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.
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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The Role Of A Multidisciplinary Care Team In Treatment
Keep in mind that the optimal treatment strategy for mCRPC is different for each person and that its a complicated disease to treat. Thats why its important to assemble a team of doctors and specialists to keep your treatment and you on track.
Your team should include an experienced urologist, advises Cookson, as well oncologists who are comfortable with the newer treatments and know how to use them.
A study published in July 2015 in the Journal of Urology agrees, finding that with so many new treatments coming on board, doctors have to juggle a lot of factors when figuring out your best next steps from what kind of symptoms you have to your personal preferences, as well as any other health conditions that may have to be taken into account when coming up with a treatment strategy.
Its also important for your care team to review the medicines youve already taken for prostate cancer, and plan the sequence of the medicines youll take next. Getting the order right is important because certain drugs can make subsequent treatments more, or less, effective.
Your care team should also watch you closely to determine whether you have any resistance to any medicines, so that they can make changes quickly if necessary.
Ideally, your care team should possess expertise in distinct domains of cancer care, such as imaging, chemotherapy, radiation, and surgery, according to a study published in the Annals of Oncology in August 2015.
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Remission And The Chance Of Recurrence
A remission is when cancer cannot be detected in the body and there are no symptoms. This may also be called having no evidence of disease or NED.
A remission can be temporary or permanent. This uncertainty causes many people to worry that the cancer will come back. Although there are treatments to help prevent a recurrence, such as hormonal therapy and radiation therapy, it is important to talk with your doctor about the possibility of the cancer returning. There are tools your doctor can use, called nomograms, to estimate someone’s risk of recurrence. Understanding your risk of recurrence and the treatment options may help you feel more prepared if the cancer does return. Learn more about coping with the fear of recurrence.
In general, following surgery or radiation therapy, the PSA level in the blood usually drops. If the PSA level starts to rise again, it may be a sign that the cancer has come back. If the cancer returns after the original treatment, it is called recurrent cancer.
When this occurs, a new cycle of testing will begin again to learn as much as possible about the recurrence, including where the recurrence is located. The cancer may come back in the prostate , in the tissues or lymph nodes near the prostate , or in another part of the body, such as the bones, lungs, or liver . Sometimes the doctor cannot find a tumor even though the PSA level has increased. This is known as a PSA recurrence or biochemical recurrence.
How Will I Know If I Have Nonmetastatic Castration
Most cases of prostate cancer that are not cured with surgery or radiation will eventually become resistant to the effects of hormone therapy. If this happens, your PSA level might start to rise. A rising PSA level could mean that the cancer is progressing.
Your PSA can be measured with a simple blood test. Your doctor will likely test your PSA level periodically while you are receiving hormone therapy to gauge how well you are responding to it.
A widely accepted definition for rising PSA levels is a 25 percent increase from the lowest point, with a minimum surge of 2 nanograms per milliliter. This rise must be confirmed one to three weeks later.
If your PSA level is rising, your doctor will order scans to see if there is evidence that the prostate cancer has spread somewhere else in your body.
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Emerging Treatments Targeting Mcrpc
Based on the above, there is a crucial need for novel alternative approaches and drugs that could overcome resistance in advanced PCa stages. In fact, several treatments, which are under development and trials, could emerge as promising therapies for patients with mCRPC and become the next-generation standards of care. Table 2 summarizes the evolving targeted treatments in mCRPC along with their relevant clinical trials.
| Ongoing trial interim results show that Ipat prolonged PFSTwo treatment-related deaths occurred in both groups |
ABI: Abiraterone ADC: antibody-drug conjugate AEs: adverse events CAR-T cells: chimeric antigen receptor T cells DDR: DNA-damage repair DOC: docetaxel ENZ: enzalutamide IgG1: immunoglobulin G1 Ipat: ipatasertib LuPSMA: lutetium-177-PSMA-617 MMAE: monomethyl auristatin E OS: overall survival PARPi: poly polymerase inhibitor PFS: progression-free survival PSA: prostate-specific antigen PSA50: > 50% decline in prostate-specific antigen PSMA: prostate-specific membrane antigen RR: response rate TGF: transforming growth factor-.
Quality Of Life With Mcrpc
According to a review published in the British Medical Journal in October 2016, you may not experience pain or other symptoms at this stage of cancer, or you may experience many. Its different for everyone. So along with treating the cancer itself, be sure to talk to your doctors about any symptoms and side effects youre experiencing in order so that the right ways to alleviate them can be found. You should also ask your care team about options for palliative care.
