This patient’s prognosis is worse because of the visceral disease. I would be much more compelled to use docetaxel with androgen deprivation therapy (ADT). I typically administer a GnRH agonist, with an antiandrogen for a few weeks until the GnRH agonist “kicks in” and castration levels of testosterone are achieved. I discuss the risks and benefits of the combined androgen blockade approach and use that approach for some of my patients. Presentation of metastatic disease is dramatic in many patients, and they may be hospitalized and started on hormone therapy before I ever see them. I may see them a couple of weeks or even a month later. At that point I discuss the CHAARTED results and whether or not the patient would be a candidate for the early use of docetaxel. If so, I administer dexamethasone prior to docetaxel 75 mg/m² every 3 weeks, with a goal of administering 6 cycles of chemotherapy. Docetaxel is well tolerated, and the survival advantage of 17 months in patients with high-volume disease is compelling.

For the older, 80-year-old patient, it’s important to consider that not all elderly patients are the same. Here I would consider the biologic age, functional status, comorbidities and the patient’s goals. I would discuss the CHAARTED data with him and then make a decision about treatment. If he were willing to undergo chemotherapy, then I would offer him docetaxel, although he may not tolerate the full dose and may require a dose reduction over time.

I would not recommend bone-targeted therapy for either the 62-year-old or the 80-year-old patient. Early use of zoledronic acid or denosumab has not been shown to be beneficial.

At our center, this patient would be eligible for the STAMPEDE trial, in which patients received ADT with zoledronic acid or docetaxel/prednisolone or celecoxib, or zoledronic acid/docetaxel/prednisolone, or zoledronic acid/celecoxib, or abiraterone, or radiation therapy or enzalutamide/abiraterone. The combination of enzalutamide with abiraterone would be one option. Off protocol, I would probably consider docetaxel in combination with goserelin and bicalutamide or goserelin in combination with bicalutamide alone. I generally administer an LHRH analogue, such as goserelin, with a short duration of bicalutamide to prevent flare reaction, in conjunction with docetaxel 75 mg/m² for 6 cycles. In the CHAARTED study, patients could receive ADT for up to 120 days prior to receiving docetaxel. Importantly, we administer dexamethasone premedication but not the daily prednisone. I don’t believe the CHAARTED data are necessarily conclusive, but I certainly discuss front-line chemotherapy with patients.

I would also discuss the possibility of local radiation therapy. Although we have no definitive evidence that it improves survival, local control would be important.

If the patient were 80 years old and frail, I would be less likely to consider chemotherapy, but age in itself wouldn’t guide my decision-making. In fact the data suggest that elderly patients derive as much benefit as younger patients.

I would not offer either the 62-year-old or the 80-year-old patient bone-targeted therapy. I do not use bisphosphonates or denosumab frequently in my practice.

I would administer ADT with 6 cycles of docetaxel to this 62-year-old, and I would proceed in exactly the same manner with an 80-year-old patient. Age is not a factor in how I approach treatment decision-making.

I would not recommend bone-targeted therapy for these patients. The risk of complications like necrosis of the jaw is higher when zoledronic acid or denosumab is administered over a long period. In a study we conducted for patients with metastatic castration-resistant prostate cancer, the addition of risedronate, a third-generation bisphosphonate, to chemotherapy failed to improve outcomes, including time to disease progression.

In our center in the Netherlands, the CHAARTED approach has been adopted for patients with higher-volume metastatic disease in the lung, viscera or bones, at least outside the vertebral column and pelvis. In our multidisciplinary team, the urologist will usually have administered an LHRH antagonist with an antiandrogen for the first 2 weeks before I see the patient. For appropriate patients, I would recommend dexamethasone premedication and docetaxel 75 mg/m², without prednisone, for 6 cycles, and that is usually initiated within 4 weeks.

