The Facts About Hormonal Therapy For The Treatment Of Prostate Cancer
Hormonal Therapy in various forms may be prescribed for patients as part of their treatment at the Dattoli Cancer Center. Simply put, certain hormones have the ability to temporarily halt or slow the growth of prostate cancer, as well as to shrink the overall size of the prostate gland. Men with enlarged prostates can benefit by reducing the size of the gland, making it a smaller target for curative radiation therapy.
Many Patients Do Not Require Hormones
It has long been known that prostate cancer is to some extent dependent on and nourished by the male sex hormone, testosterone. This is one of a group of hormones known as androgens. Since testosterone stimulates the growth of prostate cancer cells, depleting or ablating the body’s testosterone tends to shrink the size of many tumors, specifically those that are hormone-sensitive.
The goal of hormonal therapy is to decrease the production of testosterone in the body, inhibiting the growth and progression of the cancer. Hormonal therapy, also known as Androgen Deprivation Therapy (ADT), can shrink a man’s prostate by as much as 50%. Hormones have also been shown to have a synergistic effect when combined with radiotherapy, making cancer cells more sensitive and vulnerable to radiation therapy (known as “radiosensitization”). The synergy effect is equivalent to ‘one plus one equals three.’
Hormonal treatment can be optional for patients with intermediate-risk disease but is generally encouraged for patients with high-risk features, as indicated by PSA, Gleason score, the PAP test and clinical stage. With the low-risk or mildly aggressive cancers, unless the size of the gland is markedly large, we don’t normally prescribe conventional hormonal therapy in order to avoid the potential side effects of the hormones.
In these select cases, a modified version of hormones, which do not reduce testosterone but rather act as blocking agents (e.g. oral anti-androgens), are utilized, thus not allowing testosterone to bind with the receptors of the prostate cancer cells. Other non-hormonal agents that may also be utilized are oral agents such as 5 alpha-reductase inhibitors, which do not allow testosterone to convert to dihydrotestosterone (DHT), a metabolite that is 10 times as potent as testosterone in stimulating prostate cancer growth. This modified type of hormonal therapy is just enough to arrest the cancer and allow the patient to make a more relaxed decision about treatment, without the potential side effects associated with more aggressive ADT, that is, a combined hormonal blockade that uses two or more agents.
While often combined with primary therapies including radiotherapy for treating early stage prostate cancer, hormonal therapy is a standard treatment for patients whose cancer has spread beyond the prostate gland. ADT is the first-line treatment of choice for patients with advanced, late stage disease. If, after radiation or surgery or any other primary curative treatment, the patient experiences a recurrence as indicated by a rising PSA (biochemical failure) or a positive biopsy, hormonal therapy is likely to be prescribed. The same holds true for patients initially diagnosed with advanced prostate cancer who are not candidates for primary therapy. In these cases, hormonal therapy is considered a palliative therapy to pursue rather than curative treatment. And there are still more excellent treatment options for these patients that are discussed below.
What Options Are Available Once Hormonal Therapy Stops Working?
All combinations of hormonal therapy should be completely exhausted before further therapeutic options are considered. For example, if the antiandrogen Casodex® ceases to be effective as indicated by a rising PSA, when the cancer becomes castrate-resistant, consideration might be given to changing to a second-line agent, a novel hormonal therapy (NHT). As discussed below, the field of NHT now includes Xtandi® (enzalutamide) and Zytiga® (abiraterone), Erleada® (apalutamide), and Nubeqa® (darolutamide). There are many new drugs being developed for FDA-approval and clinical application. Even patients having castrate-sensitive prostate cancer (CSPC) with high-risk features and patients with metastatic castrate-sensitive prostate cancer (MCSPC) may benefit from NHT.
For prostate cancer that becomes resistant to all combinations of hormonal therapy, chemotherapy agents such as Taxotere® (docetaxel) were long regarded by oncologists as the standard of care, though that assessment has changed dramatically during recent years. Doctors often administer chemo in 2 to 3 week cycles, with each period of treatment followed by a short break for patients to recover from the adverse side effects of those drugs.
Many patients resist undergoing chemotherapy because they see it as a short-term endgame, with limited survival benefits measured in months and severe side effects (as a result of chemotherapy immuno-suppressive effects). The side effects of Taxotere® include hematological toxicities such as febrile neutropenia (low white blood cell count leading to infection and fever), which can be extremely debilitating, impacting about 10% of patients. As many as 60% or more of patients on Taxotere® develop peripheral neuropathy (short- or long-term peripheral nerve disease). Other potential side effects include fatigue, nausea, vomiting, diarrhea, hair loss, anemia, loss of appetite, mouth sores, bleeding, reduced heart function, and fluid retention. Some of these complications can be ameliorated with medications.
