731397 research-article2017
URO0010.1177/2051415817731397Journal of Clinical UrologyKamel et al.
Prostate cancer. Review Article
New horizons in the management of castrate-resistant prostate cancer
Journal of Clinical Urology 1–8 © British Association of Urological Surgeons 2017 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav https://doi.org/10.1177/2051415817731397 DOI: 10.1177/2051415817731397 journals.sagepub.com/home/uro
Mohamed H Kamel1, Omer A Raheem2 and Rodney Davis1
Abstract Castrate-resistant prostate cancer is an incurable disease. It continues to be an area of intense research to save prostate cancer patients’ lives. We aim from this review to explore the new lines of treatment that aim at extending disease-specific survival. We conducted a PubMed research on available literature pertaining to key words alone and in combination: prostate cancer, castrate-resistant, immunotherapy, hormonal therapy, chemotherapy, radiation therapy, metastasis, survival and quality of life. We also reviewed the following guidelines on castrate-resistant prostate cancer: National Comprehensive Cancer Network (NCCN), American Urological Association (AUA), the National Institute for Health and Care Excellence (NICE) and the European Association of Urology (EAU). There are four new lines of treatment in castrate-resistant prostate cancer. An immunotherapy, sipuleucel T (Provenge); new hormonal therapies – in the form of a new androgen receptor blocker, enzalutamide (Xtandi) and new adrenal androgen synthesis inhibitor, abiraterone acetate (Zytiga); a new chemotherapy, cabazitaxel (Jevtana) and new radioactive agent, radium 223 (Xofigo). There is an agreement between guidelines that patients with M0 castrate-resistant prostate cancer should not be offered any of these treatments. Similarly, patients with castrate-resistant prostate cancer and poor performance status should be offered only palliative care. There are several new lines of treatment that can be used in castrate-resistant prostate cancer, and hopefully in the near future castrate-resistant prostate cancer will be changing from a lethal disease to more of a chronic disease. Keywords New horizons, management, castrate-resistant prostate cancer Date received: 27 December 2016; accepted: 8 August 2017
Introduction Castrate-resistant prostate cancer (CRPC) is an eventual state that patients with prostate cancer on androgen deprivation therapy (ADT) reach. In that stage of the disease the prostate cancer cells cease to respond to the inhibitory response of androgen withdrawal and continue to grow with disease progression. This stage of disease progression is usually achieved with a median time of 18–24 months from the start of ADT.1 ADT works primarily by increasing the rate of prostate cancer apoptosis. CRPC stage occurs when the tumor progresses to the extent that the threshold of apoptosis progressively rises to a point at which cell proliferation exceeds cell death. This results in a population of prostate
cancer cells that are androgen independent that dictate the course of the disease at late stages.2 The exact mechanism for CRPC is not fully understood. However, the suggested mechanisms for the development of CRPC can be classified into androgen 1Department
of Urology, University of Arkansas for Medical Sciences, USA 2Department of Urology, University of California San Diego, USA Corresponding author: Omer A Raheem, Department of Urology, University of California, San Diego; 200 West Arbor Drive, San Diego, CA 92103-8897, USA. Email:
[email protected]
2 receptor (AR)-dependent mechanisms including AR amplification/overexpression, AR gene mutation (activating) and ectopic androgen synthesis (adrenal/intratumoral), and AR-dependent function problems. Other suggested non-AR-dependent mechanisms include abnormalities related to immunological escape/tolerance, proliferative or survival signals and changes in bone microenvironment.3 To define a CRPC, there are specific criteria that must be fulfilled. The prostate cancer patient must be on ADT, the serum testosterone level is in the castrate range (50 times). In addition, Xtandi inhibits AR-testosterone AR dislocation and DNA methylation. Also Xtandi lacks the partial AR agonist activity that occurs with bicalutamide resistance.14 Dosing and administration: the drug is administered in pill form through the