Geynisman Looks at the Latest Treatments in Metastatic Hormone-Sensitive Prostate Cancer

CASE SUMMARY

A 60-year-old man presented with urinary retention, fatigue, and decreased appetite. He has no family history of prostate cancer, is a widow who works full time as a commercial real estate broker, is active, and is very involved in his grandchildren’s activities. A transrectal ultrasound scan and biopsy revealed adenocarcinoma of the prostate gland, and a Gleason score of 8 [4 + 4] with disease in 10 of 12 cores. His prostate-specific antigen (PSA) level was 150 ng/mL and his hemoglobin (Hb) level was 9.7 g/dL; his absolute neutrophil count (ANC) was 1.9. The patient received a diagnosis of localized high-grade prostate cancer and he underwent robotic radical prostatectomy with a subsequent PSA decrease (0.2 ng/mL). CT and bone scans showed no residual disease, but 13 months after the initial diagnosis there was a recurrence, with a PSA level of 90 ng/mL, an Hb level of 10.4 g/dL, and an ANC of 1.5. Imaging with CT and bone scan showed multiple metastatic bone lesions in the pelvis and diffuse liver lesions. The patient now has a diagnosis of metastatic prostate cancer, but germline and somatic genetic testing are negative.

GEYNISMAN: Obviously, the formulations are somewhat different between the drugs. Abiraterone [Zytiga], for example, historically was given as 4 250-mg tablets.¹ Now you can do 2 500-mg tablets, but a lot of the systemic treatments come in 4 tablets or capsules a day.

Enzalutamide [Xtandi] now comes in 40- and 80-mg tablets, so you can do 2 instead of 4, too.² The dosage is slightly different, but the chemotherapy is completely different. And you have lots of different adverse events [AEs]. Does this come up at all [in your decision-making], how many pills a day, twice a day vs once a day? Do you ever pick based on that? Or do you pick based on what you think can be afforded, or [what can get approved] through the insurance, or what your pharmacy recommends, or the kind of assistance they can provide for patients?

HUANNOU: I consider the number of times per day, because, obviously, it’s harder for most patients to remember to take that second dose. So I think frequency is important, but with pill burden I usually don’t think about [it] so much. And of course, you are always subject to whether meds are covered and whether or not it’s easy for patient assistance to be obtained for the patient.

GEYNISMAN: Who does that, the patient assistance, in your practice?

HUANNOU: We have patient navigators that are assigned to work with the patients in terms of filling out the paperwork— which is always the hardest part, to get the patient assistance from either the foundations or the companies themselves.

BARSOUK: Yes, there is a similar system in our practice. On top of that, we have clinical pharmacists that do preteaching. Patients will receive the drug from a specialty pharmacy, and they’re instructed to bring the drug for the first session of preteaching, before they start taking it, and they will go over everything. We have assistance programs, copayment foundations for eligible patients. There is a lot of support, so not many problems nowadays.

ALTER: For your patients who are taking anticoagulants, usually the novel oral anticoagulants, I know there are interactions when you give [those] with [5α-reductase inhibitors], not with [abiraterone]. Do you just throw that to the wind? [When] patients are taking apixaban [Eliquis], do you still treat them with apalutamide [Erleada] or enzalutamide, or are you avoiding [those drugs] and just giving those patients abiraterone?

GEYNISMAN: I try not to combine them and either switch the androgen axis drug or switch the anticoagulant. There’s 1, dabigatran [Pradaxa] maybe, that doesn’t seem to have those interactions, and so I try to either switch or not use the drug, unless there’s no other option. I’m just nervous about that, especially since most of these patients have multiple comorbidities and they’re older. I try not to do it.

For adherence, do you have any programs? Are there any special pharmacy-led interventions or anything like that at your practices for adherence to these drugs? Or is it just on you to talk to the patients about it? Or is that not an issue for your population?

BARSOUK: We have a toxicity assessment built into [our] Epic program. When patients come for the toxicity assessment, they will have their pill count documented if they have more pills than they’re supposed to. But I don’t perceive this as a significant problem because patients tend to be quite [adherent]. It is being monitored and documented, for what it’s worth.