Another chemotherapy agent, Jevtana® (cabazitaxel), has been prescribed in recent years for hormone-resistant prostate cancer. This chemo agent may be prescribed when Taxotere® stops working or cannot be tolerated. Jevtana® has somewhat less overall toxicity than Taxotere®, although Jevtana® similarly impacts quality of life for many patients. Fewer patients who are prescribed Jevtana® suffer from neuropathy (less than 10%), fatigue and hair loss than those on Taxotere®; but a much higher percentage of patients experience neutropenia with Jevtana® (more than 90%).
One large study reported percentages of patients who experienced hematological and gastrointestinal toxicities with Jevtana® as follows: neutropenia (94%), anemia (97%), leukopenia (96%), thrombocytopenia (47%), diarrhea (47%), nausea (34%), and vomiting (22%). (Tsao CK, et al, The role of cabazitaxel in the treatment of metastatic castration-resistant prostate cancer; Ther Adv Urol. 2014 Jun;6 (3):97-104).
A number of newly developed, targeted therapies such as immunotherapy and therapeutic vaccines are currently being offered clinically as alternatives to chemotherapy, often with significant survival benefits and fewer and less severe side effects. At our center, when treating androgen-independent, advanced prostate cancer, we are increasingly utilizing genetic/genomic testing in order to create a “designer cocktail,” which often includes an immunotherapy agent (or PARP inhibitor) that may be given in conjunction with high-tech and infusional irradiation, with or without DART (Dynamic Adaptive Radiotherapy). Genetic markers help us determine which patients are likely to benefit from particular therapeutic agents. Genetic testing is becoming increasingly important, as is molecular profiling, to select the right drugs for the specific tumor.
A recent survey from the Memorial Sloan-Kettering Cancer Center suggests that immunotherapy agents for prostate cancer show enhanced benefits when utilized in combination with various biologic agents, vaccines, chemotherapies, and radiation (Slovin SF, Immunotherapy in metastatic prostate cancer, In J Urol. 2016 Oct- Dec; 32(4): 27-276).
When patients stop responding to hormonal therapy, we usually first consider one of two FDA-approved drugs, Xtandi® (enzalutamide) and Zytiga® (abiraterone). These are androgen-blocking agents, and they have been shown to prolong survival, irrespective of age. Both of these drugs act to inhibit the production of testosterone and dihydrotestosterone in the prostate gland and elsewhere in the body, thereby lowering PSA and slowing the growth of prostate cancer. As a second-line therapy after ADT stops working, we often combine Xtandi® and prednisone. Prior to prescribing androgen-blocking agents such as Xtandi® and Zytiga®, we employ multiple lab tests for genomic makeup that allow us to determine which of these drugs may be appropriate for each patient.
At our center, we employ multiple laboratory tests for genomic and genetic makeup that allow us to determine which specific medications and treatments may be most appropriate for each patient. We utilize both the Invitae Genetic Test and the Myriad myRisk® Hereditary Cancer testing. The Myriad test is a 35-gene panel that identifies elevated risk for eight hereditary cancers. There are a host of genetic pathways and mutations that a patient may have (including BRACA 2, BRCA1, HOXB13, ATM, CHEK2, and CDK1), and they can tell us whether or not a patient is likely to respond well to a particular agent. For example, we know that a patient with positive BRCA1 and especially positive BRCA2 gene mutations will most likely have a shorter effective run with the androgen-blocking drugs Xtandi® and Zytiga®, so other targeted therapies may be more appropriate.
It should be noted that genetic markers are also important in light of the patient’s family history. We want to know what the family history is with regard to other cancers. We can see that a patient’s daughters may be prone to breast cancer or ovarian cancer; and now we are seeing colon and pancreatic cancers enter the picture in the spectrum related to prostate cancer. These cancers are essentially on the same page in our genetic makeup. Melanoma is also genetically related to prostate cancer, and all of these cancers may occur at increased frequency in the patient tested.
While genetic testing is important for the patient’s siblings and children, (and also for the patient on occasion), there is even greater importance in sampling the actual cancerous tissue removed from the patient in order to identify somatic mutations. This is known as comprehensive genomic profiling (CGP). This test can help identify exactly which particular treatment may benefit the patient. AR-7 mutations suggest resistance to Xtandi®/Zytiga® while HRR gene mutations predict response to Lynparza® (olaparib). Checkpoint inhibitors (e.g. PD-1) suggest sensitivity to pembrolizumab.
We have been using FoundationOne®CDx as the best genomic test currently available for identifying somatic mutations. This test searches 324 genes for cancer-relevant mutations in the DNA.
Xtandi® and Zytiga® as well as Erleada® and Nubeqa® have a side effect profile similar to that of hormonal therapy. In conjunction with these agents, we also use metaformin, which has an anti-cancer mechanism and has been shown to enhance the efficacy of Xtandi® and Zytiga®. Metaformin works in the pancreatic insulin pathway.
