During a Targeted Oncology™ Case-Based Roundtable™ event, Atish D. Choudhury, MD, PhD, and Alicia Morgans, MD, MPH, discussed with participants about selecting next-line therapy for metastatic castration-resistant prostate cancer after use of enzalutamide and docetaxel.
A man aged 75 years presented with intermittent left hip pain and was unremarkable except for a prostate nodule on rectal examination but had an ECOG performance score of 1. Prostate-specific antigen (PSA) level was 16.2 ng/mL and a transrectal ultrasound biopsy showed the patient was Gleason 5 + 4 grade group 5. The patient was diagnosed with stage cT2N0M0 disease, and germline and somatic testing results were negative for pathogenic alterations. External beam radiation therapy plus androgen deprivation therapy (ADT) was initiated for 24 months, but 6 months after initiation the patient had undetectable PSA and was asymptomatic. Unfortunately, the patient did not return for regularly scheduled PSA follow-ups and 36 months later, he experienced progression and had to receive ADT plus enzalutamide (Xtandi) at 160 mg/d orally. An initial good PSA (nadir, 3.9 ng/mL) and symptom response were seen, but he developed metastatic castration-resistant disease progression and was started on docetaxel 75 mg/m2 intravenously every 3 weeks plus prednisone 10 mg/d. After 4 cycles of therapy, the patient worsened and 3 months later an abdominal/pelvic CT showed enlargement of known pelvic lymph nodes and 1 new liver lesion (< 2 cm).
MORGANS: Does anybody feel comfortable [talking] us through how they think about this treatment situation? We’ve got a patient who’s progressing, and this patient has liver metastases. [They have] exposure to enzalutamide and docetaxel [Taxotere], and some intolerance of docetaxel, but in a very short interval they got liver metastases. Does anyone have comments on second-line chemotherapy vs lutetium [lutetium Lu 177 vipivotide tetraxetan; Pluvicto]?
GEORGES: I am a little confused about this case. It is unusual that someone who received treatments was not being followed up with PSA [testing]. Do we have a testosterone level to ensure he’s castration-resistant?
MORGANS: We can assume in this case that the patient has castration-resistant disease. But I would say it is unclear on the enzalutamide, but maybe the patient hasn’t exhausted androgen receptor [AR] inhibition.
GEORGES: His disease is progressing fast and that concerns me. This is probably where I would repeat a biopsy to make sure he doesn’t have any neuroendocrine components to his disease and use platinum-based doublets for that. The other thing is if he is truly on enzalutamide and progressing, I don’t think abiraterone [Zytiga] has any benefits in that case as we are seeing minimal response. Sometimes I’ve had patients where they’ve been on abiraterone as first-line treatment, and their PSA starts to go up, and I’ll switch them to enzalutamide, and I get a PSA response and it dips again. But I haven’t seen this happen vice versa. I would biopsy this patient and make sure he doesn’t have any neuroendocrine component to his disease. When truly pressed for [an answer in this case], I would go with cabazitaxel [Jevtana] given his burden of disease. I would order the prostate-specific membrane antigen [PSMA] PET scan locally and get him down to a tertiary cancer center where we can look at lutetium as an option.
GULATI: I agree… Now, we didn’t get the exact timetables of how much time we had on disease-free intervals and control with the hormonal therapy. Liver metastases early on get me nervous. I like the idea of considering neuroendocrine differentiation biopsy, resending the next-generation sequencing [NGS], and evaluating for lutetium eligibility. But good luck getting lutetium [due to the current drug shortage]. I think we can put the patient on chemotherapy as we’re doing other things and hoping something pops up. But you’ve also got to think about his back pain; you may want to think about some targeted therapy. He’s going to benefit from denosumab [Xgeva] as well. I wouldn’t be surprised, even if the NGS testing is negative, if we see some of those aggressive variant mutations like AR-V7 or something like that.
MORGANS: I agree with you. Any time you see liver metastases popping up in short order, as you have both mentioned, biopsy to make sure that the patient hasn’t developed neuroendocrine disease. When we need a fast response, chemotherapy it is.
GEORGES: If I met this patient today and he has metastatic hormone-sensitive [disease], I would talk to him from the beginning about combination therapy, whether abiraterone or darolutamide [Nubeqa] with docetaxel as first-line agents, given the high-risk disease. Patients with newly diagnosed, metastatic hormone-sensitive disease, with bone disease and a high Gleason score, are considered high risk. Now, we have strong data on abiraterone plus docetaxel, or, more recently, darolutamide plus docetaxel, as combinations in [the] first line. I’ve used them on a couple of patients recently.
KOCH: I agree with that. I think the studies are PEACE1 [NCT01957436] and ARASENS [NCT02799602]. Both studies showed some superior results in castrate-sensitive prostate cancer in patients who had a high disease burden.1,2 I think it would make great sense to do this as initial treatment for a patient who fits that category.
MORGANS: I misunderstood you, Dr Georges. I thought you meant you would do this if he was progressing in the metastatic castration-resistant prostate cancer [mCRPC] setting.
