Experts Discuss Diagnostic and Treatment Options for a Patient With mCRPC

Daniel P. Petrylak, MD

During a Targeted Oncology Case-Based Roundtable event, Daniel P. Petrylak, MD of Yale School of Medicine and Susan F. Slovin, MD, PhD or Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, discuss the case of 75-year old man with metastatic castration resistant prostate cancer.

Targeted Oncology^TM: What would you recommend for this patient now that the disease is progressing?

PETRYLAK: I think the most appropriate action would be to check for microsatellite instability [MSI] and DNA repair deficiency. [If the patient were to test positive for either of these markers], we have PARP inhibitors that may give a good response, delay progression, and improve overall survival [OS]. We also have pembrolizumab [Keytruda] for the 3% of patients who have MSI. If the patient were to test negative for either of those 2 markers, then cabazitaxel [Jevtana] would be an appropriate treatment. The patient has already had enzalutamide and it is unlikely that he would respond to abiraterone [Zytiga] and prednisone.

Would you consider biopsy?

PETRYLAK: Yes. Tissue biopsy is the better [option]. However, if it is going to be difficult to do a tissue biopsy— for example, if the patient is on warfarin [Jantoven] or has a lesion that can’t be biopsied for other reasons—I think it’s appropriate to consider a liquid biopsy.

Susan F. Slovin, MD, PhD

SLOVIN: If we could do both tissue and liquid biopsies, that would be best. It is our custom, as a patient’s disease becomes more refractory to each subsequent therapy, to try to biopsy tissue. It doesn’t have to be the same tissue, but if a patient develops metastases in the liver, lung, or brain, we want to know as much as possible about the heterogeneity to find the drug that best addresses all of these different phenotypes.

What treatment choices would you consider for this patient now, and what factors would influence your decision?

PETRYLAK: You should always be thinking about a clinical trial for these patients. [From among the therapies listed in the National Comprehensive Cancer Network (NCCN) guidelines for subsequent systemic therapy for metastatic castration-resistant prostate cancer (mCRPC) adenocarcinoma with prior docetaxel and prior novel hormone therapy, I would consider] cabazitaxel [Jevtana].¹ I would avoid docetaxel rechallenge in a patient like this who has neuropathy. [Compared with docetaxel], cabazitaxel has a superior adverse event [AE] profile and neuropathy doesn’t seem to accelerate as fast [as it does with docetaxel] rechallenge. [I would use] pembrolizumab [Keytruda] for MSI-high patients, and I’ve recently used mitoxantrone in patients who have exhausted every other treatment.

In what situations would you use cabazitaxel plus carboplatin, another recommendation of the NCCN?

SLOVIN: I would use it in a patient whose cancer [appears to be] poorly differentiated, [in which case] we need platinum, either carboplatin or cisplatin. If a patient’s PSA level or radiographic results indicate markedly accelerating disease, or if you feel that visceral [metastasis] is imminent, this would be a reasonable option.

PETRYLAK: Yes. In fact, I [have] a patient who had a very low PSA level; [it] went from 0.6 mg/mL to 1.0 mg/mL to 1.2 [to] 1.6 mg/mL. He was on abiraterone and prednisone plus ADT for hormone-sensitive disease. [Upon scanning], we discovered that he had a large liver metastasis, which turned out to be a poorly differentiated carcinoma with no neuroendocrine features. [Because of this metastasis], we gave him carboplatin and docetaxel. He achieved a great response in the liver, almost a 75% reduction [of the metastasis], but his PSA level is going slightly up.

You have to consider all parameters to understand how to take care of these patients, and PSA level is not the only thing to look at. But I do like the combination of carboplatin with a taxane. Data have shown that combination to be very effective in these patients with poorly differentiated disease.²

Do you have experience using cabozantinib (Cabometyx) in the third- or fourth-line setting, though it is off-label, either to avoid chemotherapy or because chemotherapy is no longer working?

SLOVIN: I have a 94-year-old patient who is on it. I started using a half dose, then escalated to the full dose. He has tolerated it very well [with the exception of] a little fatigue; he wanted a drug holiday recently. But [we achieved] a very profound decline in PSA level after multiple treatments. It can be done.