With patients for whom Xtandi® and Zytiga® or Erleada® and Nubeqa® are not effective or are unlikely to be effective as indicated by positive genetic markers (BRCA1 and BRCA2), we may prescribe Lynparza®, which is known as a PARP inhibitor (poly ADP-ribose polymerase). Many patients fare quite well with Lynparza®. Another immunotherapy agent, Keytruda® (pembrolizumab) is known as a PD1 inhibitor. We are finding that patients who are not responding well to Lynparza may benefit from Keytruda.
We have a growing arsenal of medications at our disposal for patients with advanced or recurrent disease. Both hormonal therapies and immunotherapies are associated with far less toxicity than chemotherapy, as they are “targeted therapies.”
For more information about the Myriad myRisk® Hereditary Cancer Test, visit online: https://myriad.com/products-services/hereditary-cancers/myrisk -hereditary-cancer/
To learn more about Invitae Genetic Testing, visit online: https://www.invitae.com/en/detect-hereditary-prostate-cancer/
The National Comprehensive Cancer Network (NCCN) offers patients recommendations on genetic testing and describes Medicare coverage here: https://myriad.com/products-services/hereditary-cancers/myrisk-hereditary-cancer/
Additional information on the FDA approved FoundationOne ®CDx Test is available here: https://www.foundationmedicine.com/test/foundationone-cdx
The immunotherapy agent, Provenge® (sipuleucel-T) is a therapeutic vaccine that received FDA approval in 2010 for treating prostate cancer patients. While the reported overall survival improvement with this drug was only four months for patients with advanced disease, this positive development gave hope to many patients who had few options and were facing grim prospects at that time. We have come a long way since then. Research developing Provenge® soon led to a number of similar prostate cancer immunotherapeutic drugs that have also won FDA approval. Other novel therapeutic agents are now regularly being prescribed for hormone-refractory prostate cancer.
As with enzalutamide and abiraterone, some studies have shown that apalutamide combined with ADT for newly diagnosed, advanced cancer patients achieves greater overall survival than ADT alone with patients starting hormonal therapy for the first time (Armstrong AJ, et al, ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer, J Clin Oncol, 2019 Jul 22:JCO1900799; also see: Hoyle AP, et al, Abiraterone in “High-” and “Low-risk” Metastatic Hormone-sensitive Prostate Cancer, Eur Urol, 2019 Aug 22; S0302-2838(19)30620-7).
An FDA-approved infusional irradiation agent, Xofigo® (Radium-223) is an alpha particle radioisotope, which can be delivered to patients in a one-minute infusion and attacks prostate cancer that has spread to the bones. Not only does Xofigo® relieve bone pain, but it also improves overall survival (Parker C, et al, Efficacy and Safety of Radium-223 Dichloride in Symptomatic Castration-resistant Prostate Cancer Patients With or Without Baseline Opioid Use From the Phase 3 ALSYMPCA Trial; Eur Urol, 2016 Nov; 70(5): 875-883).
Xofigo® is now being combined with Zytiga®, Xtandi®, Provenge®, Erleada® and Nubeqa®and and these combinations appear to be synergistic. For patients with multiple bone metastases, we are having success with a 3X protocol combining Xgeva®, Xtandi®, and Xofigo®. For patients with visceral metastases (e.g. liver and/or lung) we may intervene with Zytiga® and prednisone. If metastases are confined to lymph nodes only, we may stay with only intensive combination ADT, which usually brings PSA down to nadir value.
A large multi-institutional Phase III clinical trial reported that Zytiga® plus prednisone combined with ADT showed significantly improved survival versus ADT alone for patients with advanced disease: “Adding abiraterone acetate (Zytiga) plus prednisone to standard hormonal therapy for men newly diagnosed with high-risk, metastatic prostate cancer lowers the chance of death by 38%” (2017 American Society of Clinical Oncology (ASCO) Annual Meeting. press release, June 3, 2017; also see: Fizazi K, et al, Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomized, double-blind, phase 3 trial, Lancet Oncol, 2019 May;20(5):686-700. doi: 10.1016/S1470-2045(19)30082-8).
Both Xofigo® and Provenge® are expensive, as are Zytiga® and Xtandi®. Xofigo® costs more than $60,000 for six injections; and Provenge® costs more than $90,000 for three infusions. Zytiga® now retails for more than $9,000 per month; and the cost for Xtandi® is more than $12,000 for a 1-month supply of 120 capsules (40 mg). On our staff we have oncology nurses who try to work with insurance companies to make these agents more affordable for patients.
