Park Considers Treatment for mCRPC By Line of Therapy

Chandler Park, MD

During a Targeted Oncology Cased-Based Roundtable event, Chandler Park, MD, the Norton Cancer Institute codirector, and Genitourinary Oncology Clinical Trials clinical professor at the University of Kentucky College of Medicine, University of Louisville School of Medicine, discussed the case of a 75-year-old patient with metastatic castration-resistant prostate cancer (mCRPC).

Targeted Oncology^TM: What treatment regimen is recommended in patients with advanced prostate cancer?

PARK: According to the advanced prostate cancer guidelines [by the American Urological Association, the American Society for Radiation Oncology, and the Society of Urologic Oncology], clinicians should consider prior treatment and sequencing agents, use therapy with an alternative mechanism of action, and offer radium 223 dichloride [Xofigo] to patients with symptoms of bony metastases from metastatic castration-resistant prostate cancer [mCRPC] without any visceral disease or lymphadenopathy.¹

What are some contraindications and indications for radium 223 dichloride?

ZOGHBI: Visceral disease would be a contraindication.

BALLOUZ: Thrombocytopenia.

PARK: Yes, absolutely. Thrombocytopenia of grade 2 or 3. What about the hemoglobin?

MICHALSKI: Yes. If it is less than 10 g/dL.

PARK: That’s right. They don’t want to check the complete blood count, do they? It’s a monthly treatment for 6 treatments. Have you noticed the PSA level going up while they’re on radium 223?

MICHALSKI: PSA is not a good tracker of response to radium 223. You’re probably dealing with an end-organ effect at the osteoclast, and it’s not a true anti–prostate cancer agent. It’s probably more of a skeletal agent.

PARK: I agree. They see the radiation oncologist and then come back for a 3-month follow-up, and we check the PSA and it’s elevated.

MATTAR: I agree with that. It’s like sipuleucel-T [Provenge], which is PSA independent. I tell my patients this is different. You don’t want to monitor PSA anymore. You monitor the scan and imaging.

BADIN: The alkaline phosphatase usually correlates well with the response. The patients have symptoms and that’s why we give radium 223. Clinically, if their pain is better, or their alkaline phosphatase is going down, that is reassuring. I do not monitor PSA with these patients, as my colleagues said.

MICHALSKI: Another contraindication is they shouldn’t be on abiraterone acetate [Zytiga] for sure. Enzalutamide [Xtandi] is suspect as well.

BAUMANN: You don’t have to have bone pain to meet symptom criteria for radium 223. If you have cancer-related fatigue, that’s considered a symptom and radium would be approved and indicated. A lot of people think you must have the pain to be a radium candidate.

Apart from radium 223, what other treatment regimens can be considered?

PARK: We offer a PARP inhibitor to patients with deleterious or suspected germline or somatic mutations. We offer pembrolizumab [Keytruda] for mismatch repair deficiency or MSI-H [microsatellite instability–high] with [tumor mutational burden] greater than 10 [mutations per megabase]. Clinicians may offer sipuleucel- T to asymptomatic or minimally symptomatic patients. Cabazitaxel [Jevtana] is offered to patients who receive prior docetaxel with or without prior abiraterone, or enzalutamide. Platinum-based chemotherapy is offered to patients with deleterious or suspected deleterious germline or somatic mutations.¹

What treatment choices would you recommend for this patient? What factors do you consider when deciding on treatment?

PARK: Factors include patient fitness, [ECOG] performance status, age, tolerance of prior therapy such as docetaxel, and patient preference.

BANDI: Probably [ECOG] performance status and prior tolerance to treatments. If they ended up with no significant marrow suppression, cytopenia, or neuropathy, that might decide third-line treatment options down the road.

MICHALSKI: I agree. [ECOG] performance status and laboratory results suggest the patient tolerates more therapies. Hopefully, lutetium PSMA [177Lu-PSMA-617] will be ready for such patients.

PARK: We got accepted for the VISION trial [NCT03511664] for the ASCO [2021 American Society of Clinical Oncology Annual Meeting] plenary session.2 [So, for prior docetaxel and prior novel hormone treatment], cabazitaxel, and olaparib [Lynparza] for [men with a homologous recombination repair gene mutation] are a category 1 recommendation.³

How do you decide between chemotherapy and androgen receptor (AR)–targeted therapy in a patient who has received both? Would you give cabazitaxel to a patient who did not tolerate docetaxel?