oral route. The dose is 160 mg (four pills). Side effects: fatigue, dizziness, hot flash, musculoskeletal pain, headache, hypertension, lower seizure threshold and diarrhea. Oncological outcome: the landmark trial that led to the FDA approval for the use of enzalutamide in CRPC is the ‘Enzalutamide in metastatic prostate cancer before chemotherapy’ known as the PREVAIL trial. In this trial, patients were randomly assigned to either enzalutamide versus placebo. Patients in the enzalutamide arm enjoyed a median overall survival of 32.4 months versus 30.2 months in the placebo arm.15 Enzalutamide has been studied in patients progressing after docetaxel in the AFFIRM trial. In this trial, patients in the enzalutamide arm enjoyed median overall survival of 18.4 months versus 13.6 months in the placebo arm.16 Summary on enzalutamide: 1. Enzalutamide has the advantages of being oral, once daily and no prednisone is needed. It can be taken with or without food. Also, there is no required monitoring. 2. In clinical trials 0.9% of patients developed seizures. The drug should not be administered in patients who have a history of seizures or have undergone recent brain surgery. 3. The cost of the drug in the United States is $9000 per month. The average cost of treatment based on an 8.5-month treatment in the UK is £25,269.17
Androgen receptor splice variant-7 (AR-V7) and resistance to enzalutamide and abiraterone The normal AR is made of eight exons. Exon 1 encodes the N-terminal domain containing transcriptional activation sites. Exon 2–4 encode the DNA-binding domain and exons 5–8 encode the ligand binding domain (LBD). Alternative spliced variants (lacking LBD) are constitutively active; they bind DNA and activate transcription independent of ligands. In a prospective study conducted at the Johns Hopkins Institute, the AR-7 variants were identified prior to treatment of 62 patients with M1 CRPC. Of these 62 patients, 31 were treated by enzalutamide and 31 patients were treated by abiraterone. There were 18 patients identified as AR-V7. None of these 18 patients achieved a 50% or more reduction in PSA and only one patient with AR-V7 showed any PSA reduction (enzalutamide group). AR-V7 was associated with worse clinical or radiographic progression-free survival and overall survival.18
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Novel chemotherapy: Cabazitaxel – Jevtana: cabazitaxel is a new chemotherapy drug that is indicated in CRPC patients who fail docetaxel. Mechanism of action: cabazitaxel is a microtubule inhibitor. In the cancer cell, microtubules are important cell structures for mitosis and cell division. Microtubule inhibition with cabazitaxel leads to microtubule assembly and stabilization with inhibition of cell transport and mitosis.19 Dosing and administration: the drug is administered in a dose of 25 mg/m2 intravenous infusion over 1 hour every 3 weeks. The patient receives concurrent prednisone 10 mg per day. Also patients are usually pre-medicated with antihistamines, corticosteroids and an H2 antagonist 30 minutes before each dose. Side effects: mainly hematological with febrile neutropenia, anemia and thrombocytopenia. Other side effects are gastrointestinal and include diarrhea, nausea, vomiting and taste changes. Di Lorenzo et al. conducted a study on 34 patients receiving cabazitaxel and showed that prophylactic administration of granulocyte colony stimulating factor (G-CSF) with cabazitaxel reduced the risk of grade 3 or more neutropenia and/or febrile neutropenia per patient and per cycle seven times than when G-CSF was not used.20 In another study, Di Lorenzo et al. showed that higher doses of cabazitaxel at 25 mg/m2 compared to 20 mg/m2 was associated with a higher risk of grades 3 and 4 neutropenia.21 Oncological outcome: the landmark trial that led to the FDA approval for the use of cabazitaxel is the ‘Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial’ known as the TROPIC trial. In this trial, 755 patients from 146 sites in 26 countries were randomly assigned either to receive cabazitaxel + prednisone versus mitoxantrone + prednisone. The median overall survival in the cabazitaxel group was 15.1 months versus 12.7 months in the mitoxanterone group.22 Summary on cabazitaxel: 1. The drug is used in patients with CRPC who received previous docetaxel. 2. Use G-CSF to prevent severe neutropenia. 3. Complete blood count should be checked weekly during the first cycle and before each cycle treatment. 4. Patient should be prepared for diarrhea and taste changes while receiving this drug, with dietary changes and the use of loperamide or diphenoxylate/atropine. 5. The cost of cabazitaxel in the United States is $10,000 per cycle. The cost in the UK is £3696 per cycle.13 Radioactive agent: Radium 223 (Xofigo): radium 223 is an alpha emitting radioactive particle. Mechanism of