In our practice everybody who presents de novo with or develops non-castration-resistant, metastatic prostate cancer is offered the CHAARTED approach. Our standard is to use an LHRH agonist with a nonsteroidal antiandrogen, which is usually discontinued after about 30 days. Patients will usually receive docetaxel 75 mg/m² for 6 cycles 4 to 6 weeks later.

A 62-year-old patient with extensive bony metastases and minimal complaints of pain would be a good candidate for initial treatment with an LHRH antagonist and then a flip over to an LHRH agonist. Certainly, based on the CHAARTED trial the risks and benefits of adding chemotherapy should be discussed with the medical oncologist.

Additionally, it is clear that the use of zoledronic acid or denosumab would be reasonable for patients with extensive bone metastases. I believe we have data to support the use of bone-targeted agents in patients with extensive bone disease. We prefer denosumab over zoledronic acid at our center due to the ease of administration, efficiency of moving the patient through the clinical care continuum and fewer concerns about changes in creatinine.

The liver metastases are much more ominous and concerning, and I would probably want to consider a liver biopsy to make certain that this is a routine adenocarcinoma or to determine if the disease has neuroendocrine features.

If the patient is 80 years old, you need to evaluate the glomerular filtration rate, liver function and overall performance status before committing to a prolonged course of chemotherapy for 6 cycles. If there are no contraindications to chemotherapy, then I believe you have to offer it to the patient.

This patient would be classified as having high-volume disease according to the CHAARTED trial entry criteria. Without question I would administer ADT, but I would also discuss the results of that trial with the patient. I would inform him that on the basis of the CHAARTED trial results I would now be inclined to recommend docetaxel because he’s in good shape and could probably tolerate 6 cycles easily. I would definitely also administer a bone-targeted agent, and I would use denosumab in this situation.

With regard to the ADT, I tend to use a combination of LHRH analog, typically leuprolide, and an antiandrogen, typically bicalutamide. For the LHRH agonist I use the standard dose with either the monthly dosing because I follow the patients with metastatic disease with monthly laboratory tests anyway or the every 3-month dosing because that’s the interval at which we see our patients in the clinic.

We administer the antiandrogen as a 2-week lead-in and then 2 weeks after the first injection. After that it’s a matter of debate whether we continue it indefinitely as long as the LHRH agonist is used, assuming that the patient will stay on continuous therapy. But we would use it until the patient showed signs of castration resistance.

With regard to the timing at which we start docetaxel in relation to the ADT, I try to follow the spirit of the CHAARTED trial, which is to start it early, either concurrently or within the first 3 months. I do have some concern about the use of dexamethasone premedication, however.

When the trial was presented at ASCO, the only mature results were for the patients with so-called high-volume disease. Data for patients with so-called low-volume disease were not yet mature. So it’s not quite as clear that those patients benefit or that all patients benefit. Frankly, I’m even a little uncomfortable with the huge media hype around this being practice changing, because these data have not yet been peer reviewed.

I am anxious to see the full peer-reviewed analysis because I’ve looked at the data from the analysis that was presented at ASCO and the interesting aspect is that on a docetaxel arm, of course 100% of the approximately 400 patients received docetaxel, whereas on the ADT-alone arm, the proportion of patients who had received docetaxel at the time of the report was less than a third.

So you’re not comparing early versus late docetaxel, as was part of the intent of the study. The question is more like, is using docetaxel early up front better than waiting until patients become castration resistant? But in fact two thirds of the patients, at least at the time of the report at ASCO, had not received docetaxel at all. So I believe it’s premature right now to apply these data across the board.

I would not be influenced by age alone when contemplating a treatment approach for this patient. Given the good performance status in this scenario, I would again treat with ADT and denosumab. I would not typically reduce the dose of docetaxel for an 80-year-old patient, but I would watch him like a hawk and administer growth factor if needed.

Now that I have seen the results of the CHAARTED trial, I would apply those methods for this patient. However, I would not recommend any bone-targeted treatment unless he had osteopenia or osteoporosis.

