Editing Castrate-Resistant Prostate Cancer (section)

=== Non-metastatic CRPC[https://pubmed.ncbi.nlm.nih.gov/32907777/ §] ===

* First-generation androgen receptor antagonists (flutamide, bicalutamide, nilutamide) should be discontinued in patients already receiving these agents
* '''<span style="color:#ff0000">If PSADT'''
** '''<span style="color:#ff0000">≥ 10 months: observation or secondary hormonal treatments'''
** '''<span style="color:#ff0000">< 10 months (high-risk nmCRPC) AND estimated life expectancy > 5 years'''
*** '''<span style="color:#ff0000">First-line options (2):'''
***# '''<span style="color:#ff0000">Apalutamide'''
***# '''<span style="color:#ff0000">Enzalutamide'''
***# '''<span style="color:#ff0000">Darolutamide'''
**** All options should be with continuous ADT
**** Until 2018, there was no standard of care and no approved regimen for the nmCRPC state.
*** '''Second-line options in high-risk nmCRPC who are felt to be unsuitable or refuse approved therapies:'''
***# '''Observation'''
***# '''Use of first-generation androgen receptor antagonists may be attempted [if patient not previously on first-generation androgen receptor antagonist]'''
** PSADT < 10 months has been associated with worse outcomes and has been used in recent clinical trials as the definition for high-risk nmCRPC.

==== Randomized trials in non-metastatic CRPC ====
* '''All 3 trials:'''
*# '''Included patients with PSA doubling time ≤10 months'''
*# '''Primary outcome was metastasis-free survival'''
*#* Given the time required for maturation of OS data in such trials, MFS is now a commonly used surrogate endpoint defined as time from randomization to date of first evidence of recorded distant metastases or death, whichever occurred first.§
*# '''Found significantly improved overall (≈12 months) and metastasis-free survival (≈22 months)'''

===== Apalutamide =====
* '''See [[Hormonal Therapy|Hormonal Therapy Chapter Notes]]'''
*'''Particular attention should be paid to monitoring thyroid stimulating hormone (TSH) in individuals with known hypothyroidism given observed changes in thyroid function with apalutamide treatment'''

====== <span style="color:#ff00ff">SPARTAN ======
* Population: 1207 men with non-metastatic CRPC and PSA doubling time ≤10 months
* Randomized to apalutamide (240mg daily) or placebo
* Primary outcome: metastasis-free survival
* Results:
** Median follow-up: 52 months (2021 update)
** Metastasis-free survival significantly improved by 24 months in the apalutamide arm (40 months apalutamide vs. 16 months placebo (HR for metastasis or death, 0.28)
** Overall survival significantly improved by 14 months in the apalutamide arm (74 apalutamide vs. 60 months placebo, HR=0.78; 95% CI, 0.64 to 0.96; p=0.00002).
** Additionally, secondary endpoints including time to symptomatic progression (HR= 0.45, p<0.001) and time to metastasis (HR=0.27, p<0.001) were significantly longer in the apalutamide arm compared to placebo. Median progression-free survival was 40.5 months in the apalutamide group versus 14.7 months in the placebo group (HR=0.29; p<0.001).
** Overall, 10.6% of patients receiving apalutamide discontinued treatment due to adverse events compared to 7.0% of patients receiving placebo.
* [https://www.ncbi.nlm.nih.gov/pubmed/29420164 Smith, Matthew R., et al."Apalutamide treatment and metastasis-free survival in prostate cancer." New England Journal of Medicine 378.15 (2018): 1408-1418.]
* [https://pubmed.ncbi.nlm.nih.gov/32907777/ Smith, Matthew R., et al."Apalutamide and overall survival in prostate cancer." ''European urology'' 79.1 (2021): 150-158.]
===== Enzalutamide =====
* '''See [[Hormonal Therapy|Hormonal Therapy Chapter Notes]]'''

====== <span style="color:#ff00ff">PROSPER ======
* 1401 men with non-metastatic CRPC, PSA doubling time ≤10 months and PSA ≥2ng/mL
* Randomized to enzalutamide or placebo
* Primary outcome: metastasis-free survival
* Results:
** Median follow-up: 48 months (2020 update)
** Metastasis-free survival significantly improved by 22 months in the enzalutamide arm (37 enzalutamide vs. 15 months placebo (HR for metastasis or death, 0.28))
** Overall survival
*** Original 2018 publication: median OS was not reached in either group; however, there was a 20% reduction in the relative risk of death with enzalutamide compared to placebo.
*** Updated 2020 publication: significantly improved by 11 months (67 enzalutamide vs. 56 placebo, HR 0.73)
** Additionally, median time to PSA progression was approximately 33 months longer in patients receiving enzalutamide compared to those receiving placebo with a 93% reduction in the relative risk of PSA progression (37.2 months in the enzalutamide group compared to 3.9 months in the placebo group; HR= 0.07; P<0.001).
** Adverse events as the primary reason for treatment discontinuation occurred in 87 patients (9%) receiving enzalutamide compared to 28 (6%) receiving placebo. Deaths due to adverse events on trial irrespective of attribution occurred in 32 patients (3%) receiving enzalutamide and 3 patients (1%) receiving placebo. Adverse events noted to occur more frequently with enzalutamide included convulsion, hypertension, neutropenia, memory impairment disorders, and major cardiovascular events
* [https://www.ncbi.nlm.nih.gov/pubmed/29949494 Hussain, Maha, et al."Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 378.26 (2018): 2465-2474.]
* [https://pubmed.ncbi.nlm.nih.gov/32469184/ Sternberg, Cora N., et al. "Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer." ''New England Journal of Medicine'' (2020).]

===== Darolutamide =====
* '''See [[Hormonal Therapy|Hormonal Therapy Chapter Notes]]'''

====== <span style="color:#ff00ff">ARAMIS ======
* Population: 1509 men with nonmetastatic, CRPC and a PSA doubling time ≤10 months
* Randomized to darolutamide (600 mg [two 300-mg tablets] twice daily) vs. placebo
* Primary outcome: metastasis free survival
* Results:
** Metastasis-free survival improved by 22 months in the darolutamide arm (40 darolutamide vs. 18 months placebo)
** Overall survival significantly improved by 6% at 3 years in the darolutamide arm (83% darolutamide vs. 77% placebo)
** Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event.
* [https://www.ncbi.nlm.nih.gov/pubmed/30763142 Fizazi, Karim, et al."Darolutamide in nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 380.13 (2019): 1235-1246.]
* [https://pubmed.ncbi.nlm.nih.gov/32905676/ Fizazi, Karim, et al."Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide." ''New England Journal of Medicine'' 383.11 (2020): 1040-1049.]
'''Detection of metastases and imaging in untreated patients§'''
* '''Recommended screening for patients who progress on ADT without evidence of distant metastases:'''
** '''Modalities:'''
*** '''Bone scans''' for bone metastases
*** '''Imaging of the chest/abdomen/pelvis''' to monitor for lymph node and visceral metastases/progression
**** Imaging techniques most commonly used include abdominal/pelvic CT and chest X-ray.
**** The role of positron-emission tomography (PET) such as PSMA-PET are still unclear and the benefits unknown
** '''Frequency of imaging'''
*** '''PSADT <10 months or PSA >20: every 3–6 months'''
**** At high risk for developing metastases earlier
*** '''PSADT > 10 months: every 6–12 months'''
** If metastases are detected, patients should be treated based on metastatic CRPC recommendations.