PETRYLAK: Cabozantinib continues to perplex us. [Cabozantinib and atezolizumab (Tecentriq) each generate] a 5% objective response rate when used alone but produce a 30% response rate when used together.³ I’m excited about the data and the biology behind it.

What data might influence your choice between chemotherapy and androgen receptor (AR)-targeted therapy for patients who have received both?

PETRYLAK: [That choice was explored in] the CARD trial [NCT02485691]. This was a multicenter, randomized, open-label trial; median follow-up was about 9 months. The patients had mCRPC and had previously progressed [during a year] of next-generation hormone therapy— abiraterone or enzalutamide—before [or after] having received docetaxel therapy. [After randomization], the patients received either cabazitaxel at the standard dose, 25 mg/m² every 3 weeks, or the next-generation antiandrogen therapy [that they had not previously received], either enzalutamide or abiraterone. The primary end point was radiographic progression-free survival [rPFS]. The secondary end points included OS, PSA response, tumor response, pain response, time to symptomatic skeletal events, safety, and quality of life.^4,5

This was a well-balanced trial. About one-third of the patients were more than 75 years of age. About two-thirds of the patients had pain related to their tumors.

About 30% to 40% of patients had M1 disease at diagnosis, and the percentage of patients [who had received] docetaxel or abiraterone in the context of hormone-sensitive disease was 10.9% in the cabazitaxel group and 0.8% in the abiraterone-enzalutamide group. [Of patients who received cabazitaxel], the prior hormone therapy was abiraterone in about 43%...and enzalutamide in about 56%…; prior hormone therapy was received before docetaxel in about 39% of the patients and after docetaxel in about 61% of the patients. The median duration of the prior hormonal therapy was about 8 months.⁴

How did patients do on the CARD study?

PETRYLAK: The study met its primary end point. There was a 4.3-month difference in the rPFS, with an HR of 0.54 [95% CI, 0.40-0.73; P < .001]. The [results of all] preplanned subgroup analyses, which included groups defined by the presence or absence of visceral metastases, by Gleason score, and by previous therapies, favored cabazitaxel over the alternative hormonal therapy.5 OS was impressive; there was a 2.6-month difference in median OS in favor of cabazitaxel [HR, 0.64; 95% CI, 0.46-0.89].^4,5 When PFS—excluding radiographic progression, symptomatic progression, or death from any cause—was examined, the results again favored cabazitaxel: median PFS was 4.4 months for the cabazitaxel group vs 2.7 months for the abiraterone-enzalutamide group [HR, 0.52; 95% CI, 0.40-0.68; P < .0001].^4,5 Additionally, PSA response was superior with cabazitaxel [35.7% vs 13.5%; P = .0002]. The objective tumor response [rate was similar]: 36.5% vs 11.5% [P = .004]. The pain response rate was 45% vs 19.3% [P < .0001]. Finally, regarding time to the first symptomatic skeletal event, the median was not reached in the cabazitaxel arm vs 16.7 months in the next-generation antiandrogen arm [HR, 0.59; 95% CI, 0.35-1.01; P = .05].^4,6

As we expect with chemotherapy, there were more AEs leading to treatment discontinuation in the cabazitaxel arm than in the abiraterone-enzalutamide arm, almost 20% vs 9%, respectively. However, serious AEs leading to death occurred in 5.6% vs 11.3% of patients, in favor of cabazitaxel.^4,5 Regarding health-related quality of life at 3 months, there was a lower probability of deterioration in patients who received cabazitaxel vs those who received abiraterone or enzalutamide. Prostate-specific and pain-related concerns for well-being also trended in favor of cabazitaxel [P = .11 for prostate-specific concerns; P < .001 for pain-related concerns].⁷

In my opinion, [these results] affirm what we knew already: [in comparison with a] next-generation antiandrogen therapy used in a select group of patients like this one, we tend to see better results with chemotherapy.

