Srinivas Evaluates 3 Novel Hormonal Agents for a Patient With nmCRPC

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Sandy Srinivas, MD of Stanford Health Care, discussed the treatment of a 57-year-old Black man with nonmetastatic castration-resistant prostate cancer over the course of 4 years.

Sandy Srinivas, MD

Sandy Srinivas, MD

Sandy Srinivas, MD, a genitourinary oncologist, professor of Medicine, and Clinical Research group leader, in the Urologic Program at Stanford Health Care, discussed the treatment of a 57-year-old Black man with nonmetastatic castration-resistant prostate cancer (nmCRPC) over the course of 4 years.

How would you go about treating a patient such as this?

SRINIVAS: The National Comprehensive Cancer Network [NCCN] guidelines for patients who have conventional imaging studies that [are] negative for metastasis [show] we need to continue androgen deprivation therapy [ADT] and [manage the disease] based on the PSA doubling time.1 If the PSA doubling time is greater than 10 months, [we can] either observe the patient or give them secondary hormonal therapy, such as bicalutamide. For patients with a PSA doubling time of less than 10 months, [the NCCN recommends, in no particular order, 3 category 1] drugs, [namely apalutamide (Erleada), darolutamide (Nubeqa), and enzalutamide (Xtandi)], all of which are androgen receptor inhibitors.

What do findings of the SPARTAN trial [NCT01946204] tell us about apalutamide treatment for nmCRPC?

The SPARTAN trial looked at [over 1000] patients who had nmCRPC and a PSA doubling time of less than 10 months. The study also included patients with small pelvic lymph node [lesions] that extended to less than 2 cm below the iliac bifurcation [ie, N1 disease].2,3 Patients were randomized to either apalutamide or placebo; both groups were maintained on ADT. The [primary] end point of this trial was metastasis-free survival [MFS]. This trial was interesting because [patients who progressed to metastatic disease were allowed to start on physician-directed therapy, including open-label abiraterone acetate (Zytiga) plus prednisone]. So the trial design [enabled evaluation of further progression or death as a secondary end point among] patients who progressed on apalutamide or placebo and then received open-label abiraterone.4

Diving deeper [into the characteristics of patients in the SPARTAN trial], we see that three-quarters of patients had a PSA doubling time of less than 6 months, and 90% of patients didn’t receive any bone-targeting agents,2 which is the standard of care [in this patient group]. We [usually] use bone-modifying agents for patients who have metastatic CRPC, and I suspect that the 10% of patients who [received bone-modifying drugs in this trial] got it for osteoporosis. Most of the trial patients had prior therapy, [of that group], three-quarters of them [had received] a first-generation antiandrogen, such as bicalutamide.

The results of [the SPARTAN trial showed] a nice separation of curves [for the primary MFS end point]. The apalutamide arm had a median MFS of 40 months compared [with 16 months in the] placebo arm.2 [The findings corresponded to] an impressive hazard ratio of 0.28, which was statistically significant. [An analysis of trial follow-up, published] in 2020, showed that apalutamide improved OS [overall survival] compared with placebo.4 [This finding is not] surprising given that these novel hormonal agents, not apalutamide [per se], but other agents, have been shown to improve OS.

What adverse events (AEs) are associated with apalutamide?

[In general, novel hormonal agents are associated] with fatigue, [and in the SPARTAN trial, fatigue was more common in the apalutamide arm compared with the placebo arm].4 About one-third of patients in the apalutamide arm had hypertension, [including about 16% of patients who had] hypertension of grade 3 or 4. Diarrhea [was also more common in the apalutamide arm compared with the placebo arm], but falls, fatigue, and hypertension [are the most important AEs associated with apalutamide].5

One AE that is unique to apalutamide is rash, and we need to [counsel] our patients about this. About a quarter of patients [on apalutamide] get a rash, including about 5% [of patients who have a rash of] grade 3 or higher. The rash is usually macular or maculopapular, and onset usually occurs during the second and third month [of treatment]. The rash usually resolves [without systemic treatment], [but a] small fraction of patients require systemic corticosteroids. The rash reoccurs in about half of patients who are rechallenged [after suspending apalutamide treatment], results in dose interruption in one-third of patients, and [leads to] discontinuation of the drug in about 10% of patients.5

What do findings of the PROSPER trial tell us about enzalutamide treatment for nmCRPC?

Enzalutamide has been in [the prostate cancer] armamentarium for more than a decade. The PROSPER trial [NCT02003924], which has a design similar to that of the SPARTAN trial, [evaluated enzalutamide for treatment of nmCRPC].6,7 The trial enrolled 1400 patients who were nonmetastatic based on conventional imaging, had a PSA of greater than 2, [and had] a PSA doubling time of less than 10 months. Patients were randomized to receive either enzalutamide or placebo, and the trial’s primary end point was MFS. Patient characteristics [in the PROSPER trial] were similar to [those of] the SPARTAN trial. Three-quarters [of PROSPER trial patients] had a PSA doubling time of less than 6 months; the median PSA doubling time was [less than 4 months in] both arms of the study.7

The PROSPER trial evaluated MFS as the primary end point [and OS as a secondary end point],6,7 as was done in the SPARTAN trial. The median MFS was 22 months longer [among patients who received] enzalutamide compared with placebo, [corresponding to] a 71% [lower] risk of radiographic progression.7 At 48 months of follow-up, the enzalutamide arm had significantly better OS than the placebo arm [median survival in months, 67.0 vs 56.3; HR, 0.73].6 So we can now tell patients who are going on [enzalutamide] that the median OS is greater than 5 years.

