Physicians Discuss Targeted Treatment for Prostate Cancer Subtypes

DISCUSSION QUESTION

• Have you used carboplatin plus cabazitaxel (Jevtana)? In what scenarios did you use it?

MUFADDAL HAMADEH, MD: There is a subtype of prostate cancer that is not prostate-specific antigen [PSA] producing, and it acts more aggressively with more visceral metastases, and on more than 1 occasion, I have used carboplatin [to treat these patients]. I think that would be a great place to use carboplatin earlier with cabazitaxel, and even earlier than third or fourth line of treatment.

JOSHUA LANG, MD, MS: There are other aggressive subtypes of prostate cancers, as you said. One is neuroendocrine prostate cancer.¹ Some physicians also use the term aggressive variant prostate cancer. Neuroendocrine is classically defined as having expression of synaptophysin or chromogranin A [CgA], so oftentimes, if I am doing a biopsy of visceral disease including liver, lungs, or others…not only [do I need to get] enough tissue for next-generation sequencing [NGS], but also to stain for synaptophysin or CgA to look for that neuroendocrine prostate cancer signature, which helps me to help prepare my patients.

Joshua Lang, MD, MS​

Associate Professor

Department of Medicine

School of Medicine and Public Health

University of Wisconsin​

Madison, WI

This is a situation where we may need to use the platinum [therapy] earlier rather than later, whether that is carboplatin, cabazitaxel, or cisplatin/etoposide, for example. That’s a great point to look for neuroendocrine prostate cancer, or an aggressive variant where it is a bulky lymph node disease larger than 5 cm, has lytic lesions, a short duration of response to low PSA, or short duration of response to hormone therapies.

DISCUSSION QUESTION

• Would you give cabazitaxel to a patient who did not tolerate docetaxel well?

LANG: For patients who initially present with metastatic prostate cancer at first diagnosis, we have a few different treatment options based on the PEACE-1 [NCT01957436] or ARASENS [NCT02799602] trials.… We still use docetaxel in [this] setting, usually with the combination of abiraterone [Zytiga] or darolutamide, although there are some patients where we skip the docetaxel just go with antigen-deprivation therapy [ADT] and abiraterone, for example. When those patients develop castration-resistant prostate cancer [CRPC], that important question of do we have to use docetaxel first, or could we have used cabazitaxel? Cabazitaxel is FDA approved,² and especially if patients have other high-risk features, whether that’s genomics, liver metastases, etc, we could still consider the addition of a platinum agent at that time as well.

In the CRPC setting, if patients presented with metastatic disease, and they got docetaxel already, then it’s easy to stick with cabazitaxel next. I think from a payer perspective, I don’t struggle to get cabazitaxel covered relative to docetaxel. The other side of that is what if [a patient] had a prostatectomy or treatment of the primary [tumor], and then they’ve gone on only to receive ADT, and now they have CRPC treated with enzalutamide, for example. Do we have to go with docetaxel? I still tend to lean towards docetaxel first and use cabazitaxel for rechallenge as a second-line taxane therapy. But, if there are other risk factors, like someone who has a baseline peripheral neuropathy, that would be an indication to go with cabazitaxel first instead of docetaxel.

ANASTAS PROVATAS, MD: For patients who are on triplet therapy up front, has anyone looked at cabazitaxel in the second-line setting, or can we extrapolate data?

LANG: In terms of for patients who have received doublets with ADT and docetaxel, there is a clinical trial in the ECOG working group…of abiraterone with or without cabazitaxel.³ We’ve had that trial open at our institution as well; it has completed enrollment and we are hopeful to have data that we will report [soon]. In my practice, cabazitaxel in that setting is highly efficacious. It works well and is well tolerated, no adverse events [AEs] beyond what I would already expect from the other clinical trials.

CHRISTOS KYRIAKOPOULOS, MD, MS: There was a retrospective analysis of a study that examines the role of docetaxel for hormone-sensitive disease.⁴ What they found is that for patients who received docetaxel up front, when they were rechallenged with docetaxel, the responses were worse compared with patients who were docetaxel-naive. But I think, even though technically patients who received docetaxel up front can receive docetaxel again, cabazitaxel is probably a better choice.

