Treatment options for metastatic castration-sensitive prostate cancer

“The backbone of any treatment is androgen deprivation therapy [ADT]. These drugs suppress the level of testosterone in the body because testosterone is the fuel needed for the growth and spread of prostate cancer,” Choudhury explained.

Although ADT remains a key part of treating patients with mCSPC, Choudhury pointed out that ADT only works for a few patients. He explained that scaling up ADT with different treatment modalities has been linked to prolonged survival.

Specifically, Choudhury mentioned docetaxel chemotherapy; androgen receptor (AR) targeting agents, including abiraterone acetate (Zytiga), apalutamide (Erleada), and enzalutamide (Xtandi); and radiotherapy as viable modalities to intensify therapy.

“It’s not clear from [completed] studies that one of these agents is superior to any other in terms of overall survival,” Choudhury explained. “We can only conclude that they are all superior to ADT alone.”

Choudhury cited 2 studies – ARCHES (NCT02677896), looking at enzalutamide plus ADT, and TITAN (NCT02489318), looking at apalutamide plus ADT – as research that confirmed positive survival data with these drugs in mCSPC.1.2 Additionally, both trials led to FDA approval of their respective agents for patients in this setting.3.4

ARCHES built on previously reported results from the Phase 3 ENZAMET trial (NCT02446405), which studied enzalutamide for metastatic prostate cancer. A significant reduction in the risk of death or progression was noted in the ARCHES cohort of patients who received enzalutamide plus ADT compared to placebo plus ADT (HR, 0.39; 95% CI, 0.30-0.50; P P P <.0001>2

“These data confirm the results of previous studies which all demonstrated prolongation of overall survival when an AR pathway inhibitor was added to the initial ADT,” Choudhury explained.

In addition, triple therapies – with abiraterone plus docetaxel/ADT in the PEACE-1 trial (NCT01957436)5 and darolutamide (Nubeqa) plus docetaxel/ADT in the ARASENS trial (NCT02799602)6— showed benefit over docetaxel plus ADT alone for patients with mCSPC.

“It appears from the studies presented [to date] that even patients with low-volume metastatic disease benefit from treatment intensification,” Choudhury explained. “Quality of life [QOL] data from these studies also suggest that patients will benefit from earlier treatment with these agents.

Choudhury further explained the quality of life benefits that emerge from scaling up therapy.

“Even though there is [toxicities, these agents] clearly decrease adverse effects associated with the cancer itself,” Choudhury said. “The quality of life with these agents is superior [to that of] patients treated with ADT alone.

Overall, Choudhury emphasized the importance of starting therapy earlier in the process. Unless there is a contraindication for patients, he suggested that survival and quality of life data support the early integration of intensified therapy into mCSPC therapy.

“There is no cancer or quality of life reason not to consider these agents earlier in the process,” Choudhury said.

Unmet needs for mCSPC

“There are a variety of unmet needs to understand how best to manage each patient,” Choudhury acknowledged. These include determining the optimal treatment for patients with localized disease; the role of intensification of androgen receptor therapy for patients treated in the neoadjuvant or adjuvant setting; use molecular diagnostics to determine whether a patient should escalate or taper treatment; and who should receive salvage radiotherapy and when it should be initiated.

Of note, Choudhury mentioned that the recommendations of the US Task Force on Preventive Services in 2012 played a key role in changing the diagnosis and management of patients with mCSPC and specifically cited the decrease in prostate-specific antigen (PSA) screenings in this setting.7

“It’s unclear where the new imagery comes in,” Choudhury explained. “Should all patients who have a PSA less than 0.2 get a [prostate-specific membrane antigen]/PET scan as part of radiological planning? I don’t think this answer has been developed yet.

Final Thoughts

“So much progress has been made in hormone-sensitive prostate cancer that survival has been dramatically prolonged,” Choudhury explained. “Some patients may discontinue treatment and still retain benefits. It’s an ever-changing space and we have to adapt from patient to patient. [basis] and make sure our recommendations are individualized.

Despite the obvious need to individualize treatment, Choudhury said the benefit of scaling up is clear. “[That] all patients would benefit from some form of scaling up is the most important lesson we have learned in the past year,” he said. “The data that has been presented recently supports that patients’ quality of life is better with the addition of these other agents, even though many providers are concerned about their toxicities.”

The references

  1. 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-responsive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799
  2. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final analysis of survival from the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488
  3. The FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. FDA. December 17, 2019. Accessed February 16, 2022.
  4. The FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA. September 18, 2019. Accessed February 16, 2022.
  5. Fizazi K, Galceran JC, Foulon S, et al. A phase III trial with a 2×2 factorial design in men with de novo metastatic castration-sensitive prostate cancer: overall survival with abiraterone acetate plus prednisone in PEACE-1. Anne Oncol. 2021;32(supplement 5):S1283-S1346. doi:10.1016/announce/announce741
  6. Smith MR, Hussain M, Saad F, et al. Overall survival with darolutamide versus placebo in combination with anti-androgen therapy and docetaxel for metastatic hormone-responsive prostate cancer in the ARASENS phase 3 trial. J Clin Oncol. 2022;40(supplement 6):13. doi:10.1200/JCO.2022.40.6_suppl.013
  7. Prostate cancer: screening. US Task Force on Preventive Services. May 8, 2018. Accessed February 16, 2022.

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