action: radium 223 mimics calcium. It complexes with the hydroxyapatite of the bone at areas of high bone turnover such as metastasis. The linear energy released breaks the double strand of the DNA in the cancer cells with cell death. The alpha particle range from radium-223 dichloride is less than 100 micrometers which limits damage to the surrounding normal tissue. Dosing and administration: the drug is given as an intravenous pushover 1 minute every 4 weeks for 6 months. Side effects: gastrointestinal side effects: nausea, vomiting, diarrhea and peripheral edema. Oncological outcome: the landmark trial that led to the FDA approval for the use of radium 223 is the ‘Alpharadin in symptomatic prostate cancer’ known as the ALSYMPCA trial. In this trial 809 patients with CRPC and symptomatic bone metastasis and no visceral metastasis were randomly assigned to either radium 223 (six injections at 4-week intervals) + best standard of care versus placebo + best standard of care. The median overall survival was 14.9 months in the radium 223 group versus 11.3 months in the placebo group.23 Summary on radium 223: 1. Radium 223 is only used in CRPC with skeletal metastasis and in the absence of visceral metastasis. 2. No restrictions on family contact. 3. Patient instructed to use condom for the first 6 months after treatment. 4. Bathroom hygiene: radium 223 is excreted through feces. Patients are instructed to flush the toilet several times and to wash their hands. 5. The cost of treatment with radium 223 in the United States is $84,000$. The cost of treatment in the UK is £24,240.24 Combination therapy trials: There are currently several ongoing trials on the use of combination therapy in CRPC. Cabozantinib-s-malate is investigated in a phase I/II trial (NCT01683994) when given in combination with docetaxel and prednisone in CRPC. A phase III trial (NCT02111577) comparing biological dendritic cells (DCVAC) and standard chemotherapy versus standard chemotherapy alone on overall survival is currently underway. Also the MK-3475-365/KEYNOTE-365 study (NCT02861573) is designed to assess the safety and efficacy of pembrolizumab (MK-3475) combination therapy in patients with metastatic CRPC. There will be three cohorts in this study with 70 participants enrolled in each cohort: cohort A will receive pembrolizumab + olaparib, cohort B will receive pembrolizumab + docetaxel + prednisone, and cohort C will receive pembrolizumab + enzalutamide. Outcome measures will be assessed individually for each cohort. We have detailed some of the ongoing combination clinical trials in Table 1.
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Kamel et al. Table 1. Combination clinical trials for castrate-resistant prostate cancer. ClinicalTrials. gov identifier
Organizer
Phase
Examined drug
Control drug
Primary endpoint
Estimated enrollment
Estimated completion date
NCT01683994
Yale/NIH
I/II
Cabozantinib Docetaxel + prednisone
Docetaxel + prednisone
Safety of cabozantinib Tumor progression
81 patients
June 2018
NCT02111577
Sotio a.s.
III
Biological dendritic cell Docetaxal + prednisone
Docetaxel + prednisone
OS
1170 patients
June 2019
NCT02861573
Merck Sharp & Dohme Corp
I
Pembrolizumab + olaparib, Pembrolizumab + docetaxel + prednisone Pembrolizumab + enzalutamide
N/A
≥50% reduction in PSA Adverse events Percentage of patients drop due to adverse events
210 patients
April 2020
NCT02194842
EORTC
III
Enzalutamide + radium 223
Radium 223
rPFS
560 patients
April 2021
NCT01907009
Barts and the London NHS Trust
II/III
IV Melphalan + autologous whole blood stem cell transplant
N/A
PFS
39 patients
September 2017
NIH: National Institute of Health; EORTC: European Organization for Research and Treatment of Cancer; OS: overall survival; rPFS: radiological progression-free survival; PFS: progression-free survival; ADT: androgen deprivation therapy.
