Andrew Siegel MD 10/26/19
Most, but not all, initial treatments for prostate cancer are curative. However, patients with a recurrence can often be cured or sustain a remission with a secondary treatment, e.g., radiation therapy following radical prostatectomy or androgen deprivation therapy following radiation therapy.
When prostate cancer progresses, it does so through a sequence of discrete stages including: “biochemical recurrence” (PSA rises after treatment) to “non-metastatic castration-sensitive prostate cancer” (PSA declines in response to androgen deprivation therapy) to “non-metastatic castration-resistant prostate cancer” (PSA rises despite androgen deprivation therapy) to “metastatic castration-resistant prostate cancer” (prostate cancer spreads despite androgen deprivation therapy).
BIOCHEMICAL RECURRENCE OF PROSTATE CANCER
20-25% of men after prostatectomy experience a biochemical recurrence within 10 years of surgery, despite the surgery performed by the most proficient and talented urological surgeons. This often responds to radiation therapy, although a percentage of patients will have an initial satisfactory response to the radiation (PSA drops to undetectable levels), but subsequently experience a second biochemical recurrence, indicative of a failure of the radiation therapy to cure the recurrence. Similarly, a small percentage of men after primary radiation therapy will experience a biochemical recurrence, despite the therapy delivered by highly competent radiation oncologists.
Biochemical recurrences are typically due to “micro-metastases,” small numbers of cancer cells that spread from the primary tumor site to a separate part of the body and are undetectable despite the use of the most advanced imaging methods available. These cells can remain dormant for years and are the reason behind the importance for long-term follow up of any patient who has been treated for prostate cancer.
CASTRATE-RESISTANT PROSTATE CANCER (CRPC)
Androgen deprivation therapy (ADT) is commonly started when biochemical recurrence occurs following surgery, primary radiation therapy or adjuvant or salvage radiation after surgery. Even after surgery followed by radiation therapy eventually followed by ADT with the achievement of castrate levels of testosterone (blood levels < 50 nanograms/dl), 10-20% of patients will develop resistance to the ADT within 5 years, manifested with a rising PSA or imaging evidence of prostate cancer progression. This is castration resistant prostate cancer (CRPC), historically also referred to as “hormone-resistant prostate cancer” or “hormone-refractory prostate cancer.” The average time to the occurrence of CRPC after starting ADT is 19 months. 30-40% of men with non-metastatic CRPC will progress to metastatic CRPC within 18-24 months.
SURGERY–>RADIATION–>ADT–>CASTRATE SENSITIVE–>CASTRATE RESISTANT
The longer the exposure one has had to ADT, the more likely the prostate cancer cells can adapt, mutate and develop unique ways to protect themselves, resulting in the prostate cancer cells thriving, growing, and spreading. Mutations can even result in the prostate cancer cells producing their own testosterone. Regardless of whether the CRPC is metastatic or not, all patients with CRPC are advised to continue with ADT to maintain castrate levels of testosterone, since testosterone is often the primary driver of the cancer. The good news is that in patients with metastatic CRPC, numerous new options are available.
When prostate cancer progresses despite ADT, it can be asymptomatic and noted only because of a rising PSA, or it can be symptomatic, most commonly causing pain from bone metastases. The initial approach is to ensure that castrate levels of testosterone have been achieved and to obtain staging information via imaging studies that may include computerized tomography, bone scan and perhaps some of the newer, advanced imaging techniques. After imaging is complete, a patient can be classified as not having metastatic spread or having metastatic spread.
GENETIC TESTING IN MEN WITH CRPC
More than 20% of men with metastatic CRPC have defects in those genes that repair DNA, including BRCA, ATM, MMR, etc. Men with metastatic CRPC should have genetic testing and DNA sequencing of the cancer, or at a minimum have the tumor tested for certain biomarkers and assessment of genetic mutations.
Defective DNA repair genes may predict the response to PARP (poly-ADP-ribose polymerase) inhibitors that repair damaged DNA, currently undergoing clinical trials, as well as platinum-based chemotherapy. 5-10% of prostate cancers have MMR mutations and MSI (micro-satellite instability—the condition that results from the MMR mutation) and may be candidates for immune checkpoint inhibitors.
ANTI-ANDROGENS FOR CRPC
Anti-androgens are medications that function to block the action of testosterone or compete with the binding of testosterone at the cellular level, resulting in the testosterone rendered incapable of stimulating the growth of the prostate cancer cell.
In the case of non-metastatic CRPC, if an anti-androgen has not been used, it is worthwhile to trial a medication of this class in addition to the LHRH analog or LHRH antagonist. First generation anti-androgens include bicalutamide (Casodex), flutamide (Eulexin) and nilutamide (Nilandron). Ketoconazole (Nizoral), although primarily used to treat fungal infections, is also used as second-line hormonal therapy to treat advanced prostate cancer via suppression of adrenal testosterone synthesis, although concerns about side effects have encouraged the development of the newest-generation agents.
New options to manage CRPC
Years ago, once CRPC occurred, the only option was chemotherapy with docetaxel. However, since 2010, there have been unparalleled changes in the field of advanced prostate cancer with the availability of numerous new-generation treatments capable of improving the quality of life and survival for those with CRPC. Pharmaceutical companies have created the following complex and memorable names for some of the novel medications: cabazitaxel (Jevtana), denosumab (Xgeva), enzalutamide (Xtandi) abiraterone (Zytiga), and radium 223 (Xofigo). Apalutamide (Erleada) was FDA approved in 2018 for non-metastatic CRPC and the newest entry, darolutamide (Nubeqa), was FDA approved in July 2019 for non-metastatic CRPC. These new treatments can be sub-categorized into advanced hormonal therapy, bone-targeted therapy, immunotherapy, and cytotoxic therapy, to be discussed in next week’s entry.
Wishing you the best of health,
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Dr. Andrew Siegel is a physician and urological surgeon who is board-certified in urology as well as in female pelvic medicine and reconstructive surgery. He is an Assistant Clinical Professor of Surgery at the Rutgers-New Jersey Medical School and is a Castle Connolly Top Doctor New York Metro Area, Inside Jersey Top Doctor and Inside Jersey Top Doctor for Women’s Health. His mission is to “bridge the gap” between the public and the medical community. He is a urologist at New Jersey Urology, the largest urology practice in the United States.
The content of this entry is excerpted from his new book, PROSTATE CANCER 20/20: A Practical Guide to Understanding Management Options for Patients and Their Families
Video trailer for Prostate Cancer 20/20
Preview of Prostate Cancer 20/20
Andrew Siegel MD Amazon author page
Prostate Cancer 20/20 on Apple iBooks
PROSTATE CANCER 20/20: A Practical Guide to Understanding Management Options for Patients and Their Families is now on sale at Audible, iTunes and Amazon as an audiobook read by the author (just over 6 hours).
Dr. Siegel’s other books:
PROMISCUOUS EATING— Understanding and Ending Our Self-Destructive Relationship with Food
MALE PELVIC FITNESS: Optimizing Sexual and Urinary Health
THE KEGEL FIX: Recharging Female Pelvic, Sexual, and Urinary Health
Our Greatest Wealth Is Health 