SLOVIN: I agree. I was not overwhelmed with the data, but it was nice to see, [in light of] some of the trials we’ve been doing with a combination of cabazitaxel and abiraterone vs abiraterone followed by cabazitaxel upon treatment failure. What surprised me was the fact that they used 25 mg/m². When we started using cabazitaxel, everybody was terrified; you read articles about horrible neutropenia, particularly in elderly [patients]. Yet surprisingly, it’s proved to be a very well-tolerated treatment with minimal neuropathy. I routinely administer 20 mg/m².

PETRYLAK: I usually give 20 mg/m², or 25 mg/m² if I think the patient can tolerate it. Sometimes I’ll start a patient at 20 mg/m², then escalate to 25 mg/m² if they do fine with [the lower dosage]. I’ve been pleased by what I’ve seen, [though] there are randomized data showing that there’s probably not much of a difference [between the dosages].8

How many cycles of cabazitaxel therapy have you used in patients?

SLOVIN: We have never gone past 10 cycles but I think patients would be able to go…to 12 or 14 cycles.

PETRYLAK: We’ve had patients who have gone further than [10 cycles on cabazitaxel] and [the treatment was] well tolerated. You do have to watch carefully for neuropathy.

What is your approach to managing the toxicities associated with cabazitaxel?

PETRYLAK: Three important points are to watch carefully for neuropathy, give growth factor for the low blood counts, and give loperamide [Imodium A-D] for diarrhea.

Are there biomarkers that could help you decide whether extended hormonal therapy might be appropriate for some patients?

PETRYLAK: You are absolutely right [to raise the question], but in my opinion it’s still empiric. The patients I would consider for second hormonal manipulation are those who have a prolonged [first-line] response to abiraterone or enzalutamide. This is a different group [than that studied in] the CARD trial. Patients in the CARD trial had progressed within a year of abiraterone or enzalutamide therapy.^4,5

Something that I like to do with abiraterone is to switch steroids. There are data that [address] the question of switching from prednisone to dexamethasone.⁹

I’ve [had] some durable secondary responses [with this]; some [PSA responses have lasted] a year. You need to see how quickly the patient is progressing and consider whether you have time to do this. I think it’s appropriate to consider it in the right patient.

SLOVIN: It’s a great question. We continually look for biomarkers that will help us make the transition to different drugs as the patient transitions [from one] clinical state [to the next]. We are [investigating] cell surface markers and genomic profiles of circulating tumor cells as biomarkers of response. We are still in a learning curve, and we hope that we can find the appropriate biomarker that will point us in the direction of the right hormonal agent [for a given patient].

How do you counsel patients regarding infusion vs oral options and their tolerability profiles?

PETRYLAK: I’ve had some oral agents that have [been very poorly tolerated]. One of the first patients I treated with enzalutamide, who had been on both docetaxel and cabazitaxel, told me that he felt worse on the enzalutamide than he had on chemotherapy. He had the central nervous system toxicity that [is characteristic of] enzalutamide. You have to tell patients that “oral” doesn’t necessarily mean “better.”

How do you think the use of cabazitaxel will evolve in the coming year as we anticipate the approval of lutetium 177–prostate-specific membrane antigen- 617 [177Lu-PSMA-617] therapy?

PETRYLAK: I think that the 177Lu-PSMA-617 data are impressive,10 but [that therapy is just] another tool in the toolbox. We’re not seeing complete cures, [so] these patients should be exposed to all forms of treatment. For the appropriate patient, the question is whether you should give cabazitaxel or PSMA-targeted therapy; I think there are randomized data that [address] that question in terms of PSA and PSA progression. The survival data [are not available] yet, so we’re going to have to [learn] how to use these agents.

SLOVIN: For the patient who [is not impressed with the 2-month survival benefit offered by cabazitaxel, remind them] that 2 months is the median. The treatment may be very beneficial to a subset of patients. It is worth trying when your options are limited, even if you have to dose-attenuate it or change the treatment schedule.

Can you expand upon the data that support the use of 177Lu-PSMA-167 in PSMA-positive mCRPC?

