Drug Resistance In Metastatic Castration
Amani Yehya1,# Fatima Ghamlouche1,# Amin Zahwe1,# Yousef Zeid1 Kevork Wakimian1 Deborah Mukherji2 Wassim Abou-Kheir1
1Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon.
2Division of Hematology/Oncology, Faculty of Medicine, American University of Beirut Medical Center, Beirut 1107-2020, Lebanon.
#Equally contributing authors.
Correspondence to: Dr. Wassim AbouKheir, Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Bliss Street, Hamra, Beirut 11072020, Lebanon. E-mail: wa12@aub.edu.lb Dr. Deborah Mukherji, Department of Internal Medicine, Division of Hematology/Oncology, Faculty of Medicine, American University of Beirut Medical Center, Cairo Street, Hamra, Beirut 11072020, Lebanon. E-mail: dm25@aub.edu.lb
Received: First decision: Revised: Accepted: Available online: Academic Editors: Copy Editor: Production Editor:
© The Author 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License , which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Other New Approaches In Mcrpc
Other drugs in clinical trials for mCRPC do not rely on the presence of defined mutations. Here, I discuss only those that already have promising preliminary results:
Most prostate cancer cells express a protein called PSMA on their surface. In fact, PSMA is almost exclusively found on prostate cancer cells, making it a good therapeutic target. The novel drug 177Lu-PSMA-617 is a radioactive molecule attached to another molecule that specifically targets cells expressing PSMA. The most recent results from a randomized clinical trial where men received either LuPSMA or the chemotherapy drug cabazitaxel show that response rate was higher with LuPSMA than with cabazitaxel.
Currently, there are two other radionuclide conjugates that target PSMA in trials: BAY 2315497 and 225AcJ591.
PSMA can also be targeted by other means, one of which is a very interesting approach known as CAR T-cell treatment, currently available in two trials. CAR T-cell treatment is beneficial in liquid tumors of the blood or bone marrow, but has yet to be validated in solid tumors like prostate cancer. However, some results are promising. The presence of a good target for these engineered cancer-killing immune cells is a good omen in prostate cancer, because identifying specific targets in solid tumors is a major hurdle in designing CAR T-cell treatments.
Mutational And Genetic Testing In Mcrpc
All cancers, including prostate cancer, arise because of genetic mutations in cells. The first type mutations to be appreciated as causative in driving mCRPC were in genes involved in repair of damaged DNA. These mutations, often hereditary, were identified long ago as predisposing to the development of breast and ovarian cancers in women.
In prostate cancer, mutations in one of these DNA-repair genes are found mostly in late-stage prostate cancer in about 12% to 20% of patients. These mutations predict whether treatment with drugs known as PARP inhibitors might be effective. The FDA has already approved two drugs in this category: olaparib and rucaparib . New clinical guidelines now dictate testing for these mutations in tumors of mCRCP patients.
A recent study reported that men with deficiencies in one of 13 genes related to DNA damage repair had a higher response rate and a longer progression-free and overall survival when treated with the PARP inhibitor olaparib versus an anti-androgen treatment.
A new drug called berzosertib, an inhibitor of the DNA-repair protein ATR, has shown very promising results in a variety of cancers with relevant mutations, and is currently being tested in a trial for mCRPC in combination with chemotherapy.
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Debate: Comparative Effectiveness Of Surgery Versus Radiation
Dr. Laurence Klotz and Dr. Mack Roach, III presented a debate on Comparative Effectiveness of Surgery and Radiation: Surgery Is Better versus Radiotherapy Yields Better Oncologic Outcomes than Radical Prostatectomy for Clinically Localized Prostate Cancer at the 6th Symposium on the Treatment of Prostate Cancer , which was held in Lisbon, Portugal between October 14th and 16th 2016.
Editorial: Metastatic Castration Resistant Prostate Cancer: Prognosis And Treatment
- 1Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
- 2Department of Urology, University of Kansas Medical Center, Kansas City, KS, United States
- 3Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
- 4Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, United States
Editorial on the Research TopicMetastatic Castration Resistant Prostate Cancer: Prognosis and Treatment
Figure 1 Diagnosis and treatment landscape of prostate cancer. Figure was created using BioRender.com.
Irrespective of the treatment modalities, most CRPC patients develop bone metastasis. The metanalysis by Tong et al. assessed the prognostic value of skeletal-related parameters in mCRPC overall survival. This study examined the association between alkaline phosphatase, bone-specific alkaline phosphatase, urinary N-telopeptide, bone scan index, and overall survival in patients with metastatic PCa. The analysis revealed that higher levels of ALP, BSAP, and uNTx, progression of BSI, as well as BPI-SF scores were associated with lower OS in randomized controlled trials published between 2010 and 2019. Considering the ambiguity of the PSA value in mCRPC, bone-related parameters, AR variants, and, more importantly, CTC can help stratify the risk of mCRPC patients before the start of treatment.
