA despite medical or surgical castration. This is typically defined as a patient with a rising PSA and no radiologic evidence of metastatic prostate cancer. The Prostate Cancer Clinical Trials Working Group 2 defines PSA only failure as a rising PSA that is greater than 2ng/mL higher than the nadir the rise has to be at least 25% over nadir, and the rise has to be confirmed by a second PSA at least three weeks later. In addition, the patient is required to have castrate levels of testosterone and no radiographic evidence of metastatic disease.16 These patients represent a relatively common clinical presentation and the earliest clinical manifestation of castration resistance.

Guideline Statement 1

Clinicians offer apalutamide or enzalutamide with continued androgen deprivation to patients with non-metastatic CRPC at high risk for developing metastatic disease.

Discussion

Enzalutamide: Enzalutamide is a novel AR signaling inhibitor. It is a competitive inhibitor of androgen binding and also inhibits nuclear translocation of the AR, DNA binding and coactivator recruitment.18 This drug binds AR with a five- to eight-fold higher affinity than bicalutamide.18

Guideline Statement 2

Clinicians may recommend observation with continued androgen deprivation to patients with non-metastatic CRPC at high risk for developing metastatic disease who do not want or cannot have one of the standard therapies.

Index Patient : Symptomatic Mcrpc With Poor Performance Status And No Prior Docetaxel Chemotherapy

Clinical trials have generally excluded patients with a poor performance status from participation. Thus, most data regarding management of such patients is extrapolated from randomized trials of eligible patients who had a better performance status, as well as from some smaller trials and registries. Even a Phase 3 clinical trial that was presumptively designed for a population considered “unfit” for docetaxel still only allowed a performance status of ECOG 0-1. However, treatments with acceptable safety profiles do exist and should be considered, even in poor performance status patients. This is especially true in those patients in whom the poor performance status may be considered to be directly related to the cancer itself and thus whose status might improve with effective treatment. Treatments must be individually tailored in these patients after a careful discussion of risks and benefits with particular attention to patient QOL.

Guideline Statement 11

Clinicians may offer treatment with abiraterone plus prednisone or enzalutamide to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy.

Discussion

Guideline Statement 12

Clinicians may offer treatment with ketoconazole plus steroid or radionuclide therapy to patients with symptomatic, mCRPC with poor performance status and no prior docetaxel chemotherapy who are unable or unwilling to receive abiraterone plus prednisone or enzalutamide.

Discussion

Guideline Statement 13

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To Put That Into Context

PSA-TRICOM is a vector-based therapeutic cancer vaccine regimen consisting of recombinant poxviruses containing transgenes from PSA and three T-cell costimulatory molecules. The vaccine was studied in a nonblinded phase II trial of patients with nonmetastatic CRPC and a rising PSA level, despite a castrate level of testosterone the participants were randomly assigned to either the vaccine or nilutamide. Patients were only required to have castrate levels of testosterone, to have undergone AAWD for 4 to 6 weeks, and to not be immunocompromised. Prior nilutamide therapy was an exclusion criterion. Nilutamide was given at a dosage of 300 mg daily for 1 month, followed by 150 mg daily subsequently. The vaccine was given as an initial priming dose of admixed recombinant vaccinia-based vaccine and then as a booster of recombinant fowlpox-based vaccine monthly. Subjects were followed every 3 months with CT and bone scans and with monthly PSA testing. Patients who developed rising PSA levels could cross over to the other arm. The time to treatment failure-defined as progression, secondary malignancy, or toxicity-was 9.9 months with the vaccine and 7.6 months with nilutamide . The median survival was 5.1 years for patients who received the vaccine vs 3.4 years for patients who received nilutamide alone . There were no grade 3 toxicities in the vaccine arm.

Orteronel

Abiraterone

Enzalutamide

ARN-509

ODM-201

Rationale For Treating Nmcrpc

About Non

Progression of nmCRPC to metastatic disease is likely to involve lymph nodes and/or bone approximately one-third of patients will develop osseous metastasis within 2 years, most commonly involving sites in the pelvis, spine, or ribs . Among patients with nmCRPC, a higher PSA concentration at diagnosis, shorter PSADT, higher Gleason score, a history of primary intervention, and a shorter interval from ADT initiation to the diagnosis of CRPC, have been associated with shorter time to metastasis . It is generally accepted that poor prognosis of patients with nmCRPC is most closely suggested by shorter PSADT . Following the development of metastases, the prognosis for OS diminishes .

Patients with bone metastases are at significant risk of developing symptomatic skeletal events history of an SSE is considered a negative predictor of survival . The association of SSEs with mortality might be explained by the presence of advanced disease, declining performance status, loss of independence, and pathological fractures . While SSEs cause pain and adversely impact quality of life, their management is associated with significant healthcare resource utilization, which has been found to be consistent in global, multinational studies .