With regard to the type of chemotherapy I would administer and again according to the CHAARTED trial, I would always use docetaxel at 75 mg/m² every 3 weeks for 6 cycles. I generally use leuprolide acetate and bicalutamide, the latter of which I would generally administer as a 3-month injection, which is 22.5 mg every 3 months. Bicalutamide is administered at 50 mg per day continuously.

I generally start docetaxel within a few weeks of the leuprolide. I have had some patients who had already started hormonal therapy elsewhere whom I’ve started on docetaxel maybe after a month or 2, but my standard practice if I see somebody who hasn’t received treatment yet is to start them at the same time, as on the CHAARTED study. I do not use dexamethasone premedication but I do administer methylprednisolone at 80 mg intravenously on the day the patient will receive docetaxel.

I would also apply the CHAARTED trial approach to the older patient in this scenario, and I would not typically adjust the docetaxel dose.

I would administer ADT and chemotherapy to a 62-year-old patient with extensive bone and liver metastases. Standard androgen deprivation is still a mainstay in the treatment of metastatic disease, but this patient would fit the bill for the CHAARTED approach, and that’s a standard now. I would not offer any kind of bone-targeted treatment for a patient like this until his response to ADT and docetaxel was assessed. If he has a good response, then you might not need anything further. I believe bone-targeted therapy like radium-223 is for patients who have castration-resistant disease.

With regard to the details of administration, I would have to defer to our medical oncologists because few urologists are administering the patient’s chemotherapy directly, but I believe they’re using the same 75 mg/m² once every 3 weeks for 6 cycles that was the basis of the original FDA approval of docetaxel for men with metastatic disease.

In more general terms, I view the CHAARTED trial results as practice changing. People have wondered about this question for decades. We performed some neoadjuvant chemotherapy trials for men with locally advanced prostate cancer, administering docetaxel or other agents prior to surgery, with the idea that patients with locally advanced disease have micrometastatic disease and if you treat that first, they might fare better.

Having said that, those neoadjuvant trials did not show any advantage in the short term. It was hard to demonstrate any clinical benefit. However, we’re in the process of putting together the 10-year follow-up on our cohort of about 30 patients who received neoadjuvant docetaxel with a slightly different regimen. We can’t yet prove that this approach helps, but the idea here is that earlier chemotherapy is beneficial when you have metastatic disease.

All that is to say yes, CHAARTED was a “game changer” for men with metastatic disease. The survival statistics are remarkable.

For an 80-year-old patient, I’d be more concerned with the performance status than with his age as a contraindication. Obviously you can’t predict how someone will respond to chemotherapy. But an 80-year-old who’s healthy, with a good performance status, should not be denied the best therapy just because he is older.

I offer patients with hormone-naïve metastatic prostate cancer docetaxel-based therapy in addition to ADT because of the beneficial effects of chemotherapy that were demonstrated in the CHAARTED study. I believe the results of the CHAARTED trial are practice changing considering the 17-month improvement in median survival with the addition of chemotherapy to ADT for patients with high-volume disease. The hazard ratio of 0.6 for overall survival is the most significant hazard ratio that we have seen.  

The differences in the results between the CHAARTED and the GETUG-AFU 15 study, which showed no survival benefit with chemotherapy, may be due to how patients were selected and the proportion of patients with high-volume versus low-volume disease in one study versus the other. The GETUG study was also smaller and may have been underpowered. Patients with a poor prognosis generally benefit from chemotherapy as demonstrated in CHAARTED. A higher number of patients had experienced normalized PSA after 6 months, which has been shown to be a good prognostic factor.

I administer docetaxel at the standard dose and schedule of 75 mg/m² every 3 weeks for 6 cycles and initiate chemotherapy within the first 3 months of ADT. I do not administer prednisone but I do use dexamethasone premedication. In terms of ADT, I administer leuprolide and bicalutamide. I also use degarelix for initial induction.

