Metastatic castration-resistant prostate cancer (mCRPC) presents with a wide spectrum of symptoms with varying effects on patient quality of life. It is estimated that more than 90% of patients with metastatic castrate resistant prostate cancer (mCRPC) develop bone metastases that result in a significant increase in the risk of morbidity.1
The extent of bone involvement in mCRPC has also been found to be associated with patient survival. While most patients are clinically asymptomatic, those with symptoms may experi.ence either pain and/or skeletal-related events (SREs). Patients can have low-volume disease with very few symptoms and a good quality of life, but there are also patients who present with high-volume disease that causes significant and painful symp.toms. So, the aim of therapy in patients with mCRPC is to match the appropriate strength therapy to the appropriate level of patient symptoms and disease burden.
For patients who have a good prognosis, it can also be wise to wait 2 to 3 months before starting therapy to get a sense of the pace of their disease. As long as patients remain in a good prognostic category, asymptomatic, and with less aggressive tumor biomarkers—such as alkaline phosphatase and lactate dehydrogenase—waiting 2 to 3 months is often not problematic. Once the clinician obtains additional information about the pace of the patient’s cancer progression over several months, it becomes easier to choose the most appropriate therapy.
In addition, seizures are a known side effect of higher doses of enzalutamide. In the two major clinical trials on enzalutamide— AFFIRM and PREVAIL—seizures were fairly rare, but this therapy should be avoided in patients with a history of seizures3,4.
For patients with mild baseline pain, abiraterone acetate plus prednisone therapy may be preferable instead. Since abiraterone is given with low-dose prednisone, patients may derive a significant treatment effect from taking the steroid. Approximately 25% of patients who received prednisone alone in the COU-AA-302 study showed a 50% or greater decline in PSA, and patients who experienced this large a decline in PSA survived longer than patients who did not4. The steroid use in abiraterone acetate plus prednisone may also favor use of this treatment in older, frailer patients, who may already have signs of mild adrenal insufficiency5,6.
At the same time, abiraterone can cause fluid retention, and so it should be avoided in patients with a history of heart failure. If a patient has diabetes or renal failure, enzalutamide should also be strongly considered over abiraterone, since abiraterone can have mineralocorticoid-related or cardiotoxic effects. In the COU-AA-302 study, adverse events due to cardiac disorders occurred in 19% of the patients in the abiraterone-pred.nisone treatment group vs. 16% of patients in the predni.sone-alone group. Hypertension was also more common in the abiraterone-prednisone treatment group (22% vs. 13%), as was fluid retention and edema (28% vs. 24%) and hypokalemia (17% vs. 13%)5.
The patient’s age should not be the only factor one should weigh in choosing whether to treat a patient with enzalutamide or abiraterone. In the COU-AA-302 study, the magnitude of benefit of abiraterone-prednisone therapy was preserved in elderly men 75 years of age or older. The COU-AA-302 trial data showed that abiraterone plus prednisone did not induce harm, and conferred significant benefit in overall survival rates and radiographic progression-free survival rates in elderly men2. In contrast, chemotherapy in elderly patients with prostate cancer has the potential to induce harm, and many elderly men cannot undergo chemotherapy5,6,7.
In the COU-AA-302 study, elderly men did have increased rates of liver toxicity and cardiac events, however. These findings reflect the fact that elderly men are generally more frail; thus, the fluid retention syndrome that abiraterone causes can negatively affect older men with less cardiac reserve. Elderly men also tend to take more medications and have more comorbid illnesses that can adversely affect liver toxicity5,6.
Still, choosing between enzalutamide and abiraterone can be challenging, even for clinicians with considerable expertise in using these medications. It’s unlikely that a randomized clinical trial comparing these two medications will be performed, due to the impracticality of such an effort.Yet, patient-centered compar.ative effectiveness trials would be possible. Such studies could focus on the quality of life benefits, patient-reported outcomes, and patient-reported adverse events with the use of these medications8.
