Key Factors Influence Treatment in Chemotherapy-, AR-Refractory mCRPC

Edwin M. Posadas, MD

Medical Director, Urologic Oncology Program

Samuel Oschin Comprehensive Cancer Institute

Clinical Co-Chief

Associate Professor of Medicine

Division of Hematology/Oncology

Department of Medicine

Cedars-Sinai

CASE SUMMARY

A 75-year-old man presented with intermittent right hip pain. His physical exam was unremarkable. Prostate-specific antigen (PSA) was 32.6 ng/mL, bone scan and abdominal/pelvic CT scan were negative. Transrectal ultrasonography biopsy showed Gleason 4 + 4 grade group 4. He was diagnosed with stage T2N0M0 prostate cancer; ECOG performance status was 1. He received external beam radiation therapy plus androgen deprivation therapy (ADT), planned for 18 months. He had an undetectable PSA level at 6-month follow-up; testosterone at castration level; and was asymptomatic.

Six months later, the patient developed new hip pain and urinary frequency. PSA was 29.4 ng/mL. Testosterone was 10 ng/dL. Bone scan showed evidence of 2 osteoblastic lesions in the right hip (0.8 cm and 1.1 cm). Abdominal/pelvic CT showed a 2.1-cm left pelvic lymphadenopathy. He is now considered metastatic and castration resistant.

The patient started treatment on enzalutamide (Xtandi) 160 mg by mouth daily. PSA decreased to nadir of 3.9 ng/mL 4 months after starting enzalutamide. After 8 months on enzalutamide, the patient had a PSA level of 60.7 ng/mL. Abdominal/pelvic CT showed enlargement of known pelvic lymph nodes. Bone scan showed progressive disease. The patient was started on docetaxel 75 mg/m2 intravenously every 3 weeks and daily prednisone 5 mg by mouth every 12 hours. After 6 cycles, the patient developed bilateral digital neuropathy and docetaxel was held. After 3 months, he had rising PSA and new back pain.Imaging shows enlargement of known pelvic lymph nodes and 1 new liver lesion.

EDWIN M. POSADAS, MD: What are you most likely to recommend now that the patient’s disease is progressing, with new liver involvement? I think that’s a key feature of this case.

ALBERT DEKKER, MD: I voted for [liver biopsy] but it is more to know if there is disease transformation into small cell because of such unusually aggressive course. The majority of my patients in this situation would be controlled about twice as long.

POSADAS: I strongly agree with your thought there. This is a rather unusually aggressive clinical course, and despite the fact that we’re seeing PSA changes during this intermediate transformative phenotype, there is preservation of the androgen receptor [AR] cistrome that will lead to PSA production while still gaining lineage plastic markers and signals of neural differentiation. I think looking at your next-generation sequencing is an excellent way to go. It seems like at least half of us would feel strongly about that. Cabazitaxel [Jevtana] came in as a second choice at 33%, and that’s not an unreasonable decision in this case either. Like I said, I don’t think it had to be an either/or because I think some of these things make sense altogether. I like Dr Dekker’s thought about this, looking for small cell transformation.

DISCUSSION QUESTIONS

• How do you select next line of therapy for a patient with metastatic castration-resistant prostate cancer who has received docetaxel and an AR-targeted therapy?​
• What factors do you consider when deciding on treatment?

AMIR MODARRESSI, MD: I think, in general, [the most important factors are] performance status and how many lines of therapy the patient has received in the past. The majority of these patients are elderly and have comorbidities. On the other hand, usually when the patient fails the first line of chemotherapy, it is hard to find reasonably good treatment options. These new radionuclides are coming but they’re not widely available. Clinical trial participation would be another interesting thing, too, if it is available. But, especially in a case like this with liver involvement, I don’t think we have tons of time to scratch our heads. I think a lot of these things can happen at the same time. The patient probably will have a biopsy, start cabazitaxel, or get a referral to a tertiary center for clinical trial consideration and so on.