Because it can be very stressful to have advanced prostate cancer, and tough to talk about what it all means for your future, the ASCO urges men to have an open and honest conversation with their care team. Discuss what youre worried about, and whats important to you. There are many ways to look for and get emotional support.
Additional reporting by Andrea Peirce
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New Treatments For Nmcrpc
Guidelines for treatment of CRPC that has not yet spread emphasize careful monitoring for possible development of metastases via imaging and measuring blood levels of a protein called prostate specific antigen , a marker of prostate cancer progression. PSA doubling time , the amount of time it takes for PSA levels to double, is a good predictor of cancer progression. If PSADT is longer than 10 months, patients can continue to be observed and continue treatment with ADT. If PSADT is less than 10 months, patients should receive, in addition to the ongoing ADT, a drug that curbs androgen signaling, such as apalutamide, darolutamide, or enzalutamide to try and stave off development of metastases.
Of those three drugs, apalutamide is a newer option. In the pivotal SPARTAN trial, the median metastasis-free survival time for nmCRPC patients who took apalutamide alongside standard ADT was 40.5 months, compared to 16.2 months for patients who received a placebo alongside ADT.
In short, there has been significant evolution in the development of new drugs to treat CRPC, especially mCRPC, and patients are encouraged to explore treatment options available in clinical trials. For more information on any of the treatments discussed in this article, and how to access them, I invite you to get support from Cancer Commons.
How Prostate Cancer Is Treated
In cancer care, different types of doctorsincluding medical oncologists, surgeons, and radiation oncologistsoften work together to create an overall treatment plan that may combine different types of treatments to treat the cancer. This is called a multidisciplinary team. Cancer care teams include a variety of other health care professionals, such as palliative care experts, physician assistants, nurse practitioners, oncology nurses, social workers, pharmacists, counselors, dietitians, physical therapists, and others.
The common types of treatments used for prostate cancer are described below. Your care plan may also include treatment for symptoms and side effects, an important part of cancer care.
Treatment options and recommendations depend on several factors, including the type and stage of cancer, possible side effects, and the patients preferences and overall health.
Cancer treatment can affect older adults in different ways. More information on the specific effects of surgery, chemotherapy, and radiation therapy on older patients can be found another section of this website.
Because most prostate cancers are found in the early stages when they are growing slowly, you usually do not have to rush to make treatment decisions. During this time, it is important to talk with your doctor about the risks and benefits of all your treatment options and when treatment should begin. This discussion should also address the current state of the cancer:
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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.
Diagnosing Nmcrpc In Clinical Practice
The most widely adopted definition of nmCRPC, derived from the recommendations of the Prostate Cancer Working Group 3, is a 25% increase from the PSA nadir in men with castrate levels of serum testosterone, with a minimum rise of 2ng/mL, which must be confirmed with a second value obtained 13 weeks later without evidence of metastases .
Various imaging techniques are routinely utilized to stage prostate cancer and to detect metastases and tumor recurrence. The National Comprehensive Cancer Network Clinical Practice Guidelines for Prostate Cancer recommend CT or magnetic resonance imaging for staging with the addition of conventional bone scans for the detection of metastases . Next-generation techniques, such as positron emission tomography /CT or PET/MRI, are only recommended to address equivocal findings. The guidelines note that conventional bone scans are rarely positive for asymptomatic men with PSA< 10ng/mL. However, since the risk of metastases or death increases as PSA doubling time shortens, skeletal scintigraphy should be performed more frequently when PSADT is 8 months . The European Association of Urology guidelines on prostate cancer recommend that a conventional bone scan and CT scan should be performed when PSA is 2ng/mL in asymptomatic patients . If the scans are negative, they should be repeated when PSA is 5ng/mL, and again after every doubling of the PSA. Symptomatic patients should undergo relevant investigation, regardless of PSA level .
