Posted: Thursday, October 11, 2018
Localized disease and metastatic castrate-resistant prostate cancer (CRPC) represent opposite ends of the spectrum of disease states that characterize prostate cancer overall. Local therapies, such as surgery or radiation, are used to treat tumors before they have spread, with hormone therapy sometimes added to radiation. Systemic treatments, including hormonal suppression/antiandrogen therapy, immunotherapy, bone antiresorptive agents, radioactive isotopes, and chemotherapy, are used in advanced, inoperable disease to slow tumor growth and to prevent or mitigate the infirmities associated with advancing metastases. However, there is a small but potentially growing cohort of men whose disease has progressed (eg, with a rising prostate-specific antigen [PSA] level) despite adequate androgen deprivation who do not have visible signs of metastatic disease. This disease setting is labeled as nonmetastatic CRPC,1 and the decision about whether and when to initiate treatment has been somewhat controversial because there have been no FDA-approved treatments in this setting until recently.
To Treat or Not to Treat? An Individualized Decision
According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines),2 for men in this “in-between” group, ie, with nonmetastatic CRPC, continued androgen-deprivation therapy (ADT) and observation may suffice, especially if the PSA doubling time is longer than 10 months (ie, disease is slower growing). In contrast, when the PSA doubling time is 10 months or shorter (ie, disease is faster growing), treatment with secondary hormonal therapy, including 1 of 2 FDA-approved second-generation antiandrogens—apalutamide3 or enzalutamide4—may be considered.
Noting that the decision to treat should be individualized, Maha Hussain, MD, Genevieve E. Teuton Professor of Medicine (Hematology and Oncology) and Deputy Director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine in Chicago, explained, “Providers have to make a judgment about if and when to treat these patients because they are asymptomatic or mostly asymptomatic by default. Assessment of risks and benefits should take into consideration PSA level, PSA doubling time, and the presence or absence of significant comorbidities. A patient with significant, potentially lethal comorbidities and a slow PSA doubling time, for example, may not benefit from therapy. On the flip side,” she told JNCCN 360, “treatment may be of benefit in someone with a short PSA doubling time and fewer or well-managed comorbidities.”
These patients have disease that is definitely “castration resistant but technically not visibly metastatic,” Dr. Hussain observed. “In my view,” she said, “the term ‘nonmetastatic’ is artificial because micrometastases are undoubtedly present but not yet apparent with today’s imaging techniques. This situation does not represent a large cohort but may increase as more men are treated with hormone therapy after failure of local therapy or in combination with local therapy.”
The term ‘nonmetastatic’ is artificial because micrometastases are undoubtedly present but not yet apparent with today’s imaging techniques.
The approval of two agents in this setting (ie, nonmetastatic CRPC with a rising PSA level), suggests, according to Dr. Hussain, that moving such treatment into earlier-stage disease can provide “more meaningful clinical benefit because less-bulky, less-resistant disease is likely to be more responsive.”
Enzalutamide has been approved for the treatment of patients with metastatic CRPC for several years. It was first indicated in 2012 for use as a second-line option after disease progression on first-line docetaxel.4 In 2014, it was approved for the first-line treatment of men with metastatic CRPC.5 In July 2018, it was approved for men with nonmetastatic CRPC and a rising PSA level.6
New Indication for Earlier-Stage Disease
The new approval for enzalutamide in the nonmetastatic CRPC setting was based on data from the randomized multicenter PROSPER trial.7 In that study, all patients continued to receive ADT with any gonadotropin-releasing hormone agonist or antagonist; in addition, those in the investigational group received oral enzalutamide at 160 mg daily, whereas those in the control group received placebo.
When asked whether patients with nonmetastatic disease were different in some way from those who are treated in the metastatic setting, a team of nurses at Carolina Urologic Research Center in Myrtle Beach, South Carolina, pointed out that chemotherapy is no longer used as much as in the past for many of these patients who are newly diagnosed with metastatic prostate cancer. “There are no differences in how enzalutamide is used or tolerated in the metastatic versus nonmetastatic castrate-resistant setting,” explained Rebecca Floyd, RN, Certified Clinical Research Coordinator.