BALLOUZ: I think I would give cabazitaxel in a patient who did not tolerate docetaxel. I don’t know why they did not tolerate it, but it’s obviously something I’d think about.

MATTAR: The [adverse events (AEs)] profile is more diarrhea and neutropenia vs the neuropathy seen with docetaxel.There are a lot of patients with diarrhea on cabazitaxel. One can start with a lower dose. In our protocol, we lower the dose for the first cycle and the company came up with a way of adjusting the dose from the initial approval.

PARK: Absolutely. The CARD trial [NCT02485691] had cabazitaxel vs an AR-targeted agent in the study design. It was a multicenter randomized open-label study. Enrollment was from November 2015 to November 2018. The median follow-up was 9.2 months. Eligible patients had mCRPC that had progressed in less than 12 months on AR blockade before or after docetaxel.^4,5 Cabazitaxel dose was at 25 mg/m².

In the CARD study, most of the patients were enrolled in Europe, but there was a comparable study where cabazitaxel 25 mg/m² vs 20 mg/m² was used. The 25 mg/m² was with [granulocyte colony-stimulating factor] support.5 In the CARD trial, patients who received enzalutamide got randomized to the abiraterone and those who received abiraterone got randomized to enzalutamide in the alternative arm.^4,5

The primary end point in the CARD trial was radiological progression-free survival [rPFS], and key secondary end points were overall survival [OS], PFS, PSA response, and tumor response. The baseline specifics for the cabazitaxel vs abiraterone or enzalutamide arms are very balanced when it comes to age, ECOG performance status, visceral metastases, and pain. The PSA, radiographic [progression], Gleason score, and the N1 disease are also balanced between the 2 arms.^4,5

The median rPFS was 8.0 months for cabazitaxel vs 3.7 months for the AR-targeted therapy [HR, 0.54; 95% CI, 0.40-0.73; P < .001].⁵ [In the subgroup analysis], all subgroups seem to favor the cabazitaxel arm. These include ECOG performance status, initiation from AR-targeted treatment whether it’s less than 6 months or 6 to 12 months, timing of the AR inhibitor whether docetaxel was given first or second, duration of the ADT, age, and absence of visceral metastases.

The median OS was 13.6 months with cabazitaxel vs 11.0 months for the AR-targeted inhibitor [HR, 0.64; 95% CI, 0.46-0.89; P = .008]. This validated cabazitaxel as the third-line therapy in a prospective study. Before this study, there was a question of sequencing and, if one was on enzalutamide, whether they should be put on abiraterone next. The CARD trial showed that cabazitaxel was superior.

The median PFS was 4.4 months for cabazitaxel vs 2.7 months for the AR-targeted inhibitor arm [HR, 0.52; 95% CI, 0.40-0.68; P < .0001].

The PSA, tumor, and pain response comparisons are important. The PSA [response rate] is 35.7% vs 13.5% [P = .0002], objective tumor response rate is 36.5% vs 11.5% [P = .004], and the pain [response rate] is 45.0% vs 19.3% [P < .0001] for the cabazitaxel and AR-targeted therapy, respectively. The median time to symptomatic skeletal event was not reached for the cabazitaxel arm vs 6.7 months for the AR-targeted therapy arm [HR, 0.59; P = .05].^5,6

Occurrence of AEs was 98.8% for the cabazitaxel arm vs 94.4% for the AR-targeted therapy arm. Grade 3 AEs were comparable for the 2 arms even though cabazitaxel is a chemotherapy agent. Serious AEs were also comparable. AE rates leading to treatment discontinuation were 19.8% for the cabazitaxel arm vs 8.9% for the AR-targeted therapy arm. Rates for AEs leading to death were 5.6% for cabazitaxel vs 11.3% for the AR-targeted therapy arm.5 Cabazitaxel has a better health-related quality of life compared with abiraterone or enzalutamide.^7,8

Because of COVID-19 concerns, what percentage of your patients fit for chemotherapy asked for an alternative treatment option? Have you selected an alternative treatment strategy for patients with advanced cancers?

