Analyzing Therapeutic Sequencing in Metastatic Prostate Cancer

Joshi Alumkal, MD (MODERATOR)

Professor of Internal Medicine

Coleader, Translational and Clinical CCSG Research Program

University of Michigan Rogel Cancer Center

Ann Arbor, MI

CASE SUMMARY

• A 75-year-old man presented with intermittent left hip pain.
• Physical exam: unremarkable except for a prostate nodule on rectal exam
• ECOG performance score: 1

Clinical workup

• Prostate-specific antigen (PSA) level: 16.2 ng/mL
• Gleason score 5 + 4, grade group 5 per transrectal ultrasound–guided biopsy
• Bone scan and abdominal/pelvic CT scan were negative.
• X-ray of the pelvis indicated osteoarthritis.
• The patient was diagnosed with category cT2N0M0 prostate cancer.
• Germline and somatic genetic testing were negative for pathogenic alterations.
  

Treatment and follow-up

• External beam radiation therapy plus androgen deprivation therapy (ADT) was initiated (planned for 24 months). Six months after initiation of therapy, PSA was undetectable and the patient was asymptomatic.
• Unfortunately, the patient did not return for regularly scheduled PSA follow-ups, and 36 months later, he experienced progression.
• The patient received ADT plus enzalutamide (Xtandi) 160 mg once daily before noon; his initial PSA (nadir, 3.9 ng/mL) and symptom response were good.
• Because of a busy travel schedule, the patient did not return for routine PSA monitoring.
• He developed metastatic castration-resistant prostate cancer (mCRPC) and was started on docetaxel 75 mg/m² IV once every 3 weeks plus prednisone 10 mg once a day.
• The patient responded clinically to treatment (ie, resolution of pain, improved energy, and declining PSA).
• He completed 4 cycles of treatment but developed worsening bilateral digital neuropathy throughout therapy. Therapy was stopped, and cycle 5 was not administered.
• Three months later, the patient showed rising PSA, new back pain, and shortness of breath on exertion.
• Abdominal/pelvic CT showed enlargement of known pelvic lymph nodes and 1 new liver lesion (< 2 cm).

PARTICIPANT LIST: Sapna Patel, MD | Ming Yin, MD | Pallavi Jasti, MD | Tareq Al Baghdadi, MD | Vivek Abhyankar, MD | Michael Nemunaitis, MD | Elaine Beed, MD

EVENT REGION California, Nevada, Arizona

DISCUSSION QUESTIONS

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

ALUMKAL: What are your thoughts… as you think about what comes next for a patient who’s had docetaxel and an AR-targeted agent? What things are top of mind for you in terms of decision-making?

PATEL: What comes first to mind when we first see [a patient] is the tumor burden, the visceral disease, how symptomatic they are, and, of course, performance status and age.

ALUMKAL: Yes. I think those are great considerations, and they certainly might take certain therapies out of the question, like radium 223 [(Xofigo) for patients who] have visceral disease…. If you need a high response rate, there are certain options like a second AR signaling inhibitor [ARSI], which is probably not a great option. Do other folks want to weigh in on some of the considerations that Dr Patel didn’t cover and that are foremost in your mind as you’re thinking about what comes next after [a patient progresses on docetaxel and an ADT]?

YIN: I would consider prior treatment response for patients with disease progression after a chemotherapeutic drug and AR-targeted therapy, then I would like to use an agent with a different antitumor mechanism. That would be lutetium 177 vipivotide tetraxetan [Lu 177; Pluvicto].

ALUMKAL: I think that’s a great point. If they had a short time from ending docetaxel to progressing or if they didn’t have a great response, either radiographically or with respect to PSA level, those are patients for whom you would worry about cross-reactivity and use an agent in a different class, for example, Lu 177 or radium 223. Does anyone else have anything to add?

JASTI: I do take into consideration treatment access and the time that it’s going to take for them to receive Lu 177 treatment. That also has a bearing.

ALUMKAL: Of course, that’s also a great point. Those conversations, these days, are a lot more fraught in my practice. A lot of patients come asking for Lu 177. And with the challenges of being able to deliver that through nuclear medicine—we certainly discuss that, but we’re often looking for another option to buy some time, whether that’s a clinical trial or moving to cabazitaxel [Jevtana].

AL BAGHDADI: I think one thing you have to keep in mind is the possibility of neuroendocrine differentiation, especially if there’s a discrepancy between [the patient’s] PSA level and their clinical progression and/or if there are liver metastases. One [reason] why I [might do] next-generation sequencing [NGS] is to get a biopsy of the liver and make sure it’s not neuroendocrine, and then I would submit the NGS again. That becomes an issue every now and then, with an impact on prognosis and the availability of additional treatments.