What AEs are associated with enzalutamide?

Similar to apalutamide, [enzalutamide is associated with] hypertension of grade 3 or greater in about 5% of patients.7 Asthenia occurred in 1% [of patients who received enzalutamide and was more common in the enzalutamide arm compared with the placebo arm].

What do findings of the ARAMIS trial tell us about darolutamide treatment for nmCRPC?

The ARAMIS trial [(NCT02200614) evaluated one of the more recent novel hormonal therapies], darolutamide [Nubeqa].8,9 The trial enrolled close to 1500 patients who had a PSA doubling time of less than 10 months. Patients were randomized to darolutamide [or placebo]. Darolutamide, [unlike] apalutamide and enzalutamide [is taken twice daily]. The trial’s end points were MFS and OS, [respectively], as they were in the SPARTAN and PROSPER trials. Patient characteristics in the ARAMIS trial were also similar [to those of the other trials]; 70% of patients had a PSA doubling time of less than 6 months, and most had not received a bone-[targeting] drug,8 as is appropriate for this group of patients.

[ARAMIS] is the third trial showing that novel hormonal therapy improves MFS. Median MFS was 40 months [in the darolutamide arm], compared with 18 months in the placebo arm, [corresponding] to approximately a 60% reduction in the risk of metastases.8 [Darolutamide also significantly improved OS compared with placebo (HR, 0.69)].9 So all 3 drugs improve MFS and OS [in patients with nmCRPC].

What AEs are associated with darolutamide?

In the [ARAMIS trial], [6.6% of patients in the darolutamide arm experienced] hypertension, about 16% of patients experienced fatigue, [and about 4% of patients experienced falls].8 [But these and other AEs occurred at a similar frequency] in the darolutamide arm and placebo arm.

How do novel hormonal therapies for treatment of nmCRPC compare with one another?

Apalutamide, enzalutamide, and darolutamide [are all associated with similar improvements in MFS (range of HR for MFS, 0.28-0.41) and in OS (range of HR for OS, 0.69-0.78)].10

It’s difficult to compare these 3 drugs side-by-side, [in terms of AEs], but we tend to do that when we have similar drugs in the same space. Fatigue [seems to be more of concern with] enzalutamide [and apalutamide, occurring in about] a third of patients. Hypertension [also appears to occur more often with] both apalutamide and enzalutamide. Falls and fractures [occur less often] with darolutamide [than with the other 2 drugs]. People speculate [that this] may be because of darolutamide’s lipid-binding affinity, [which may result in] less central nervous system penetration for darolutamide compared with the other 2 drugs.

How will the use of conventional imaging to evaluate metastases fit into the paradigm of nmCRPC management in the future?

I think 18F-DCFPyL prostate-specific membrane [PSMA] PET scan is likely to become available to all of us by the end of the year. If we were to do [PSMA PET imaging of patients who are nonmetastatic by conventional imaging], maybe the nonmetastatic space would disappear as [many these patients would have] low-volume metastatic disease. In [patients with low-volume metastatic disease], we wouldn’t even [consider] PSA doubling time, rather we would just put them on a [novel hormonal agent]. [Thus far], we have had access to PSMA [PET imaging primarily] through research groups. However, I’ve been at meetings outside of the United States, where PSMA PET scans [are widely available], and [our colleagues have] just laughed at us; they have said [that] nmCRPC [no longer] exists because of PSMA PET imaging; patients have either oligometastatic disease or more [extensive] disease and, [therefore], automatically go on one of these [novel hormonal] drugs.

What is your takeaway from these trials?

These patients are [usually] asymptomatic with no evidence of metastases, so we have to weigh the remarkable [benefits of improved] MFS and OS [against the risk of] getting these AEs.

Overall, the conclusion [that we draw from these] 3 large trials is that early [treatment with novel hormonal therapies] results in meaningful improvements in MFS and OS for patients with nmCRPC. We now have 3 [novel hormonal] drugs approved for nmCRPC: Apalutamide, darolutamide, and enzalutamide, [which are] somewhat distinct from one another in their safety profiles.


  1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2021. Accessed August 2, 2021.
  2. Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546
  3. Small EJ, Saad F, Chowdhury S, et al. Apalutamide and overall survival in nonmetastatic castration-resistant prostate cancer. Ann Oncol. 2019;30(11):1813-1820. doi:10.1093/annonc/mdz397
  4. Small EJ, Saad F, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). J Clin Oncol. 2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516
  5. Erleada. Prescribing information. Janssen; 2018. Accessed May 7, 2021.
  6. Sternberg CN, Fizazi K, Saad F, et al; PROSPER Investigators. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892
  7. Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36(suppl 6):3. doi:10.1200/JCO.2018.36.6_suppl.3
  8. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671
  9. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. N Engl J Med. 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342
  10. Gupta R, Sheng IY, Barata PC, Garcia JA. Non-metastatic castration-resistant prostate cancer: current status and future directions. Expert Rev Anticancer Ther. 2020;20(6):513-522. doi:10.1080/14737140.2020.1772759
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