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The Role Of Genetic Testing For Inherited Prostate Cancer Risk

Dr. Veda N. Giri, MD, commenced the Philadelphia Prostate Cancer Consensus 2017 by explaining the purpose and need for creating updated, centralized guidelines regarding genetic testing for inherited prostate cancer. Dr. Giri urged the conference members to focus on addressing the criteria for referring a patient, how genetic counseling is relevant to men at risk for prostate cancer, which genes to test, and how this informs the management of patients.

Integrating The Aua Guidelines Into Your Practice

Michael S. Cookson, MD, MMHC, describes how urologists can use American Urological Association guidelines to better manage metastatic castration resistant prostate cancer patients. He stresses the importance of urologists serving as the primary caregiver, the multidisciplinary care model, and organized sequencing of treatments and therapeutics.

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New Imaging Modalities Will Redefine The Classification Of Prostate Cancer

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Treatment Advances In Non Metastatic Castration

Treating Non-Metastatic Castrate Resistant Prostate Cancer | Ask a Prostate Expert, Mark Scholz, MD

Background

Since the seminal work of Huggins and Hodges1 seventy years ago, androgen deprivation therapy has formed the cornerstone of management for advanced prostate cancer with indications including concurrent therapy with primary curative-intent radiotherapy, salvage therapy after recurrence following local therapy, and in the treatment of metastatic disease. While efficacious, nearly all patients will eventually develop castration resistance with disease progression despite castrate levels of testosterone. Among patients who receive ADT for biochemical recurrence following radical prostatectomy or radiotherapy, the development of castration resistance typically occurs prior to the identification of metastasis on conventional imaging, nonmetastatic castration-resistant prostate cancer . NmCRPC is typically identified on the basis of the PCWG3 consensus definition for prostate-specific antigen progression on ADT, namely a 25% PSA increase from nadir , with a minimum rise of 2 ng/mL in the setting of castrate testosterone .2 In these patients, treatment is aimed at delaying the development of metastasis, preserving quality of life, and increasing overall survival.

Study Design

Each of the three trials used a 2:1 randomization schema with allocation to the experimental agent and placebo, respectively. Patients continued on ADT throughout.

Primary analysis: metastatic-free survival and toxicity

Health-related quality of life

Overall survival

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Treatment By Stage Of Prostate Cancer

Different treatments may be recommended for each stage of prostate cancer. Your doctor will recommend a specific treatment plan for you based on the cancers stage and other factors. Detailed descriptions of each type of treatment are provided earlier on this same page. Clinical trials may also be a treatment option for each stage.

Early-stage prostate cancer

Early-stage prostate cancer usually grows very slowly and may take years to cause any symptoms or other health problems, if it ever does at all. As a result, active surveillance or watchful waiting may be recommended. Radiation therapy or surgery may also be suggested, as well as treatment in clinical trials. For those with a higher Gleason score, the cancer may be faster growing, so radical prostatectomy and radiation therapy are often recommended. Your doctor will consider your age and general health before recommending a treatment plan.

ASCO, the American Urological Association, American Society of Radiation Oncology, and the Society of Urologic Oncology recommend that patients with high-risk early-stage prostate cancer that has not spread to other areas of the body should receive radical prostatectomy or radiation therapy with hormonal therapy as standard treatment options.

Locally advanced prostate cancer

Watchful waiting may be considered for older adults who are not expected to live for a long time and whose cancer is not causing symptoms or for those who have another, more serious illness.

An Update On Nonmetastatic Castration

and

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Index Patient : Symptomatic Mcrpc With Poor Performance Status And Prior Docetaxel Chemotherapy

The American Society of Clinical Oncology has posted recommendations regarding treatment for patients with advanced solid tumors particularly in the last months of life. ASCO advocates for an increasing emphasis on a patient’s QOL and concentrates on symptom management. Treatment given in the last months of life may delay access to end of life care, increase costs and add unnecessary symptom management. Patients with poor performance status should not be offered further treatment. .

Guideline Statement 20

Clinicians should offer palliative care to patients with mCRPC with poor performance status who received prior docetaxel chemotherapy. Alternatively, for selected patients, clinicians may offer treatment with abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid or radionuclide therapy.

Discussion

Enzalutamide: Enzalutamide is indicated for the treatment of patients with mCRPC who have previously received docetaxel. The previously discussed AFFIRM study found that enzalutamide significantly prolonged the survival of men with mCRPC after chemotherapy. Method of action and dosing information are previously referenced.

Ketoconazole: Ketoconazole provides an available but fairly toxic treatment plan for patients with mCRPC who have received prior docetaxel chemotherapy with poor performance status. Method of action and dosing information are previously referenced.

Guideline Statement 21

Discussion

Clinical Trial Endpoints And Clinical Benefit In Nmcrpc

Metastatic Castrate Resistant Prostate Cancer Management

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M0 Space And The Spartan Trial

Eric J. Small, MD, defines nonmetastatic castration-resistant prostate cancer, or M0 disease. He then discusses the design, implementation, and results of the SPARTAN trial, which he also presented at the 2018 Genitourinary Cancers Symposium. The study tested the efficacy of apalutamide in men with M0 disease.