ALUMKAL: I think that’s an excellent point. And certainly, if I were to find neuroendocrine [differentiation], then I’d have a much lower threshold for using carboplatin in addition to cabazitaxel. These aggressive variant tumors that [are characterized by] visceral disease and low PSA out of proportion to the amount of disease that’s present, those are patients for whom we often add a platinum agent. And one doesn’t know what one’s treating unless [one does] a biopsy. Sometimes it can be clear-cut, with rapid progression of disease in the absence of PSA expression or PSA being detectable in the blood. But in some cases, it’s more subtle because there could be a low amount of PSA being produced per tumor cell, but the PSA is still rising because there are so many more tumors. So, if there is an accessible lesion and you have any concern at all that there could be a change in the differentiation status of the cancer, I think [it would be a good idea to] evaluate that with a metastatic biopsy and look at the phenotype of the cells microscopically. And that’s [also] an opportunity to do NGS to see if there’s an actionable alteration that may have developed on therapy.

ALUMKAL: As I mentioned, cabazitaxel is one of the principal options we think of, in addition to radium 223, for patients who don’t have visceral disease. This drug can be used in patients who have had docetaxel; that’s where it is approved.^1,2 But certainly in patients who are at risk of peripheral neuropathy, there’s a lower incidence of that with cabazitaxel. I have a patient who has preexisting neuropathy from a spinal tumor unrelated to his prostate cancer. We were worried about peripheral neuropathy, and he was progressing on enzalutamide, and so we prescribed cabazitaxel instead.

That’s certainly something to consider when patients need chemotherapy but you’re worried about some of the adverse events [AEs], including the neuropathic symptoms. I often use [a cabazitaxel dose of] 20 mg/m²… and if we combine it with carboplatin, which is administered according to an area-under-the-curve value of 4 or 5 per m², then the 20 mg/m² cabazitaxel dose is commonly what we recommend.³

DISCUSSION QUESTIONS

• Would you give cabazitaxel to a patient who did not tolerate docetaxel well?
• If this patient had completed at least 6 cycles of docetaxel, would your recommendation differ?

ABHYANKAR: I have used multiple cycles of docetaxel, and patients generally do well with it. I [will stop treatment] around cycle 9. Interestingly, I’ve been doing this for 19 years or so and I have yet to give cabazitaxel. I can’t convince patients to take the next line of chemotherapy after docetaxel. Maybe that’s the way I’m pitching things, but I haven’t been able to treat anyone [with cabazitaxel].

ALUMKAL: What do you give instead?

ABHYANKAR: A lot of patients choose to watch and not do anything. I’ve tried to get patients to [try] Lu 177. I had a patient who had progressive axillary disease, and I treated him with docetaxel. He had severe headaches, and I referred him for Lu 177 therapy, but I can’t get him [to take the treatment] and he won’t call the center back. He recently went back into the hospital with more progressive disease. It seems like a lot of my patients don't want to be too aggressive.

ALUMKAL: Yes. I certainly have patients like that as well, and they’re not eager to do more chemotherapy, particularly if they’ve had 9 or 10 cycles of docetaxel and they’re looking for an alternative.

ABHYANKAR: Yes.

ALUMKAL: How about the combination of cabazitaxel plus carboplatin? Can anyone share some experience on that?

AL BAGHDADI: I’ve not used that combination. I’ve used carboplatin plus docetaxel, and I’ve used carboplatin plus etoposide. I have to say, in general, I’ve been disappointed by those combinations. They’ve never lived up to my expectations or the patients’ expectations. I think the sensitivity of any prostate cancer is limited to platinum agents. With regard to cabazitaxel, what I’ve seen in many patients when I transition them from docetaxel to cabazitaxel is that neuropathy often improves on cabazitaxel. It might help if you mention this to your patients. That’s just a testament to the difference between cabazitaxel and docetaxel in terms of the risk and severity of neuropathy. So, it’s not unusual that I transition [the patient from docetaxel to cabazitaxel] and they tell me that the neuropathy is getting better. Not stable, but better. And if you use the 20 mg/m² dose with granulocyte colony-stimulating factor, they tend to tolerate it well. There are patients who do much better and have a much longer response on cabazitaxel vs docetaxel. I can’t identify those patients up front. It’s just trial and error.

ALUMKAL: I think those are excellent points. Does anyone else have something to add?