GHANEM: The COVID-19 pandemic didn’t have much effect on my practice. We continued because we give chemotherapy and our patients are critical. That was never a problem with me, but I have a small practice. I’m not a big multiphysician practice. I was in control of the patient flow, so it did not affect us at all. I saw some interference because of delayed biopsy or scan results, but if the patient needed intravenous chemotherapy, I proceeded.

What are some unique cabazitaxel toxicities that you have noticed in your practice? What advice can be given for handling them?

MATTAR: I have had problems with diarrhea. In general, it’s very well tolerated, but we need to start at a lower dose. I’ve had 1 patient who had 1 chemotherapy session and the PSA level went from 1200 to 200 ng/mL, but they had diarrhea for almost 4 or 5 weeks. I was able to rechallenge him later. This was one of my experiences with diarrhea and 25 mg/m² of cabazitaxel. Sometimes, I start at 20 mg/m², especially with people in the mid- to late 70s who have a good [ECOG] performance status.

BADIN: The problem is cabazitaxel is usually reserved for fifth-line therapy. My patients usually have been on androgen blockade and then they go on to abiraterone, enzalutamide, docetaxel, before you get to cabazitaxel. The patient population is heavily pretreated. They don’t have the best performance status and we wait so long to get to it.

When the COVID-19 pandemic hit, most of the patients avoided chemotherapy. The question is not cabazitaxel or docetaxel. It’s cabazitaxel vs oral agents. Patients prefer a chemotherapy-free regimen. When you offer them oral vs intravenous therapy, they almost always want oral therapy.

The CARD study will not change much of what I do. I wish there was a trial comparing cabazitaxel with docetaxel, or at least trying to bring it into the practice earlier before waiting to use it as the fourth or fifth line of treatment.

PARK: In my practice, the patients get almost all the treatments whether it is sipuleucel-T or radium 223 dichloride. The CARD trial has changed my practice pattern a little bit as I am aware of the OS data, so I try to get them to use cabazitaxel as soon as we can in earlier lines of treatment like the third line if I can.

I’ve noticed when treating patients with cabazitaxel with prior radiation treatment that they get unrelenting hematuria and when I send them to the urologist, they do a cystoscopy, and you have hemorrhage. I’ve had some luck with patients on hyperbaric oxygen and we hold the treatment. I think the incidence of patients with prior external beam radiation on cabazitaxel is about 5% to 7%, and it’s hard to control that hematuria. So consider hyperbaric oxygen treatment if you have a patient like that.

What would you say this case teaches us going forward?

PARK: The biology of metastatic prostate cancer is complex with notable intratumor heterogeneity. Understanding of the disease biology continues to evolve and influence management and therapeutic development. Therapeutic sequencing is an important component of treatment planning. ADT remains the foundational therapy even with the emergence of new therapies. Switching mechanism of action of therapy is associated with improved survival.

_REFERENCES:

_{1. Lowrance WT, Breau RH, Chou R, et al. Advanced prostate cancer: AUA/ ASTRO/SUO guideline part I. J Urol. 2021;205(1):14-21. doi:10.1097/ JU.0000000000001375}

_{2. Morris MJ, De Bono JS, Chi KN, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(suppl 15):LBA4. doi:10.1200/JCO.2021.39.15_suppl.LBA4}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed August 3, 2021. https://bit.ly/3jHaDXi}

_{4. de Wit R, Kramer G, Eymard JC, et al. CARD: randomized, open-label study of cabazitaxel (CBZ) vs abiraterone (ABI) or enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2019;30(suppl 5):v851- v934. doi:10.1093/annonc/mdz394}

_{5. de Wit R, de Bono J, Sternberg CN, et al; CARD Investigators. Cabazitaxel vs abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206}

_{6. 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}

_{7. Fizazi K, et al. Pain response and health-related quality of life (HRQL) analysis in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) vs abiraterone or enzalutamide in the CARD study. Poster presented at: Genitourinary Cancers Symposium; February 13-15, 2020; San Francisco, CA. Abstract 16.}

_{8. Fizazi K, Kramer G, Eymard JC, et al. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel vs abiraterone or enzalutamide (CARD): an analysis of a randomised, multicentre, open-label, phase 4 study. Lancet Oncol. 2020;21(11):1513-1525. doi:10.1016/ S1470-2045(20)30449-6}