DISCUSSION QUESTION

• How do you counsel patients who are afraid of chemotherapy?
• Regarding infusion versus oral options and their tolerability profiles?
  
  

BETY CIOBANU, MD: For the patients who progress on hormonal therapy, I think if they are already on an oral medication, and their duration of response is short, they are more prone to accept the chemotherapies in that scenario versus if you just propose chemotherapy up front. The question that I have is how do you decide between a triplet therapy versus cabazitaxel for a patient [with CRPC] who is high risk?

LANG: In the CRPC setting, I continue leuprolide or ADT lifelong. At that time, especially if someone has progressed on abiraterone or enzalutamide [Xtandi], that is where I lean towards docetaxel or cabazitaxel, and especially for patients who, if there’s peripheral neuropathy, I do push more towards cabazitaxel. With visceral involvement, I am thinking about the addition of carboplatin with a platinum doublet for those patients, and especially in those patients who have neuroendocrine disease. In terms of some of the tolerability questions, that is also where, in my experience, nausea and vomiting are quite rare these days. Our medications, in terms of what we do for pretreatment and on treatment management, are so much better than when I finished my fellowship that I think nausea and vomiting are relatively rare. It does happen [though], and we need to be aggressive about it if it does.

I talk to my patient about neutropenia infection risk [being] the biggest concern for me with chemotherapies. They have our triage number. They know to call us because if we can treat them quickly with [intravenous] antibiotics, everyone does well. That helps build a safety net for my patients, so they always know to call 24 hours a day, 7 days a week if they need it. I will [use] granulocyte colony-stimulating factor prophylaxis, too. Unfortunately, it is a challenge these days, with every insurance provider seeming to have their own preference in terms of what they will allow us to prescribe. Regardless, though, I think it’s critically that patients have access to that, especially [if they’re on] cabazitaxel.

SANGGYU BAE, MD: If [a patient] harbored a BRCA mutation [in their disease], and you are considering a PARP inhibitor, [but] the patient took enzalutamide and progressed, would you prefer to use it before chemotherapy or after?

LANG: One of the things that I try to do in my clinical practice is that, when patients have metastatic disease, we try to send any biopsy we can. We also send germline samples to look for BRCA1/2, or other related mutations in that [DNA damage response and repair] cluster of genes. We have new data showing that the combination of olaparib [Lynparza], or niraparib [Zejula] even, with an androgen receptor–signal inhibitor is superior, especially for those patients who have BRCA2 mutations.^5,6 So, if I am going to start a patient who has metastatic disease, I try to find out if they have a BRCA1/2 mutation even before I start abiraterone, for example. If they do, I will see if I can get approval for olaparib for the combination. If someone has already had abiraterone, and they are progressing, that is where I do go straight to the PARP inhibitor rather than chemotherapy.

^References:

^{1. Yamada Y, Beltran H. Clinical and Biological Features of Neuroendocrine Prostate Cancer. Curr Oncol Rep. 2021;23(2):15. doi:10.1007/s11912-020-01003-9}

^{2. Paller CJ, Antonarakis ES. Cabazitaxel: a novel second-line treatment for metastatic castration-resistant prostate cancer. Drug Des Devel Ther. 2011;5:117-24. doi:10.2147/DDDT.S13029}

^{3. Lin J, Den RB, Greenspan J, et al. Phase I Trial of Weekly Cabazitaxel with Concurrent Intensity Modulated Radiation and Androgen Deprivation Therapy for the Treatment of High-Risk Prostate Cancer. Int J Radiat Oncol Biol Phys. 2020;106(5):939-947. doi:10.1016/j.ijrobp.2019.11.418}

^{4. Clarke NW, Ali A, Ingleby FC, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019;30(12):1992-2003. doi:10.1093/annonc/mdz396}

^{5. de Bono J, Mateo J, Fizazi K, et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440}

^{6. Chi KN, Rathkopf D, Smith MR, et al; MAGNITUDE Principal Investigators. Niraparib and Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2023;41(18):3339-3351. doi:10.1200/JCO.22.01649}