To complete these patient-centered outcome studies, researchers could use validated tools such as the PRO-CTCAE, a patient-reported outcome measure developed to evaluate symp.tom toxicity in patients on cancer clinical trials, and many of the validated quality-of-life measure now available. As a result of such research, clinicians would be able to identify patients who are more likely to benefit or experience side effects from treatments such as abiraterone and enzalutamide therapy.8
One of the major challenges we face in treatment of mCRPC is that resistance to abiraterone and enzalutamide typically develops after 11 to 18 months of beginning therapy. Although many “responders” to these drugs show an impressive decline in PSA, along with radiographic disease control, other patients who respond present with a slowly rising PSA. Thus, rising PSA should not be the sole criteria used to decide whether to discontinue one of these medications. Instead, radiographic disease progression, clinical deterioration, and adverse events should be considered together in making decisions about stopping or switching treatments. (See Figure 1)
In patients who are on abiraterone or enzalutamide therapy, and develop resistance but do not have significant symptoms, it’s often possible to switch the patient to another of these andro.gen-receptor targeted drugs. The clinician should keep in mind, however, that retrospective analyses suggest that the second agent is likely to have a more modest degree of activity in patients who do not respond to their first treatment with enzalutamide or abiraterone. As yet, there are few safety concerns with sequential treatment.
Studies are also evaluating these agents in combination, in the hope of obtaining a response rate that is superior to that achieved with abiraterone or enzalutamide alone. The ALLIANCE phase III clinical trial is currently testing this approach in patients who have not had prior taxane-based chemotherapy or treatment with enzalutamide or abiraterone.Yet, since data from this trial will not be available for another two years, combining abiraterone and enzalutamide is not currently recommended in clinical practice.
Recently, we were informed that a Phase 4 clinical trial (PLATO) investigating longer-term use of enzalutamide as a combination treatment for patients with metastatic castration-re.sistant prostate cancer (mCRPC) did not reach its primary goal of improved progression-free survival. The trial is concluding, but data will continue to be eval.uated, according to Pfizer and Astellas Pharma. Top-line results failed to show that continued treatment with enzalutamide in combination with the chemo.therapy, abiraterone acetate and prednisone, improved progression-free survival (PFS) in chemotherapy-naive mCRPC patients whose PSA levels had progressed despite previous enzalutamide therapy9.
The trial is a double-blind, placebo-controlled study, designed to assess the safety and efficacy of continued treatment with enzalutamide plus abiraterone acetate and prednisone following confirmed PSA progression. The study enrolled 509 patients with mCRPC who had never received chemotherapy treatment before, and was divided into two parts. In part one, patients received enzalutamide (160 mg/day) until an increase in their PSA levels was confirmed. In the second part of the trial, patients were randomly assigned to either continue enzalutamide treatment, now combined with abiraterone acetate (1,000 mg/day orally) and prednisone (5 mg administered orally twice daily), or begin treatment with placebo plus abiraterone acetate and prednisone. Its primary goal was progression-free survival, defined by either radiographic progression, unequivocal clinical progression, or death9.
Patients, who develop symptomatic disease and skeletal metastases while being treated with or following treatment of enzalutamide or abiraterone, should be considered for treatment with radium-223. Radium-223 has been shown to significantly delay the development of symptomatic skeletal events. More importantly, radium-223 is a life-prolongation therapy, as shown in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer) Phase III trial, which demonstrated a statistically significant improvement in overall survival for the radium-223 treatment arm10. In this trial of 921 patients who had not received or could not receive docetaxel, radium-223 was compared to placebo.
In the trial, patients who received six injections of radium-223 had a median survival rate of 14.9 months vs. 11.3 months in patients receiving placebo (HR=.70, P <0.0001.) In addition, the median time to the first symptomatic skeletal event was 15.6 months in the radium-223 group vs. 9.8 months in the placebo group (HR=.66, P <0.001)10.
Radium-223 is approved as a course of therapy consisting of 6 cycles. It is not approved for any additional cycles, although this is being studied. Future trials may show that additional cycles or even higher dosages may be of further benefit. Ongoing studies are evaluating additional combination strategies. The only con.comitant agents that are contraindicated in the labeled approval for radium-223 are taxane-based chemotherapies. In addition to investigating new treatments, researchers have begun to identify mechanisms of resistance to these treatments. These mechanisms of resistance are genetic mutations that affect androgen receptors or are related to DNA repair, and affect treatment outcomes. Recent genomic analyses have revealed that somatic inactivation or germline mutations in genes such as BRCA1, BRCA2, CKD12, and ATM occur in as many as 25% of advanced prostate cancers10.