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What Is Metastatic Castration
Metastatic castration-resistant prostate cancer and its precursor, metastatic hormone sensitive prostate cancer , are advanced forms of the condition that dont respond to initial treatments, such as surgery and hormone therapy, and have started to spread beyond the prostate.
The type mCRPC differs from mHSPC in that the latter disease still responds to standard hormone treatment called androgen deprivation therapy , even though it has spread to other parts of the body. Specifically, the castration-resistant form mCRPC is particularly dangerous and leads to a very poor prognosis.
Continuing Care For Your Patients With Metastatic Crpc
Michael S. Cookson, MD, talks about the importance of continuing care for patients with metastatic castration-resistant prostate cancer via three over-arching guidelines. Number one is the importance of the urologist being the primary care giver, two being the establishment of a multi-disciplinary clinic, and three being the proper utilization of evidence-based therapeutic options.
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Contributions Of Funding Agencies
Scientific productivity is related to research and development expenditures.86,87,88 The distribution of the top 20 most productive funding agencies for MCRPC research is displayed in Table Table6.6. The National Institutes of Health topped the list with 809 funded articles and the highest h-index . The pharmaceutical company Johnson & Johnson ranked second with 166 funded articles. The Prostate Cancer Foundation ranked third with 161 funded articles. Pfizer and Astellas followed the Department of Defense , which funded 161 articles. The National Natural Science Foundation of China ranked 11th with 77 funded articles and an h-index of 15. Twelve of these 20 funding agencies were global pharmaceutical companies, and the remaining 8 were state-funded institutions or charitable foundations. The NIH was the world’s largest funder of biomedical research and invested approximately $30 billion per year in biomedical research.The PCF was the world’s leading philanthropic organization funding and accelerating PCa research, and it raised more than $765 million and funded more than 2000 research programs at nearly 210 cancer centers and universities. The NNSFC, the largest natural science foundation in China, invested nearly $1.1 billion in biomedical research in 2018. Compared with the NIH and PCF, the NNSFC needs to expend more efforts to not only increase research sponsorship funds but also improve the quality of academic outputs.
The Importance Of Imaging
Through imaging, your doctor can determine whether or not your cancer has metastasized. This means that it can spread to the soft tissue, lymph nodes, and bones.
The different types of imaging include bone scans, Positron emission tomography, Magnetic resonance imaging, and X-rays. Another option is a PET scan, and when using an injection it can enhance the images.
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Contributions In Leading Research Areas And Journals
A total of 4089 articles were published in the MCRPC research field, and these articles involved 52 research areas. The distribution of the top 20 research areas in MCRPC research is listed in Table Table4.4. Oncology was undoubtedly the dominant research area, with 2120 articles, followed by urology nephrology,pharmacology pharmacy,endocrinology metabolism,cell biology, and biochemistry molecular biology. There were 2120 publications in the area of oncology, comprising 51.85% of the total publications, and oncology had the highest h-index . This analysis illustrated that research hotspots were correlated with the prevention, diagnosis, and treatment of cancer. Pharmacology pharmacy ranked third, indicating that therapy was an essential area of MCRPC research. All indicated the importance of treatments such as chemotherapy, new hormone therapy, immunotherapy, radiotherapy, and targeted therapy in the MCRPC research field.
Drug Resistance In Mcrpc
Despite the significant survival benefit of the currently approved therapies, which can alleviate symptoms and prolong overall survival, mCRPC remains incurable as primary and secondary resistance develops rapidly. Drug resistance can develop due to mechanisms intrinsic to the biology of PCa or by more general mechanisms shared with diverse tumor types, as can be seen in Figure 1.
Figure 1. Mechanisms of drug resistance in mCRPC. Several mechanisms of drug resistance are well defined in CRPC, including AR amplification and overexpression, AR point mutations, AR post-translational modifications, AR splice variants, AR co-regulators, altered steroidogenesis, GR overexpression, neuroendocrine differentiation, tumor microenvironment, and other signaling alterations. AR: Androgen receptor GR: glucocorticoid receptor mCRPC: metastatic castration-resistance 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.
Learn more about the importance of tracking side effects in another part of this guide. Learn more about palliative care in a separate section of this website.
Immune Checkpoint Inhibitors In Mcrpc
This class of drugs fall into the category of immunotherapydrugs that boost the immune system to fight cancer. ICIs have significantly improved outcomes in a number of types of metastatic cancer, but were previously thought not to have much promise in mCRPC. This is still true, by and large, but a small proportion of mCRPCs may have a feature that is associated with a high probability of response to immunotherapy drugs. This feature is known as mismatch repair deficiency or microsatellite instability, and is quite rare in prostate cancer . Patients whose tumors have this feature should be offered an ICI called pembrolizumab .
Another potential marker of sensitivity to ICIs is loss of the gene CDK12, a mutation seen in about 7% of mCRPC patients. A small study demonstrated that 33% of these patients experience reduction in PSA levels in response to ICIs.