I would not consider bone-targeted therapy as we have no evidence of benefit. The CALGB-90202 study demonstrated that early treatment with zoledronic acid was not associated with lower risk of skeletal-related events in men with castration-sensitive prostate cancer and bone metastases.

I would administer ADT with docetaxel to this 62-year-old patient with extensive bone and liver metastases. I would not consider bone-targeted treatment for this patient.

Since presentation of the CHAARTED data, I’ve changed my practice. I now routinely administer chemotherapy to patients with hormone-naïve metastatic prostate cancer. In terms of reconciling the CHAARTED and the GETUG-AFU 15 studies, I believe that the patient populations were distinct and the patients on the CHAARTED study had more advanced disease overall.

I administer docetaxel typically at 75 mg/m² every 3 weeks as was done in the trial. If I’m concerned about how patients might tolerate that dose, I reduce the dose to 60 mg/m² on the first cycle. I recommend an LHRH agonist in combination with bicalutamide. I administer dexamethasone premedication to reduce the possibility of hypersensitivity reactions, but I don’t use any prednisone.

In the CHAARTED study docetaxel therapy was initiated within 120 days of starting ADT. In my practice I start chemotherapy depending on when I see the patient. Patients come to my practice from elsewhere and may have already started hormone therapy. So the exact timing of chemotherapy is dictated in part by the practicality of when I see the patient and get an assessment. I’ve started some patients on chemotherapy quite early. For others, it’s been about 3 months later because of the referral timing.

For an 80-year-old patient in the same situation, I would recommend the same therapy but reduce the initial dose of docetaxel to 60 mg/m². My goal would be to reach the 75 mg/m² dose of docetaxel since that is the dose that has shown benefit. With older patients I am more cautious with chemotherapy. I would assess how well the patient tolerates it. I would see the patient in 3 weeks and make a judgment based on how he tolerated the first cycle. If the patient were 90 years old, I would not consider chemotherapy.

This 62-year-old-patient with extensive bone and liver metastases has a good performance status, so I would recommend ADT in combination with chemotherapy. My preference would be to recommend denosumab, recognizing that bone-targeted agents have not been validated in this setting. I initiate docetaxel therapy soon after ADT at the 75 mg/m² dose for 6 cycles. We administer dexamethasone premedication and then subsequent prednisone for 6 cycles. Prior to the results of the CHAARTED trial being presented, we had not been recommending chemotherapy off protocol. After the presentation of those data, we now offer patients with high-volume, androgen-sensitive metastatic disease chemotherapy with ADT. We follow the definition of high-volume disease that was used in the CHAARTED trial, namely 4 or more bone lesions and/or visceral metastases.

The GETUG-AFU 15 study, which also evaluated chemotherapy and ADT, showed a significant improvement in progression-free survival with the addition of chemotherapy to ADT but no difference in overall survival. That study was conducted in a smaller population with approximately 200 patients in each arm. Differences in how patients were risk stratified with respect to high-volume versus low-volume disease in the 2 studies could partly account for the differences in results.

With regard to hormone therapy, I am one of the early adopters of degarelix. I have always been optimistic regarding its mechanism of action as a direct antagonist and the lack of tumor flare. However, I still use agonist therapy, especially when it’s more expedient in terms of the longer-acting formulations. With an antagonist castration is usually achieved within a 96-hour period. If you’re using an agonist, it usually takes 2 to 3 weeks before castration levels of testosterone are achieved. When administering an LHRH agonist, we sometimes combine it with an antiandrogen. I like to make sure there are no issues with bone flare.

For a patient who is 80 years old and has a performance score of 0, I would be inclined toward the same approach as for the 62-year-old and offer the patient ADT and chemotherapy. Age does factor into my concerns about inanition and potential myelosuppression with therapy. I individualize therapy on a case-by-case basis. I’m cognizant that some elderly folks are more compromised in their performance status than are younger patients. We are liberal in our use of growth factor support for patients older than 70 and those who are on docetaxel.