Dr. Hussain, who was the principal investigator for the PROSPER trial, told JNCCN 360, “Overall, the decision to start enzalutamide in this setting (ie, nonmetastatic CRPC with a rising PSA level) is a clinical one and should not be based solely on PSA numbers. To minimize potential adverse events, it is important to optimize the patient’s medical condition, if needed, before initiating treatment. The good news,” she remarked, “is that in this setting, there is some wiggle room with regard to starting treatment. You have time to stabilize the patient by addressing comorbidities. In contrast, when patients have symptomatic metastatic disease, we often feel an urgency to start treatment as soon as we can.”
Initiating Treatment: Convenience and Disease Surveillance
Once treatment is started, Dr. Hussain’s team has patients return in a month for a clinic visit and laboratory assessments. “We want to make sure the patient is tolerating the treatment and that there are no laboratory abnormalities.” Thereafter, clinic visits and laboratory tests are scheduled every 3 to 4 months, depending on the patient’s clinical condition and preferences. “We try to consolidate the patient’s needs into one visit—ie, clinical assessment, laboratory evaluations, and hormone injection—to make it more convenient for him,” Dr. Hussain explained.
Moreover, to minimize burdens on patients, Dr. Hussain schedules imaging only about once a year, “unless the patient reports new symptoms, the PSA level has started to rise again, or there are other signs of potential disease progression.”
In contrast, the practice at the Carolina Urologic Research Center is to monitor patients more frequently. Patients can be on treatment with enzalutamide for years, Ms. Floyd said, “but we monitor for disease progression with CT scans of the chest/abdomen/pelvis and bone scans every 3 to 4 months.”
Tips to Reduce Fatigue
The most common adverse effect, of all grades, reported by about one-third of patients who received enzalutamide in the PROSPER trial, was fatigue, Dr. Hussain said. Of note, it was also reported by patients in the placebo group, although not as frequently. To try to improve fatigue, “we sometimes suggest splitting the daily dose—half in the morning and half in the evening—or taking the dose before bed,” she added.
Jennifer Griffith, RN, Director for Nursing and Administration at the Carolina Urologic Research Center, offers similar advice. “When we talk to patients about the possibility of experiencing fatigue, we suggest that they take their daily dose in the evening, which may help with tolerability.” Other tips were offered by Leslie Oleszkowicz, NP, a colleague of Ms. Griffith’s. “I usually stress that any form of exercise, perhaps a walk after dinner, will help fight fatigue, and I try to enlist a family member or caregiver in helping to motivate the patient to get going.” Unfortunately, “the more you lay around, the more you want to lay around.”
Ms. Floyd also emphasized the importance of communicating with patients. “If the patient is experiencing moderate to severe fatigue, we will continue to schedule visits more often—perhaps every 2 or 3 weeks—until the fatigue becomes bearable, either by increasing activity or reducing the dose,” she explained.
Hot Flashes, Hypertension, Nausea, Diarrhea
Overall, men in the PROSPER trial tolerated treatment quite well, according to Dr. Hussain.
Patients treated with enzalutamide reported hot flashes; those in the placebo group also described hot flashes but not at the level of those in the treatment group. Perhaps highlighting the difference between clinical trials and community practice, the team at the Carolina Urologic Research Center indicated that they usually do not see hot flashes as a new symptom in these patients. According to Ms. Oleszkowicz, “to be eligible to receive enzalutamide, patients have to be ‘castrate resistant,’ which means that they have already been on hormone therapy. These patients do not usually report hot flashes with the addition of enzalutamide.”
Only a small percentage of patients in the PROSPER trial, perhaps 10% or fewer, had nausea or diarrhea, but trends were no different for patients receiving placebo, Dr. Hussain noted. In addition, “I would caution providers to make sure that patients’ cardiovascular issues, such as hypertension, are well controlled before starting treatment with enzalutamide. We did see an increase in hypertension in patients on enzalutamide in the study, so it is something to be aware of.”
I would caution providers to make sure that patients’ cardiovascular issues, such as hypertension, are well controlled before starting treatment with enzalutamide.
Again, the experience in the community appears to be a little different from that observed and reported in the clinical trial. “We haven’t noticed any problems with hypertension, so we do not generally ask patients to check their blood pressure at home,” Ms. Griffith said. “We see patients initially after 2 weeks, then monthly, and then, if they are tolerating therapy well, in 2 to 3 months. Blood pressure is measured at every visit. We will pick up a consistently elevated blood pressure during these office visits. We also check complete blood cell counts, complete metabolic panel, and PSA levels at every visit. Depending on the patient and his willingness to ’hang in there,’ we would prefer that he give the full-dose regimen a try for a month. If the fatigue is still unmanageable, we would then discuss dose reduction.”