There are now multiple clinical trials exploring ICIs in combination with other drugsincluding targeted therapy, hormonal drugs, or drugs that block the blood supply to tumors, as well as PARP inhibitors.
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Immune Checkpoint Inhibitor Therapy
Immune checkpoint inhibitor therapy has shown clinical benefit in a number of solid tumors , but unfortunately these observations have not been replicated in patients with mCRPC . Factors such as low tumor mutational burden , loss of tumor suppressors , low prevalence of DDR genetic defects, and silencing of major histocompatibility complex-1 expression may all contribute to mCRPCs relative lack of response to ICI therapy . Two early phase-3 studies of the anti-cytotoxic T lymphocyte-associated protein-4 antibody ipilimumab both failed to meet their primary endpoint of improved OS however, recent studies investigating the efficacy of the programmed death-1 inhibitor pembrolizumab have shown promising responses in patients with mCRPC. In a single-site cohort of 48 patients with mCRPC treated with pembrolizumab, 17% had50% PSA decline with 8% having90% PSA decline as best response . These exceptional responders were found to have molecular changes , TMB-high, and mutation in LRP1b), which predispose to anti-PD-1 responses.
Completed and ongoing clinical trials investigating different ICI agents in patients with mPC have been summarized . Although monotherapy ICIs have not been successful, there are many ongoing trials to combine ICIs with standard chemotherapies or targeted therapies in order to improve clinical outcomes.
Table 3 Ongoing clinical trials investigating the administration of immune checkpoint inhibitor agents in patients with mPC
Immunotherapy 101 For The Urologist
Raoul S. Concepcion, MD, summarizes the mechanism of action behind the immune response to cancer. He also provides an update on the current and emerging immunotherapies for cancer treatment, including vaccines, checkpoint inhibitors, CAR T-cell therapies, viral vectors, and adoptive cell therapy.
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Active Surveillance And Watchful Waiting
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:
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A PSA test every 3 to 6 months
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A DRE at least once every year
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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.
Other Signaling Alterations/implication Of Growth Factors Kinases Cytokines Enzymes
The aberrant activation of multiple signaling pathways plays a key role in deriving drug resistance in mCRPC. High levels of growth factors including IGF-1, EGF, and TGF-/ have been reported in mCRPC. A study showed that the overexpression and activation of EGFR mediate DOC resistance in CRPC by inducing AKT-dependent ABCB1 expression. Besides, the stimulation of EGFR was shown to derive the activation of Ack1/Tnk2, which is known to correlate positively with the progression to the mCRPC stage. In addition, PCa patients whose tumors showed moderate to strong staining of activated Ack1 displayed a poor prognosis.
Analysis of whole-exome and transcriptome sequencing of mCRPC biopsies revealed that alterations in DNA-damage repair genes including BRCA2, BRCA1, and ATM occur at higher frequencies in mCRPC than in primary PCa, of which 12.7% of the samples were identified with loss of BRCA2. Cells with deleterious mutations in BRCA1 or BRCA2 compensate for this loss by increasing their dependency on poly polymerase activity for DNA repair.
Prostate-specific membrane antigen is a type II transmembrane glycoprotein that is normally expressed in the prostate epithelium. Although it is expressed in other tissues , its levels there are minimal. Importantly, in PCa tissues, PSMA is significantly overexpressed, having the highest expression in advanced PCa and mCRPC. Moreover, following androgen deprivation and hormonal therapy, PSMA expression seems to be increased.
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Does Crpc Affect Different Ethnic/racial Groups Differently
Non-Hispanic Black people are much more likely to get prostate cancer than those of any other race or ethnicity. Prostate cancer rates are lowest among non-Hispanic Asian Americans. Black people also are more likely than non-Black people to be diagnosed with advanced prostate cancer. But in treatment, Black people have at least similar outcomes compared to non-Black people. Researchers donât fully understand the reasons for these differences.
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Who Gets This Cancer
Prostate cancer occurs only in men, and it is more common in older men than younger men. It is more likely to occur in men with a family history of prostate cancer and men of African American descent. The rate of new cases of prostate cancer was 112.7 per 100,000 men per year based on 20152019 cases, age-adjusted.
Rate of New Cases per 100,000 Persons by Race/Ethnicity: Prostate Cancer
Males
SEER 22 20152019, All Races, Males
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An Analysis Of The Most Cited Papers
Although multiple indicators were used to evaluate the impact of scientific publications, citation counts are still an important measurement of influence in this research field.120,121 The top 20 most cited publications in the MCRPC research field during 19812018 are presented in Table Table8.8. The most highly cited paper was Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. This article was published in the New England Journal of Medicine in 2010 by Kantoff, PW and headed the lists of total citations and annual citations . Abiraterone and Increased Survival in Metastatic Prostate Cancer, authored by de Bono, JS et al, took second place, with 2045 total citations and 292.14 annual citations. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy, authored by Scher, HI et al, ranked third with 1857 total citations and 309.5 annual citations.