DISCUSSION QUESTIONS

• What is your reaction to the updated results from the TITAN study (NCT02489318) of apalutamide plus androgen deprivation therapy (ADT)?
• What is your reaction to the final overall survival (OS) results from the ARCHES study (NCT02677896) of enzalutamide plus ADT for metastatic, hormone-sensitive prostate cancer?
• Please share your perspectives on the tolerability of apalutamide plus ADT vs other ADT-based combination regimens you would strongly consider for de novo metastatic, hormone-sensitive prostate cancer. What toxicities are most concerning to you in this setting? Which do you find most challenging to manage?

GEYNISMAN: For the ARCHES trial, the landmark 48-month survival was approximately 71% [median OS, not estimable].³ This was for enzalutamide plus ADT. Some have said that apalutamide plus ADT, with an OS rate of 65.1% [median OS, not reached],⁴ is a little easier to tolerate.

Have you switched, or are you still using enzalutamide?

BARSOUK: It’s still being used. It’s in our pathways, and if the patient doesn’t have issues with seizures [and has] no contraindications, it’s still being used. It’s relatively easy to use this drug. You have more asthenia, though, and more frequency of falls. So if patients are prone to falls, you try to avoid it. But I think it’s still being used; not everybody has switched to apalutamide.

PROOTHI: Those who are already on it, I’m keeping on it. But for the new patients, I’m going more with the apalutamide.

GEYNISMAN: Does anybody flip a coin? I don’t mean actually flip a coin, but does anybody here [look at all the options since they are so similar]?

HOFFMAN: In many ways, I think they’re all similar in terms of efficacy.4 The toxicity may be slightly different, but for me it comes down to formulary.

GEYNISMAN: Does anybody else want to say anything about this?

BARSOUK: Yes, [we have a] similar system. I think insurances are carrying those drugs, and abiraterone is first tier so it’s covered better and is easier to procure, so it’s a drug of choice. But we do have all drugs approved on the clinical pathways. If a patient has contraindications, then you’d have a choice. I wouldn’t necessarily choose the drug based on the “flip of a coin,” but there are other nuances such as [adverse] effects, comorbidities, and use of anticoagulants. For example, we’d have a pharmacist come to us and say, “There is more interaction, so this patient needs to be on a blood thinner,” for instance, for chronic atrial fibrillation or pulmonary embolism or something. So all this [goes] into consideration when choosing the drug. But in terms of efficacy, they’re probably similar.

GEYNISMAN: OK, great. Let’s take these drugs as a class. What are the most difficult toxicities to manage, if any, whether it’s doublet or triplet [therapy]? Because even in a triplet, the chemotherapy goes away quickly, and the patient remains on ADT and your second-generation drug, whatever it is that you may choose. What are the toughest things to manage with these drugs? What [adverse effects] are you dose reducing for or holding drugs for?

DESAI: If I’m doing it, it’s mostly for asthenia and myalgias.

BARSOUK: I do it for asthenia and abnormal liver function test [LFT] results. I have a lot of patients [for whom], if you give them the full dose, the LFT [levels] start coming up, so you need to dose reduce, even though the patients are quite asymptomatic.

GEYNISMAN: OK. Cardiovascular disease or high blood pressure—are those concerns with these drugs, things that make you think one way or another?

BARSOUK: To the degree that you want to avoid low-dose steroids, then probably you will try to avoid abiraterone. But other than that, I’m not aware.

DISCUSSION QUESTIONS

• What is your approach toward follow-up and monitoring for a patient with metastatic, hormone-sensitive prostate cancer who is receiving apalutamide? How does it differ for patients receiving docetaxel (Taxotere) plus prednisone?
• What clinical, imaging, or other findings trigger you to consider changing or adding therapy?

GEYNISMAN: Following up and monitoring for a patient who is receiving apalutamide, is it different than for patients receiving chemotherapy or maybe receiving abiraterone? Maybe we [could consider patients receiving] androgen receptor inhibitors without the prednisone vs patients on abiraterone; is there any difference in terms of monitoring, follow-up, how often you see these patients, or what you’re checking? Does that differentiate things?