POSADAS: I think you’re right, Dr Modarressi. I like the fact that performance status is at the top of the [list].

When someone has progressed through multiple lines of therapy, the first thing we try to do is establish goals of care and make sure that we have things like advanced directives on file. We need to have not just your thoughts and how good the patient looks but what the patient wants in the end as their goals of care to help make decisions, given the variation of toxicity and benefit that exists with the treatments that are available. Age is a tough one though. Patients are older but I’ve been shocked. I’ve been encouraged to be less ageist and look at performance status in order to make some of those decisions. I like the fact that you pointed out the pace of disease. The liver involvement always concerns me. It speaks to the potential for a more anaplastic phenotype where you would get your tumor suppressor losses, higher resistance, faster pace of metastasis, and trying to stay ahead of things becomes very key.

That’s where you also need to have a good goals-of-care discussion with patients to make sure. You can tell them…when you see one [liver lesion], within a couple months if you don’t do something that’s effective, you will see more and not just in the liver, but eventually in the lungs. The amount of visceral disease that we see at the time of death is often underestimated by imaging in prostate cancer, which is a bit concerning. So staying ahead can maintain good quality of life for patients if they’re fit and willing.

SUNNY PHILIP, MD: Once they have AR therapy and chemotherapy, the likelihood is another AR is probably not the best option. I’ve done it because the patient is frail, and chemotherapy was probably not the best choice. Rarely, I’ve had a response, otherwise more chemotherapy or radiotherapy is what I would consider.

POSADAS: I’ve been in that position where patients are not ready to give up but they’re not suited for chemotherapy, either due to previous adverse events [or performance status]. One of the worst problems is, given the osteotropic nature of this disease, very often you start to get marrow failure, which limits your options. They may have reasonable performance status, but if they don’t have marrow function, even the radionuclides become an issue for patient safety.

MICHAEL SCHWEIZER, MD: I [would] take into consideration tumor-specific factors like the genetics, location of the metastases, patient’s preference and their goals, and their fitness. The only other thing I would add is that when cabazitaxel first became used, we used the higher dose of 25 mg/m² and I had a lot of patients who didn’t tolerate that well. I’ve had a much better experience using something like that with the lower 20 mg/m² dose that was shown to be essentially just as effective in the PROSELICA study [NCT01308580].¹ I found that, in some ways, the AEs don’t quite overlap completely, so a patient who comes off docetaxel for neuropathy may do just fine with cabazitaxel because it has lower rates of that. I think that considering it is important, but you have to listen to the patient. If they don’t want to do chemotherapy, you’re stuck there.

POSADAS: That’s an excellent point. These are very different drugs. They’re both taxanes but the AE profile is quite different. Many of my patients have told me when they’ve tried cabazitaxel after docetaxel, “That was much easier than docetaxel.” That’s consistent with all the data that are in the literature. Even with the FIRSTANA study [NCT01308567], while there wasn’t a big difference in efficacy in the first line, the patient experience seemed to be better on cabazitaxel.² It does ring true, and it’s important that they get that proper counseling when considering whether they want to try a second round of chemotherapy.

_References:

_{1. Eisenberger M, Hardy-Bessard AC, Kim CS, et al. Phase III study comparing a reduced dose of cabazitaxel (20 mg/m2) and the currently approved dose (25 mg/m2) in postdocetaxel patients with metastatic castration-resistant prostate cancer-PROSELICA. J Clin Oncol. 2017;35(28):3198-3206. doi:10.1200/JCO.2016.72.1076}

_{2. Thiery-Vuillemin A, Fizazi K, Sartor O, et al. An analysis of health-related quality of life in the phase III PROSELICA and FIRSTANA studies assessing cabazitaxel in patients with metastatic castration-resistant prostate cancer. ESMO Open. 2021;6(2):100089. doi:10.1016/j.esmoop.2021.100089}