Whereas Xofigo® only treats bone, another injectable radioisotope, Actinium-225, attaches to prostate-specific membrane antigen (PSMA). PSMA is found on the surface of most metastatic prostate cancer cells. Therefore Actinium-225 treats not only bone, but also can target metastases in any tissue or fluid, even undetectable systemic micro-metastases. Since it is an alpha emitter (very short range), it is less toxic to bone marrow and other nearby tissues. Actinium-225 is currently in the pipeline and we hope it will be released soon (Kratochwil C, et al, 225Ac-PSMA-617 for PSMA targeting alpha-radiation therapy of patients with metastatic castration-resistant prostate cancer, J Nucl Med July 7, 2016). A similar agent, Lutetium-177 PSMA, has been FDA-approved but so far has only limited availability.
Xgeva® (denosumab) is a subcutaneous injection given monthly to treat bone metastases and to deter further bone metastases by blocking the glycoprotein known as RANKL (receptor activator nuclear factor ligand), which plays an important role in prostate cancer proliferation in bone. This agent is used in patients having documented spread to one or more bone sites. In this setting, patients receive 12 consecutive months of Xgeva® and then enter a 3-month holiday. Side effects with Xgeva® may include fatigue, weakness, headache, back and joint pain, diarrhea and nausea.
We are also currently using denosumab in patients without skeletal metastases in lower doses given once every 6 months to help strengthen the bones in prostate cancer patients who are on ADT, with the added potential benefit of deterring metastatic bone spread. Meanwhile we are awaiting the outcome of trials delivering Xgeva® monthly in patients having organ confined, high-risk non-metastatic prostate cancer (Smith MR, et al, Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer, Lancet. 2012 Jan 7:379(9810): 39-460); also see: Miller K, et al, Harnessing the potential of therapeutic agents to safeguard bone health in prostate cancer; Prostate Cancer Prostatic Dis, 2018; 21(4): 461–472).
There is also a great deal of interest in combining immunotherapies with other therapeutic agents and especially radiation. Combining radiation with immunogenic drugs has great promise since the effects of the body’s immune response to cancer is enhanced (Golden EB, et al Semin Radiat Oncol. 2015:25 (1) 7-11). These immunogenic synergistic effects of radiation and immunogenic drugs (especially those known as “checkpoint inhibitors” like PD1 and PARP inhibitors, and even Zytiga® and Xtandi®) are thought to result from ‘autovaccination’ by antigens released from dying cancer cells and fragmented, damaged DNA. Checkpoint inhibitors are immunotherapy agents that block certain proteins that stop the immune system from attacking the cancer cells.
Mechanistically, radiation (all types, including Xofigo.) has been shown to augment the afferent, as well as the efferent arms of cancer immunity. The induction of a positive T-cell immune response against cancer has been observed in numerous studies (Kapoor A, et al, Contemporary agents in the management of metastatic castration-resistant prostate cancer, Can Urol Assoc J. 2016 Nov-Dec;10(11-12):E414-E423).
There are novel immunotherapy agents that ramp up both T-cells and B-cells to attack prostate cancer cells. These are checkpoint inhibitors that encompass a class of drugs including anti-PD-1/PDL-1 inhibitors such as Opdivo® (nivolumab) and Keytruda as well as anti-CTLA-4 inhibitors such as Yervoy® (ipilimumab). These immunotherapeutic checkpoint inhibitors are currently being used in other cancers and have been FDA-approved for melanoma, lung and kidney cancers. We are hopeful that checkpoint inhibitors and other novel therapies will be “fast tracked” by the FDA, similar to the experience with Zytiga®, Xtandi®, Erleada® and Nubeqa®.
The biomarker Androgen Receptor Splice Varient-7 (AR-V7) expression in tissue, and more recently in blood, could predict resistance to Zytiga® and Xtandi®, and it could help personalize checkpoint inhibitors. AR-V7 may also possibly allow for chemotherapy to be more specifically designed for the tumor. We eagerly await AR-V7 winning FDA approval (Antonarakis ES, et al, Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men with Metastatic Castration-Resistant Prostate Cancer Treated with First- and Second-Line Abiraterone and Enzalutamide, J Clin Oncol. 2017 Apr 6; also see: Scher HI, et al, Association of AR-V7 on Circulating Tumor Cells as a Treatment-Specific Biomarker with Outcomes and Survival in Castration-Resistant Prostate Cancer, JAMA Oncol. 2016 Nov 1;2(11):1441-1449).
Finally, it should also be noted that while ADT and other therapeutic agents are important in treating metastatic disease, we have long been proponents of treating the primary tumor with external radiation, preferably DART. A number of studies have demonstrated that treating the primary tumor site with radiotherapy significantly improves overall survival for patients with metastatic prostate cancer. A recent multi-institutional position paper suggested this should be the standard of care for treating metastatic disease (Choudhury A, et al, STAMPEDE: Is Radiation Therapy to the Primary a New Standard of Care in Men with Metastatic Prostate Cancer? Int J Radiat Oncol Biol Phys, 2019 May 1;104(1):33-35).