HOFFMAN: Well clearly, with docetaxel, you’re going to have to check their complete blood count [CBC] more and [check] other symptomatology, for example, if they start complaining about nail changes, conjunctival changes, or asthenia. The fatigue is generally what patients stop with, particularly in female patients, although they’re not talking about prostate cancer. Clearly, I think with docetaxel you’re seeing the patient every 3 weeks, but it’s almost de rigueur. You’re not treating these patients at home or somewhere else; someone is seeing them. [This is] as opposed to when you’re using oral medications and patients are stable. Telemedicine is great, but every once in a while you’re still going to need to get a CBC and bone scans or CT scans or however you monitor a patient, based on where their disease is located. Often, we want to talk to the patients and see how they’re doing more than anything else, and we certainly can do that with telemedicine, or our nurse practitioners can. I think with docetaxel we worry about the neutrophil count. [And] at least two-thirds of the patients are going to have another physician—not just a urologist, but also an internist, a family practitioner, a cardiologist, a pulmonologist, etc—who is also going to be very actively involved with this patient. These patients are 70 or 75 years old or in their mid-60s, [and they’re] starting to fall apart like a used car, as opposed to somebody who’s in their 50s.

ALTER: Yes, for the abiraterone patients, I follow the guidelines1 and get their LFTs every 2 weeks for the first 3 months. Some of the patients have a little cardiac history, and I’ll probably have them come in more often, but [I] usually have their labs done every 2 weeks and I see them every 4 weeks. And that’s just for the first 3 months, and then I just make it monthly. For apalutamide, I probably see these patients every 6 to 8 weeks, eventually. I give them more leeway [because there is] less toxicity. I’m a little concerned about the thyroid and the electrolytes. The rash they can easily report over the phone, and sometimes it’s just the laboratory studies that need to be assessed.

BARSOUK: In terms of visits, there might not be a significant difference. But in terms of blood work, [there] definitely [is a difference]. If you use docetaxel, you have to do blood work every week to watch for neutropenia. With oral drugs, you start every 2 weeks, but if the patient is stable, you quickly can extend those periods to once a month or every 2 months, so there is much less blood work, less monitoring, fewer visits—not to the oncologist but at least to the lab—and so, a better quality of life.

ALTER: I tend to use growth factors on all my patients receiving docetaxel. I know it’s not the standard, the norm, but [often] 1 shot the next day gives no visits, no labs, and they’re good for the next 3 weeks. They could still [become] neutropenic and they could definitely still get neutropenic fever, but I’ve never been denied by the insurance company, and patients love not having to worry about a potential neutropenic episode. So I just give all these patients growth factors and you also have to discuss at what dose you give the docetaxel in the first place. I’m proactive in trying to protect these patients. They have other comorbid conditions, and they’re not the youngest patients, so I like to protect them.

BARSOUK: The reason I don’t it is because I don’t use docetaxel at 75 mg/m². I would [use approximately] 60 mg/m². Then I would probably use pegfilgrastim [Neulasta] preemptively for the primary prophylaxis. But if the patient does develop neutropenia with the second cycle, I would [do it].

PROOTHI: [In my experience there was] not a difference between 60 and 75 mg/m2 when it came to efficacy.

GEYNISMAN: All the trials start at 75 mg/m². You’re allowed to dose reduce,^5,6 but I think this probably depends on the patient and what you feel they can tolerate. I try to start at 75 mg/m² and get them through it, but some do need to be dose reduced.

ALTER: The older they are, the lower the dose.

_REFERENCES

_{1. Zytiga. Prescribing information. Janssen Biotech, Inc; 2021. Accessed February 5, 2023. https://bit.ly/3YiBZWO}

_{2. Xtandi. Prescribing information. Astellas Pharma US, Inc; 2022. Accessed February 5, 2023. https://bit.ly/31qAHfl}

_{3. Armstrong AJ, Azad AA, Iguchi Taro, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2022;40(15):1616-1622. doi:10.1200/JCO.22.00193}

_{4. Ong S, O’Brien J, Medhurst E, Lawrentschuk N, Murphy D, Azad A. Current treatment options for newly diagnosed metastatic hormone-sensitive prostate cancer––a narrative review. Transl Androl Urol. 2021;10(10):3918-3930. doi:10.21037/tau-20-1118}

_{5. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488}

_{6. Taxotere. Prescribing information. Sanofi-Aventis US LLC; 2021.Accessed February 5, 2023. https://bit.ly/40EobYr}