Novel Hormonal Agents Foster New Approaches in Nonmetastatic CRPC

Nonmetastatic castration-resistant prostate cancer is a more recently defined clinical state of prostate cancer, for which several approved drugs are now available.

William Kevin Kelly, DO

Nonmetastatic castration-resistant prostate cancer (M0CRPC) is a more recently defined clinical state of prostate cancer, for which several approved drugs are now available, explained William Kevin Kelly, DO, in a presentation during the 13th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.

In February 2018, apalutamide (Erleada) was the first antiandrogen to receive regulatory approval for use in in this setting, based on data from the phase III SPARTAN trial. In the trial, patients with M0CRPC and a prostate-specific antigen (PSA) doubling time of ≤10 months were randomized 2:1 to receive either 240 mg of apalutamide daily plus androgen deprivation therapy (ADT) or placebo/ADT. Metastasis-free survival (MFS), now a recognized end point by the FDA, served as the primary end point of the trial, said Kelly, professor of medical oncology and urology at Thomas Jefferson University, and director of the Division of the Solid Tumor Oncology at Sidney Kimmel Cancer Center. The results showed a significant improvement in MFS with apalutamide versus placebo (HR, 0.28; 95% CI, 0.23-0.35; P <.001).1

Similarly, in the phase III PROSPER trial, men with M0CRPC and a PSA doubling time of ≤10 months were randomized 2:1 to a next-generation antiandrogen, in this case 160 mg of enzalutamide (Xtandi) daily, plus ADT or placebo/ADT. Men who received enzalutamide experienced a significant reduction in the risk of metastasis or death versus those who were given placebo (HR, 0.29; 95% CI, 0.24-0.35; P <.001).2 In light of these data, in July 2018, the FDA approved the drug for use in this setting.

In the phase III ARAMIS trial, investigators evaluated 600 mg of darolutamide (Nubeqa) twice daily plus ADT versus placebo/ADT in patients with M0CRPC. The results demonstrated a 59% reduction in the risk of metastasis versus placebo (HR, 0.41; 95% CI, 0.34-0.50; P <.001). Data from the trial served as the basis for the July 2019 approval of the agent for use in this indication. Additionally, key secondary end points of the trial, such as overall survival (OS), time to pain progression, time to first symptomatic skeletal event, and time to cytotoxic chemotherapy all favored darolutamide.3

“This suggests that treating these patients earlier may delay the natural history of the disease; that is the need for chemotherapy down the line” said Kelly.

Additionally, patients who received darolutamide plus ADT experienced comparable quality of life (QOL) versus those who received placebo, and less fatigue, cognitive problems, and muscle weakness compared with other antiandrogens.4

However, Kelly stressed that antiandrogens, as a class, require careful monitoring of “endocrine-like” toxicities such as fatigue, muscle weakness, and falls and fractures, as well as the potential for cardiovascular events, particularly outside the confines of a randomized clinical trial setting.

For example, data from a retrospective study showed that patients with preexisting cardiovascular diseases, which comprised 67% of the study population, were more likely to experience 6-month mortality after treatment with abiraterone or enzalutamide.5

“Enzalutamide, apalutamide, and darolutamide have shown clinical benefit and are very good therapies in M0CRPC,” said Kelly. “However, all these agents have the potential to lead to serious long-term adverse events, so a multidisciplinary approach is needed.”

Turning to combination strategies in metastatic CRPC, Kelly highlighted the phase III Alliance A031201 trial, which evaluated the combination of enzalutamide and abiraterone versus enzalutamide alone. According to data presented at the 2019 ASCO Annual Meeting, the combination did not show an improvement in OS versus enzalutamide alone in men with mCRPC (HR, 0.93; 95% CI, 0.80-1.08; P =.33).6

The phase III ERA223 trial also garnered significant interest in mCRPC, said Kelly. In the trial, patients were randomized to receive radium-223 dichloride (Xofigo) plus abiraterone acetate (Zytiga) and prednisone or placebo plus abiraterone/prednisone.7 However, in November 2017, the independent data monitoring committee advised unblinding the trial due to increased fractures and death in the radium-223 arm.8

The phase III PEACE trial was similarly designed in that patients with mCRPC were randomized to an antiandrogen—in this case, enzalutamide—plus radium-223 versus enzalutamide alone. Following an interim safety analysis, in April 2017, the trial was amended to require the addition of bone-protecting agents in both arms.9

“ESMO, National Comprehensive Cancer Network, American Urological Association, and Canadian Urological Association, have all recommended that patients with advanced prostate cancer go on bone-protecting agents such as zoledronic acid or denosumab (Xgeva), especially if they’re receiving radium-223,” said Kelly.