Dizziness and Confusion
Some men in the PROSPER study had bouts of dizziness, Dr. Hussain reported, so patients should be evaluated carefully for balance issues before treatment and then questioned about any changes during treatment. Patients in the placebo group also reported some dizziness, but not as much as in the treated group.
The risk of falls and related fractures associated with enzalutamide in the PROSPER trial may be attributable to treatment-related balance and dizziness issues. “We caution patients when they start treatment to make sure that they are aware of this as a potential effect and to pay attention to how they ambulate,” Dr. Hussain said. “We also ask about dizziness and balance at every visit.”
Reflecting similar concerns about effects on the central nervous system, Ms. Oleszkowicz noted, “One of the things that we talk with caregivers about is confusion. We might explain, ‘if he is acting confused or not like himself, stop the medication and call us right away.’”
Although dizziness or feeling off balance is less frequently noted than fatigue, Ms. Floyd said, “we recommend that caregivers remove throw rugs and other items in the home that can present tripping hazards and that walkways are well lit.” She also reiterated the importance of staying well hydrated and “using caution when getting up from a seated or prone position.”
Combining Evidence and Clinical Judgment
“We also have to look at what is meaningful treatment,” Dr. Hussain remarked. If the adverse effects outweigh the benefits or the patient feels miserable, she explained to JNCCN 360, treatment can and should be adjusted. “In my experience, whether the patient is young or older, asymptomatic and fit, or has many comorbidities, we find a way to manage the adverse effects. We rarely have to discontinue treatment. Treatment may continue as long as it works and is tolerated, which may be for years.”
Whether the patient is young or older, asymptomatic and fit, or has many comorbidities, we find a way to manage the adverse effects. We rarely have to discontinue treatment.
Dr. Hussain explained that until 2004, men with prostate cancer who developed resistance to hormone therapy had very few treatment options. “What is most exciting, in my view,” she said, “is the ‘return on investment’ since 2004; research has had a significant impact on outcomes with better treatments for this disease. A great deal of that research has focused on understanding the biology of prostate cancer. Despite significant progress, advancements have been relatively marginal because of multiple challenges: treatment does not work for all patients; the average improvement in survival is modest; and there are no predictive biomarkers to help us select patients for whom particular treatments will be effective.”
In conclusion, the practice of medicine should “combine evidence and clinical judgment,” Dr. Hussain said. “The good news is that we have ever-expanding treatment choices for patients.”
Maha Hussain, MD, has disclosed that she has received research support from Pfizer, Bayer, Genentech, and AstraZeneca. She has also received honoraria/travel support from Sanofi/Aventis and participated on advisory boards for Pfizer and AstraZeneca.
Rebecca Floyd, RN, has disclosed no relevant relationships.
Jennifer Griffith, RN, has disclosed no relevant relationships.
Leslie Oleszkowicz, NP, has disclosed no relevant relationships.
- Tombal B. Non-metastatic CRPC and asymptomatic metastatic CRPC: which treatment for which patient? Ann Oncol 2012;23(suppl 10):x251–x258.
- Mohler JL, Lee RJ, Antoarakis ES, et al. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer. Version 4.2018. Accessed September 16, 2018. To view the most recent version of these guidelines, visit NCCN.org.
- Erleada (apalutamide). FDA prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210951s000lbl.pdf. Accessed October 1, 2018.
- Xtandi (enzalutamide). FDA prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203415s014lbl.pdf. Accessed September 17, 2018.
- Brooks M. FDA grants expanded indication for enzalutamide (Xtandi), September 11, 2014. Available at https://www.medscape.com/viewarticle/831548. Accessed October 1, 2018.
- Stenger M. Enzalutamide prolongs metastasis-free survival in nonmetastatic, castration-resistant prostate cancer. The ASCO Post. August 10, 2018. Available at http://www.ascopost.com/issues/august-10-2018/enzalutamide-in-nonmetastatic-castration-resistant-prostate-cancer/. Accessed October 1, 2018.
- Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 2018;378:2465–2474.