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Treatment Landscape For Patients With Mcrpc
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Figure 1 Timeline of treatments for mCRPC . 1,2Tannock, IF et al. N Engl J Med 2004 3De Bono, J et al. Lancet 2010, 4Oudard, S et al. J Clin Oncol 2017, 5Kantoff, P.W. et al. N Engl J Med. 2010 6De Bono, J et al. N Engl J Med. 2011, 7Ryan, CJ et al. N Engl J Med. 2013, 8Scher, HI et al. N Engl J Med 2012 9Beer, TM et al. N Engl J Med 2014, 10Parker, C et al. N Engl J Med. 2013, 11Nilsson S et al. Ann Oncol. 2016 12De Bono, J et al. N Engl J Med 2020 13Sartor O et al. N Engl J Med. 2021. *Approval EMA withdrawn, not available in Europe +symptomatic, bone only, LN< 3cm, visceral mets. excluded approval §EMA: BRCA1,2 FDA: HRD panel PROfound, Rucaparib **FDA only approval, not EMA. |
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Table 2 Phase III Trials Reporting Overall Survival Benefit in Metastatic Castration Resistant Prostate Cancer Setting |
Intermittent Versus Continuous Therapy
The common complications of androgen deprivation therapy include sexual dysfunction, mood disturbance, change in body composition and osteoporosis.2,3 In view of these adverse effects intermittent dosing has been considered. This is a period of androgen deprivation therapy followed by a break until disease progression, if a good response was attained. The optimal duration of androgen deprivation therapy is fairly arbitrary as the studies have looked into various periods ranging from three months to three years.
In patients with PSA relapse only , intermittent therapy has been shown to be non-inferior to continuous dosing. There was also a better quality of life with intermittent dosing.4
In patients with objective metastases, intermittent androgen deprivation therapy had numerically worse outcomes than continuous treatment, but the study was statistically inconclusive. There was less sexual dysfunction and better mental health in the intermittent group, but this effect disappeared by 15 months when most people were back on continuous treatment.5 If short-term quality of life is important, even at the risk of possible worse survival, intermittent therapy is a reasonable approach.
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Recap: Recent Advances In The Treatment Of Metastatic Castration
Expert oncologists review key studies in the metastatic castration-resistant prostate cancer treatment landscape and discuss how evidence can be applied to clinical practice to improve patient outcomes.
At an Around the Practice® program hosted by CancerNetwork®, experts spoke about treatment options for patients with prostate cancer, specifically the use of doublet or triplet therapy. The discussion was led by Neeraj Agarwal, MD, Presidential Endowed Chair of Cancer Research as well as director of both the Genitourinary Oncology Program and the Center of Investigational Therapeutics at the Huntsman Cancer Institute of the University of Utah in Salt Lake City, where he serves as professor of medicine.
The other panelists were Simon Chowdhury, MD, PhD, a consultant medical oncologist with Guys and St Thomas NHS Foundation Trust in London, United Kingdom Bobby Liaw, MD, assistant professor of medicine, hematology, and medical oncology at Mount Sinai in New York and Benjamin H. Lowentritt, MD, FACS, director of both minimally invasive surgery and the Robotics and the Prostate Cancer Care Program at Chesapeake Urology in Towson, Maryland.
Patient Selection And Unmet Clinical Needs In Nmcrpc Setting
Prostate cancer patients are often elderly men with concomitant comorbidities that require additional drug treatment. For this reason, the drug interactions of ARPIs should be carefully assessed when selecting treatment. For example, enzalutamide and apalutamide are known to cause interactions with drugs commonly used in the elderly population such as proton pump inhibitors, lipid-lowering drugs, anticoagulants or benzodiazepines.36,37 Conversely, it would appear that darolutamide has fewer drug-drug interactions. In fact, in a pre-specified post hoc analysis of ARAMIS trial, darolutamide demonstrated a lower risk of clinically relevant drug interactions with commonly used drugs in these patients.38
In summary, in the absence of direct comparisons between these three ARPIs, the factors that can help us to best choose treatment in the nmCRPC setting are represented by patient comorbidities, treatment toxicity, drug interactions, and access meaning not only approval but also reimbursement of treatments.
Finally, another unmet clinical need in this setting is what treatment to give patients who progress to metastatic disease on an ARPI in nmCRPC. Several studies demonstrated that the sequential use of ARPI is not very effective due to cross-resistance mechanisms.40,41 Based on these results, it would be intuitive to use docetaxel as the best choice of first-line therapy in the mCRPC setting in these patients.
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New Treatments For Mcrpc
mCRPC remains a clinically challenging late-stage cancer with no curative treatment options. However, the newer hormonal drugs enzalutamide and abiraterone provide a tighter inhibition of androgen signaling, and are often used as first-line treatment in mCRPC. Docetaxel is used in patients for whom treatment with enzalutamide or abiraterone has failed, but it can also be a first-line treatment for mCRPCthis is a decision usually made by oncologists that takes into account patient-specific considerations. Bone metastases, very prevalent in prostate cancer, are treated with Radium-223 or radiation to reduce pain.
In recent years, what has changed in treatment of mCRPC is that clinical guidelines now include mutational testing and analysis of markers to predict the potential effectiveness of newer treatments that involve the immune system.