Ongoing immunotherapy trials: There several ongoing clinical trials aimed at manipulating the patient immune system to create an antitumor response. The immune checkpoint points are normal immune mechanisms that allow the immune system to maintain hemostasis; however, they may represent a common mechanism of tumor cell escape. Targeting the cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) and programmed T-cell death 1 (PD-1) receptors helps to restore an immunological response against cancer cells. Several novel immunotherapeutic agents are currently being examined for CRPC in randomized, open-label, multicenter phase II trials. For example, a phase II trial (NCT02020070) combining ipilimumab (monoclonal antibody to CTLA-4), degarelix, and radical prostatectomy in men with CRPC compared with ipilimumab and degarelix in men with biochemically recurrent hormone sensitive prostate cancer (HSPC) after radical prostatectomy has been ongoing to assess the safety and efficacy of a multimodality approach combining ADT and immunotherapy, as well as to investigate the effects of ipilimumab before or after prostatectomy. Similarly, a phase II trial (NCT01377389) is examining the effect of ipilimumab with a GnRH agonist/antagonist on PSA levels, as well as the safety and immunological reactions of ipilimumab with medical castration. The IMbassador 250
is a phase III, multicenter, randomized study of atezolizumab (anti-PD-L1 sntibody) in combination with enzalutamide versus enzalutamide alone in patients with metastatic CRPC after failure of an androgen synthesis inhibitor and failure of, ineligibility for, or refusal of a taxane regimen (NCT03016312) with the primary endpoint being patient overall survival. The use of genetically engineered vaccines such as the vaccinia and the fowlpox (PROSTVAC-VF) that has a copy of the human PSA and combined with immune adjuvants such as the human GM-CSF to boost the local immune response is currently being investigated as well (NCT01322490).
Discussion We reviewed the four major guidelines on CRPC; the NCCN, AUA, NICE and EAU guidelines. Patients with CRPC who are M0 should not receive any of the previously described medications and should continue on ADT only to suppress their androgen source.4,25–27 We also summarized the main side effects of the novel drugs in Table 2. An M0 CRPC is a patient on androgen deprivation therapy with non-metastatic CRPC. The Prostate Cancer Working Group had put strict criteria for
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Table 2. Common side effects of novel drugs used in castrate-resistant prostate cancer. Drug
Sipuleucel-T7
Abiraterone acetate33
Enzalutamide34
Cabazitaxel22
Radium 22323
Side effects
Chills (54.1%) Fatigue (39.1%) Back pain (34.3%) Pyrexia (29.3%) Nausea (28.1%) ’Flu-like symptoms (9.8%) Hypertension (7.4%)
Fluid retention and edema (31%) Hypokalemia (17%) Cardiac disorders (13%) LFT abnormalities (10%) Hypertension (10%)
Fatigue (35.6%) Back pain (27%) Constipation (22.2%) Arthralgia (20.3%) Cardiac disorders (10.1%) Hypertension (13.4%) LFT abnormalities (0.9%) Seizure (0%)
Hematological Neutropenia (94%) eukopenia (96%) Anemia (97%) Thrombocytopenia (47%) Non-hematological Diarrhea (47%) Nausea (34%) Vomiting (23%)
Non-hematological Nausea (36%) Diarrhea (25%) Peripheral edema (13%) Hematological Anemia (31%) Thrombocytopenia (12%) Neutropenia (5%)
LFT: liver function test.
non-metastatic CRPC: (a) a rising PSA that is 2 ng/mL higher than the nadir with a rise of at least 25% over nadir; (b) the rise must be confirmed by a second PSA at least 3 weeks later; (c) the patient must have castration levels of testosterone (