JASTI: I’ve used cabazitaxel after docetaxel. The main issue I run into is the cytopenias, and we’ve started using growth factor support because the patients have already progressed through several lines of treatment at this point. But I’ve had experiences where I used cabazitaxel up front instead of docetaxel. One patient had metastatic disease and was diagnosed with colon cancer. He had also received oxaliplatin, folinic acid, and 5-fluorouracil and then developed severe neuropathy. So, when his prostate cancer progressed [while on] ADT and olaparib [Lynparza], I started him on cabazitaxel. That’s my experience. I didn’t want to go back to docetaxel because of the preexisting peripheral neuropathy.

NEMUNAITIS: I agree. I have a few patients with severe neuropathy on docetaxel. When we switched [one of them to cabazitaxel], he responded for over a year and his neuropathy improved. So, I’ve had some good experience with cabazitaxel in that setting.

ALUMKAL: Would anyone like to weigh in on what they use commonly in the second-line setting? Who feels comfortable using an ARSI?

AL BAGHDADI: If the patient is not a candidate for chemotherapy and I don’t have a trial option or the ability to give them Lu 177, then I do switch to the other hormonal drug. It seems that using a direct inhibitor like enzalutamide, apalutamide [Erleada], or darolutamide [Nubeqa] after abiraterone [Zytiga] is probably better than the opposite sequence. The results of the CARD trial [NCT02485691] are not surprising, and this is fertile ground for research…. I would say the 3.7 months of radiologic progression-free survival [with the ARSI] is at the upper limit of my expectation [From the Data⁴].

It’s a bit surprising as you [would] think it would be lower, but yes, there are patients every now and then [who] benefit from this strategy.

DISCUSSION QUESTION

How do you counsel patients who are afraid of chemotherapy?

ALUMKAL: How do you talk to them about that? Many of them who would be candidates for cabazitaxel have already had docetaxel. I don’t think any of us are interested in convincing our patients to do what we want them to do [if they don’t want to do it], but what are the ways you think are useful to best [educate] patients about using chemotherapy next?

YIN: I use 2 different approaches. First, I just tell my patients that I have patients who are 90 years old who can tolerate chemotherapy very well and that single-agent chemotherapy is not like a dual agent or a 3- or 4-drug [regimen]. I would say the majority of patients should be able to handle it well. The second thing I tell them is that it’s just a matter of time. We know this patient has metastatic disease. [Whether] they want to use the oral drug first or a chemotherapy drug first, eventually, they will receive all the treatments.

ALUMKAL: I find, Dr Yin, that the more symptomatic they are, the shorter this conversation is. And patients who are having a lot of symptoms related to cancer are ready to go because they realize that the treatment may be better than the disease. But for other patients who may have [high risk factors] and clinical progression rather quickly on the other agents, if they’re feeling well and asymptomatic, they’re not eager to jump into something that can make them feel worse. Those conversations are quite different, based upon how the patients are doing and what their symptomatology is. But to your point, at some point they probably will need an agent that [comes with more toxicity], and chemotherapy is one of our most active types of agent in this setting. Certainly, we wish the response rates were higher, but [chemotherapy], radium 223, and Lu 177 are our principal options. Particularly if a patient had a bad experience with the first-line ARSI, a second ARSI is unlikely to lead to any degree of durable control.

BEED: I’ve used cabazitaxel for a long time, and it came out 12 years ago at least.1 I find that it’s very helpful. Sometimes patients are old and they get confused or have Alzheimer disease, but everybody who comes in is afraid of chemotherapy. So I tell them that everyone is [afraid of chemotherapy], but you’ll probably feel better on it, and we can work with these AEs. You could stop at any time, and… if you encounter AEs that’s no problem, we’ll just stop it. But let’s give it a whirl because it’s not going to work if you don’t try it. Without therapy, you’re only going to get worse.

ALUMKAL: I think that’s a great point, Dr Beed. Many patients have had experience with family members or people in the past who have had chemotherapy. I always tell patients that, as far as chemotherapy goes, [cabazitaxel] is one of the easier ones to take. It’s not emetogenic. There aren’t severe risks of neutropenic fever, particularly if you’re using a lower dose of cabazitaxel or you’re using it with a growth factor. I often find that patients, after some conversation and some reassurance, are at least willing to give it a try. While most of them get through their planned course of therapy, unfortunately, many of them progress, but I generally am not stopping due to toxicity.

_References

_{1. FDA Center for Drug Evaluation and Research. Approval package for: Jevtana. June 17, 2010. Accessed June 13, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/201023s000Approv.pdf}

_{2. FDA approves lower dose of cabazitaxel for prostate cancer. FDA. September 14, 2017. Accessed June 13, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lower-dose-cabazitaxel-prostate-cancer}

_{3. 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}

_{4. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206}