PETRYLAK: Data from the VISION trial [NCT03511664] were presented at the American Society of Clinical Oncology Annual Meeting this year. PSMA is a surface membrane protein that is expressed in about 90% of prostate cancer cells. It is expressed in a number of different prostate cancer cells and…in the endothelium of other solid tumors. Strangely, in prostate cancer, it is not expressed in the endothelium but in the epithelium. Its [function is] unclear; there is some thought that it may be related to folate transport. The VISION trial examined patients with mCRPC who had received at least 1 AR pathway inhibitor or 1 or 2 prior taxane regimens. They were randomly assigned to receive either standard of care [SOC] plus 177Lu-PSMA-167 for 4 cycles, [which could be increased to 6], or SOC alone; SOC excluded cytotoxic chemotherapy and radium 223 [Xofigo]. The patients were then followed for survival.¹⁰

Patient screening involved a gallium 68-PSMA-11 PET scan [to identify] patients who had expression of PSMA. Unfortunately, there was a low enrollment of African American patients [6%] and of Asian patients [2.4%] in the trial. Patients had received a median of 1 prior AR pathway inhibitor and 1 prior taxane; approximately 40% to 50% had received more than 1 of either or both of these.¹⁰

Median OS was 15.3 months in the 177Lu-PSMA-167 plus SOC group vs 11.3 months in the SOC group [HR, 0.62; 95% CI, 0.52-0.74; P < .001]. This is exactly what we see with other agents. It’s impressive that we are using this targeted approach, and remember, this is a select group of patients. The improvement in median OS [was observed] across all prespecified subgroups, with the exception of those defined by the presence of liver metastases, an ECOG performance status of 2, or an age of less than 65 years. The subgroup analysis results for patients with liver metastases does not surprise me because there tends to be less PSMA expression in liver metastases. The results for rPFS are not surprising; there was about a 5.3-month difference in median rPFS [HR, 0.40; 99.2% CI, 0.29-0.57; P < .001]. Similar results were observed across [most] prespecified groups.¹⁰

As one would expect, there did seem to be more toxicity with the experimental regimen than with SOC. There was a higher rate of fatigue [for grade 3 to grade 5, 7% vs 2.4%, respectively] and of bone marrow suppression [for grade 3 to grade 5, 23.4% vs 6.8%, respectively]. Dry mouth is something unique to PSMA-targeted therapy because there is PSMA in the salivary gland [for all grades, 39.3% in the experimental group vs 1.0% in the SOC group]. Renal dysfunction and intracranial hemorrhage were observed at similar rates in both groups.¹⁰

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 1.2022. Accessed October 4, 2021. https://bit.ly/2YsTXfa}

_{2. Teply BA, Hauke RJ. Chemotherapy options in castration-resistant prostate cancer. Indian J Urol. 2016;32(4):262-270. doi:10.4103/0970-1591.191239}

_{3. Agarwal N, Loriot Y, McGregor BA, et al. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): results of cohort 6 of the COSMIC-021 study. J Clin Oncol. 2020;38(suppl 6):139. doi:10.1200/JCO.2020.38.6_suppl.139}

_{4. de Wit R, Kramer G, Eymard J, 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 versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206}

_{6. Fizazi K, Kramer G, Eymard JC, et al. Pain response and health-related quality of life (HRQL) analysis in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving cabazitaxel (CBZ) versus abiraterone or enzalutamide in the CARD study. Poster presented at: 2020 Genitourinary Cancers Symposium; February 13-15, 2020; San Francisco, CA. Accessed October 5, 2021. https://bit.ly/3BqoybZ}

_{7. Fizazi K, Kramer G, Eymard JC, et al. Quality of life in patients with metastatic prostate cancer following treatment with cabazitaxel versus 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}

_{8. 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}

_{9. Lorente D, Omlin A, Ferraldeschi R, et al. Tumour responses following a steroid switch from prednisone to dexamethasone in castration-resistant prostate cancer patients progressing on abiraterone. Br J Cancer. 2014;111(12):2248-2253. doi:10.1038/bjc.2014.531}

_{10. Morris MJ, De Bono JS, Chi KN, et al; VISION Trial Investigators. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(suppl 18):LBA4. doi:10.1200/JCO.2021.39.15_suppl.LBA4}