PARP inhibitors such as olaparib exploit defective DNA repair in BRCA1/BRCA2 tumors, including prostate cancer tumors. In the TOPARP study, a phase II trial of olaparib in patients with advanced CRPC, olaparib induced responses in tumors with mutations in other DNA repair genes, including ATM and CHEK2. According to recent research, platinum-based chemotherapy is also selective against DNA repair deficiencies11.
As we move into an era of molecularly targeted therapies, researchers and clinicians need to be mindful of the fact that empiric drug choices will not always be the right choice for every patient. Instead, we may need to perform more genomic sequencing on tumors to see if they contain mutations that can be addressed with a PARP inhibitor or platinum-based chemother.apy. In the near future, we will also be doing androgen-receptor sequencing to determine whether a patient could be resistant to a given androgen receptor-targeted therapy. Thus, we might be able to do a biomarker genomic analysis that could tell us whether a patient will respond to abiraterone, and if not, then we would avoid using this medication.
We are already moving into this era with a major effort by the Stand Up to Cancer Prostate Dream Team 2 (SU2C-PCF), which is exploring mechanisms of resistance to prostate cancer hormonal therapies. For instance, the Stand Up to Cancer Prostate Dream Team is obtaining biopsies and genomic analyses from more than 300 patients with abiraterone-resistant disease. The Dream Team hopes to find the mechanisms of resistance as well as the histological changes that can occur in mCRPC disease as it evolves. From there, the researchers will delve into the prognostic and therapeutic implications for these histological changes. So, a DNA repair defect, for example, might push clinicians toward using a PARP inhibitor or platinum-based chemotherapy that may be selective against certain mutations. Treatment changes for mCRPC is advancing at a rapid pace. A generation ago, many prostate cancer clinicians would not even begin therapy until after a patient had developed painful symptoms.
We now know that this is unacceptable. It’s crucial not to withhold a life-saving, disease-controlling therapy until a patient begins to experience painful symptoms. As we gain additional understanding in the treatment of mCRPC, it’s worthwhile for clinicians and patients to ask questions about whether genomic tissue analyses would be beneficial. Through such analyses, clinicians will gain important understand.ing into the optimal management of patients with mCRPC. The challenge for clinicians in the community, of course, is to obtain the resources for performing tissue analyses.Yet, this effort should not be relegated just to research institutions. It’s important for community clinics and clinicians to perform genomic analyses, so that these analyses become part of the standard management of prostate cancer. When treating bone metastases in CRPC, it is crucial to understand the dynamic nature of the disease, and know that the site of prostate cancer evolves as do the patient’s needs.
Treatment approaches need to focus on treating the metastases. Clinical interventions in bone metastatic disease can significantly impact outcomes, including survival, skeletal-related events and patient quality of life. In this article, I have touched on many treatment strategies and clinical approaches—some of which are still being devel.oped. We must be vigilant to accurately assess patients’ disease burden, their symptomatology and quality of life. The goal should then be to target treatments to the right patients at the right time, and base these treatment decisions on patients’ disease burden, symptoms and characteristics.
Written by: CHARLES J RYAN, MD is a prominent researcher and leading clinician in the treatment of prostate and other urologic cancers. Dr. Ryan was one of the leading researchers for the COU-AA-302 clinical trial, which led to the FDA approval of abiraterone acetate plus prednisone as the first oral therapy for treatment of chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Dr. Ryan is Professor of Clinical Medicine and Urology and Thomas Perkins Distinguished Professor in Cancer Research, Program Leader, Genitourinary Medical Oncology at the University of California-San Francisco Helen Diller Family Comprehensive Cancer Center in San Francisco, California. In the following article, he reflects on treatment considerations in using the newest treatments for mCRPC, including patient characteristics and mechanisms of resistance.
Read Part One: The Story of the COU-AA-302 Clinical Trial: Highlights From the Journey
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