GEORGES: No. I meant when I first met him with hormone-sensitive disease. As first-line therapy, I will use combinations especially if he has high-risk disease to begin with.
MORGANS: Got it. I must say, I like that. At least in my practice, I try to knock down that metastatic hormone-sensitive disease as much as possible. We get 1 first shot on goal is the way I’ve heard it described, and I try to make it the best shot I can.
BARTH: I’m thinking about the fitness of the patient, particularly in somebody who has liver metastases and progressed quickly after starting docetaxel. Do I want to make this man miserable in the last few months of his life by just giving him more chemotherapy? Is that worth the balance that we’re striking? The site of disease in the liver is a big concern there and the rapidity of his relapse, unless he’s a very fit individual or understands this may go very poorly. But I think we really must consider alternatives that are focused on just making him happy.
KIM: I think disease progression pace, extent of disease, symptoms, the patient’s comorbidities, performance, and prior lines of therapy all factor into the next line of therapy.
MORGANS: Do you have a different thought about how to treat this patient with rapid progression after docetaxel and enzalutamide?
KIM: Yes, I would consider tissue biopsy.
RAMKUMAR: The patient progressed so quickly on enzalutamide and subsequently docetaxel, and for us in a community setting to refer them to a tertiary center for lutetium, what would be the time frame? Because if the patient does not have a lot of time, we can redo a biopsy. But by the time they get there the insurance authorization and lutetium administration will take time, right? If the patient is progressing so quickly on docetaxel, what might be the time frame we have to do all this?
MORGANS: I would say the answer is in flux…[due to the shortage of this drug]. There is a severe supply chain disruption, and the details of that are, I think, to be worked out. Lutetium is available for clinical trials, but it is not sufficient for standard-of-care treatment [currently]. At least our institution [Dana-Farber Cancer Center] has a hold on starting new patients…. So, what does that mean? In my practice, if I see a patient progressing rapidly, I get PSMA PET scans, so that I know [whether] this patient is eligible for lutetium, which I think about as my next step while I’m also potentially coordinating a biopsy if I have time or the clinical suspicion that it needs to happen.
I also get that patient approved for something like cabazitaxel with or without carboplatin [Paraplatin], or radium-223 [Xofigo] for bone-only disease. I make sure that I have all my genetic testing in a row, so that I can know [whether] that patient might be eligible for pembrolizumab [Keytruda] or a PARP inhibitor. So, I’m doing all these simultaneously, which is a lot for the patient, and we need to acknowledge that as we’re trying to figure this out.
In my case, I’m lucky. Dr Choudhury has some great clinical trials available [too]. I’ve been saying, “Hey, I don’t have lutetium for you, but there is a great clinical trial using abemaciclib [Verzenio] with or without atezolizumab [Tecentriq].” I’m putting a patient on that hopefully in the next week, who is waiting for lutetium. Dr Choudhury, does that sound like how you’re thinking? Everything all at once, getting it all in a row, and thinking about clinical trials?
CHOUDHURY: Absolutely…. Lutetium is just not an option in the short term for patients [right now], which is a real tragedy because [their disease will progress] because of the shortage. So, we have clinical trials and clinical trials are a great way to manage appropriate patients. We want to consider them earlier in the disease course [now].
When this patient initially progressed on enzalutamide, for example, we would have made sure that as soon as the PSA started rising, we started to think ahead to see [whether] he might be a candidate for things that are not so cytoreductive like sipuleucel-T [Provenge] or radium-223. We would do the genomic profiling too. Prepare all these things earlier in the treatment course. Certainly, it would be a reasonable time to refer to a tertiary care center or a clinical trial before the disease becomes so accelerated and progresses to liver metastases on docetaxel.
The reality is that [such heavily] pretreated patients are less likely to benefit from targeted therapies. In a case like this, I think you’re just really stuck. If you don’t have a targetable alteration, you have cabazitaxel with or without carboplatin, and you just hope that will tide these patients over until the supply becomes available. When the supply becomes available, we honestly do not know how the doses are going to be prioritized among institutions and then within the patients at our institution because there’s going to be a big backlog.
NADEEM: What’s the percentage of patients with prostate cancer who have targetable mutations?
CHOUDHURY: Oh, it’s small. To get to the 20% to 25% that’s reported in the studies, you must add a lot of gene alterations that we know don’t have as much benefit from targeted treatments, like ATM, which is a big chunk of about 7% or 8%. Only a minority have targetable alterations, and so that’s why so many of our trials are intended to combine PARP inhibitors or checkpoint inhibitors with other agents that might make them more active in more [patients]. So, I think it’s important to look, especially if they have BRCA2 or mismatch repair, because they are likely to respond to treatment targeting those alterations.
1. Fizazi K, Foulon S, Carles J, et al; PEACE-1 investigators. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1
2. Smith MR, Hussain M, Saad F, et al; ARASENS Trial Investigators. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115