Treatment Options For Patients With Nmcrpc

In addition to apalutamide, two other novel AR-targeted therapies enzalutamide and darolutamide were evaluated in nmCRPC and are briefly discussed here.

Recent updated analysis showed that darolutamide significantly delayed pain progression as compared to placebo . The delay in pain progression with darolutamide was maintained beyond end of the study treatment. Darolutamide was associated with delayed time to deterioration of EORTC-QLQ-PR25 outcomes for urinary symptoms and for hormonal treatment-related symptoms as compared to placebo .56

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Strengths And Limitations Of This Study

  • A major strength of this study is the application of the discrete choice experiment methodology to determine the relative value that patients place on different attributes of their non-metastatic castration-resistant prostate cancer treatment.

  • Another strength lies in the development of the final DCE survey, which encompassed a series of systematic steps including literature review, qualitative exploratory interviews and cognitive interviews with patients with CRPC.

  • A limitation is the representativeness of the patients with CRPC included in this study, who were a convenient sample recruited from a few selected facilities in Japan.

  • Another limitation is that the DCE design may not have the same clinical meaning or emotional consequence of an actual treatment decision.

Treatment For M0 Crpc Patients

Focus on non-metastatic castration resistant prostate cancer

To answer the questions on treatment of M0 CRPC in Brazil, the panel agreed to assume ideal scenario based on the best clinical evidence available. Each question proposed scenarios of men with various 1) life expectancies, 2) PSAdt quantities, and 3) PSA levels.

The votes of the panel showed consensus on the initial treatment for M0 CRPC patients with life expectancy greater than 10 years and PSAdt less than 10 months, regardless PSA levels. The panel reached consensus and would start the patient on apalutamide or enzalutamide in both cases . For patients with life expectancy lower than 10 years and a PSAdt less than 10 months, the panel was also in consensus to start apalutamide or enzalutamide when PSA was greater than 2ng/mL. These results are in accordance with the NCCN guidelines version 1.2020 Prostate Cancer Version 1.2020. . Available at. < https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf> ), which support apalutamide or enzalutamide regardless of the PSA level in patients with PSAdt less than 10 months mostly because this is the most robust factor for bone metastases in this setting .

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Ethics Approval And Consent To Participate

The protocol and study materials were reviewed and approved by the Salus Institutional Review Board . All respondents in the qualitative interviews provided written informed consent prior to participating in the interviews. All respondents in the survey provided electronic agreement after reviewing the informed consent form electronically.

Role Of Apalutamide Beyond Nmcrpc

Several trials are currently underway to evaluate the role of apalutamide in early and advanced stages of prostate cancer. During ASCO 2019 meeting, the results of the TITAN trial were presented. TITAN was a Phase III trial which assessed the efficacy of apalutamide plus ADT versus placebo plus ADT in patients with metastatic hormone-sensitive prostate cancer. The patients who previously received docetaxel for advanced prostate cancer were also enrolled. The primary endpoints were radiologic progression-free survival and OS. At the time of first interim analysis, apalutamide plus ADT was associated with improved rPFS as compared to placebo plus ADT .57 OS survival data were not mature at the time of the first interim analysis. Grade 34 adverse effects were 42.2% in the apalutamide plus ADT arm vs 40.8% in the placebo plus ADT arm.57

ATLAS, a Phase III, randomized double-blind placebo-controlled trial is evaluating the role of apalutamide in combination with GnRH agonist compared with GnRH agonist alone in patients with high risk, localized or locally advanced prostate cancer who are receiving radiation therapy as initial definite therapy.63 The primary endpoint is MFS.

Table 1 Phase III trials of apalutamide in prostate cancer

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Physical Emotional And Social Effects Of Cancer

Cancer and its treatment cause physical symptoms and side effects, as well as emotional, social, and financial effects. Managing all of these effects is called palliative care or supportive care. It is an important part of your care that is included along with treatments intended to slow, stop, or eliminate the cancer.

Palliative care focuses on improving how you feel during treatment by managing symptoms and supporting patients and their families with other, non-medical needs. Any person, regardless of age or type and stage of cancer, may receive this type of care. And it often works best when it is started right after a cancer diagnosis. People who receive palliative care along with treatment for the cancer often have less severe symptoms, better quality of life, and report that they are more satisfied with treatment.

Palliative treatments vary widely and often include medication, nutritional changes, relaxation techniques, emotional and spiritual support, and other therapies. You may also receive palliative treatments similar to those meant to get rid of the cancer, such as chemotherapy, surgery, or radiation therapy.

Before treatment begins, talk with your doctor about the goals of each treatment in the treatment plan. You should also talk about the possible side effects of the specific treatment plan and palliative care options.

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