Part 1: Reviewing the Systemic Therapy Options for Metastatic CSPC

Matthew B. Rettig, MD

Medical Director, Prostate Cancer Program

Institute of Urologic Oncology

University of California, Los Angeles

CASE

• A 73-year-old man presented with urinary retention, fatigue and decreased appetite​.
• He had family history of prostate cancer​
• He is active and is very involved in his grandchildren’s activities​
• Transrectal ultrasound and biopsy revealed adenocarcinoma of the prostate gland, Gleason score 8 (4+4) with disease in 10/12 cores.​
• Prostate-specific antigen (PSA), 150 ng/mL; hemoglobin (Hb), 9.7 g/dL; absolute neutrophil count (ANC), 1.9​
• Liver function tests are abnormal​
• Patient is diagnosed with localized high-grade prostate cancer​
• He undergoes robotic radical prostatectomy with subsequent PSA decrease (0.2 ng/mL)​
• CT and bone scans showed no residual disease​

13 months later

• Patient complains of right hip pain and abdominal pain​
• Imaging with CT and bone scan showed multiple metastatic bone lesions in the pelvis and diffuse liver lesions​
• PSA, 90 ng/mL; Hb, 9.4 g/dL; ANC, 1.5​
• Patient is diagnosed with metastatic prostate cancer​
• Germline genetic testing is negative​
• He wishes to receive oral treatment/avoid chemotherapy and minimizing adverse events (AEs) is very important to him​

Targeted Oncology^TM: What do the National Comprehensive Cancer Network (NCCN) guidelines recommend for metastatic castration-sensitive prostate cancer (mCSPC)?

MATTHEW RETTIG, MD: The NCCN guidelines for disease [with at least 1 metastasis] for mCSPC, are based on level 1 evidence that androgen deprivation therapy [ADT] should be used with 1 of these 4 agents. The apalutamide [Erleada] and enzalutamide [Xtandi] can be used for any patient, irrespective of disease volume.¹ Docetaxel, at least in the CHAARTED study [NCT00309985], was indicated for high-volume disease, as it was in our patient here, and it was a selection [in the poll].^2,3 Abiraterone [Zytiga] was approved based on the LATITUDE study [NCT01715285], which only enrolled high-risk patients.⁴ So they were high-risk, [which is] very similar to high volume, except the threshold for bone disease is 3 or more bone metastases, with 1 outside of the axial skeleton. The patient had to have either visceral disease or a Gleason score of at least 8. Most of the patients who have high volume have high risk, and vice versa.

I want to emphasize that in patients who are presenting with metastatic disease with their primary tumor, de novo disease—if they have oligometastatic or low-volume disease—they should receive radiation to the primary tumor for an overall survival benefit. That was shown in the STAMPEDE [NCT00268476] and HORRAD trials,^5,6 and in STAMPEDE there was an 8% absolute improvement in in 3-year survival with radiation to the primary tumor.⁵ The rationale for that is that the primary tumor represents a continued source of metastases, and we know from autopsy series when we sequence multiple metastases from a patient who’s succumbed to prostate cancer and we create a genetic tree; what we can see is that metastases are derived from the prostate, but can metastasize back to the prostate and then back out again. So, there is a rationale to remove the prostate, and there’s now empiric evidence to establish that it improves overall survival.⁵

Low-volume disease is defined as not being high volume. High volume would be 4 or more bone metastases. If it were 3 or fewer, then we’d call that low volume.¹

How did the 4 approved therapies perform in clinical trials?

The hazard ratios for [abiraterone, enzalutamide, and apalutamide] are very similar.^4,5,7-9 In the CHAARTED study, the hazard ratio was also in the 0.6 range for docetaxel, and that was for high volume disease.² And, the enzalutamide and apalutamide both show, if anything, slightly more benefit for the patients with high-volume disease.^7,10 So, if a patient has high-volume disease, there is no requirement to use [docetaxel] chemotherapy. You can use, with similar efficacy, 1 of the hormonal agents. AEs leading to discontinuation were slightly higher with chemotherapy.¹¹ These are all fairly well-tolerated agents.

What practical considerations are there for physicians prescribing the 4 approved agents for mCSPC?

Abiraterone and methylprednisone is indicated for metastatic castration-resistant prostate cancer [mCRPC] and mCSPC.¹² Apalutamide is indicated for mCSPC and nonmetastatic CRPC.¹³ Docetaxel is for mCRPC,² and enzalutamide is mCRPC, mCSPC, as well as nonmetastatic CRPC.¹⁴

I would emphasize with abiraterone, you do have mineralocorticoid excess.¹² Adrenal insufficiency would be attributable to the prednisone and not abiraterone; the drug does not cause adrenal insufficiency. It inhibits CYP17 even in humans that have complete absence of CYP17 due to a congenital adrenal hyperplasia, they do not develop adrenal insufficiency, they only develop mineralocorticoid excess.

With enzalutamide and apalutamide, since these are older patients, I think you have to be careful with predisposing factors for seizures, because they both can cause seizures.^13,14 Patients who had predisposing factors for seizures such as stroke, transient ischemic attack, and prior seizure were excluded from the studies.^7,8 I always ask my patients about that, and let them know about of about a 0.5% risk of seizure.^13,14 Risks of falls and fractures are also relevant in apalutamide and enzalutamide, because they’re more common in this population in general.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 3.2022. Accessed March 17, 2022. https://bit.ly/36tWz0j}

_{2. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657}

_{3. Docetaxel (Taxotere). Prescribing information. Sanofi; 2020. Accessed March 17, 2022. https://bit.ly/3CPEQwF}

_{4. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174}

_{5. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3}

_{6. Boevé LMS, Hulshof MCCM, Vis AN, et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: Data from the HORRAD trial. Eur Urol. 2019;75(3):410-418. doi:10.1016/j.eururo.2018.09.008}

_{7. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307}

_{8. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835}

_{9. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799}

_{10. Armstrong AJ, Iguchi T, Azad A, et al. Overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated with enzalutamide (ENZA) + androgen deprivation therapy (ADT) by high or low disease volume and progression to mHSPC (M0 at diagnosis) or de novo mHSPC (M1 at diagnosis): Post hoc analysis of the phase 3 ARCHES trial. J Clin Oncol. 2022;40(suppl 6):115. doi:10.1200/JCO.2022.40.6_suppl.115}

_{11. Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(2):149-158. doi:10.1016/S1470-2045(12)70560-0}

_{12. Abireterone acetate (Zytiga). Prescribing information. Janssen; 2020. Accessed March 17, 2022. https://bit.ly/3tnFOgg}

_{13. Apalutamide (Erleada). Prescribing information. Janssen; 2018. Accessed March 17, 2022. https://bit.ly/3CQGFcN}

_{14. Enzalutamide (Xtandi). Prescribing information. Astellas Pharma, 2019. Accessed March 17, 2022. https://bit.ly/3KUuC0F}