Regarding chemotherapy, Kelly stated that cabazitaxel (Jevtana) has enhanced antitumor effects versus docetaxel and has become the subject of investigation in several clinical trials in the metastatic setting. For example, in a phase II trial (NCT02218606), investigators evaluated the addition of cabazitaxel to abiraterone in patients with mCRPC. The results, which were presented at the 2020 Genitourinary Cancers Symposium, showed an improvement in radiographic progression-free survival (rPFS) and time to PSA progression,10 attesting to the additive benefits of chemotherapy and hormonal therapy in this setting.

Cabazitaxel has also shown benefit as a standalone therapy after patients with mCRPC have progressed on prior antiandrogen therapy. In the phase III CARD trial, patients who progressed within 12 months of receiving antiandrogen therapy before or after docetaxel were randomized to receive cabazitaxel or abiraterone or enzalutamide, depending on which antiandrogen they had previously received. The results demonstrated a significant benefit in rPFS (HR, 0.54; 95% CI, 0.40-0.73; P <.001) and OS (HR, 0.64; 95% CI, 0.46-0.89; P =.008) with cabazitaxel versus either antiandrogen alone.11 Moreover, health-related QOL data favored the use of cabazitaxel. Although the results represent a third-line standard of care, Kelly cautioned that the population of patients with mCRPC who experience rapid progression on antiandrogen therapy in the first-line setting is relatively narrow.

“Men with mCRPC have multiple treatment options,” said Kelly. “However, the optimal sequence of [single-agent] or combination therapy still needs to be further elucidated.”

In terms of developmental agents, Kelly called attention to androgen receptor coregulators, and specifically CCS-1477, which is a small molecule CBP/P300 inhibitor that has shown efficacy against common resistance mutations such as AR-V7 in preclinical models.


  1. Smith MR, Saad F, Chowdhury S, et al; the SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi: 10.1056/NEJMoa1715546
  2. Hussain M, Fizazi K, Saad F, et al; the PROSPER Investigators. Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2018;378(26):2465-2474. doi: 10.1056/NEJMoa1800536
  3. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Eng J Med. 2019;380(13):1235-1246. doi: 10.1056/NEJMoa1815671
  4. Fizazi K, Shore ND, Tammela T, et al. ARAMIS: efficacy and safety of darolutamide in nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2019;37(suppl 7; abstr 140). doi: 10.1200/JCO.2019.37.7_suppl.140.
  5. Lu-Yao G, Nikita N, Keith SW, et al. Mortality and hospitalization risk following oral androgen signaling inhibitors among men with advanced prostate cancer by pre-existing cardiovascular comorbidities. Eur Urol. 2020;77(2):158-166. doi: 10.1016/j.eururo.2019.07.031
  6. Morris MJ, Heller G, Bryce AH, et al. Alliance A031201: a phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/AAP) for metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(suppl 15; abstr 5008). doi: 10.1200/JCO.2019.37.15_suppl.5008
  7. Smith MR, Parker CC, Saad F, et al. ERA 223: a phase III trial of radium-223 (Ra-223) in combination with abiraterone acetate and prednisone/prednisolone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naïve (pts) with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2018;29(suppl 8; abstr LBA30):viii723. doi: 10.1093/annonc/mdy424.035
  8. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-419. doi: 10.1016/S1470-2045(18)30860-X
  9. Tombal BF, Loriot Y, Saad F, et al. Decreased fracture rate by mandating bone-protecting agents in EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis. J Clin Oncol. 2019;37(suppl 15; abstr 5007). doi: 10.1200/JCO.2019.37.15_suppl.5007
  10. Slovin SF, Knudsen KE, Halabi S, et al. Abiraterone acetate (AA) with or without cabazitaxel (CBZ) in treatment of chemotherapy naive metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(suppl 6; abstr 84). doi: 10.1200/JCO.2020.38.6_suppl.84
  11. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi: 10.1056/NEJMoa1911206