Background: The CHAARTED study showed that adding docetaxel (Doc) to androgen deprivation therapy (ADT) in men initiating treatment for mHSPC prolongs survival, particularly in high-volume disease. Androgens are known drivers of both mHSPC and metastatic castration resistant prostate cancer (mCRPC). Lower nadir testosterone (T) is associated with better outcomes in men treated with ADT for biochemical relapse, while higher androgens at mCRPC are associated with better prognosis and increased benefit from abiraterone. Methods: We evaluated the association of serum steroid levels at 24 weeks with overall survival (OS) and time to CRPC (TTCRPC) in 588 men with available samples from the CHAARTED study. Steroid levels were measured using mass spectrometry. Results: The median (med) T level at 24 weeks was 8 ng/dl and did not differ in the ADT alone vs ADT plus Doc arms. Achieving a nadir T below 20ng/dl was not associated with OS or TTCRPC in either arm. In the ADT arm pregnenolone (preg) and T levels > med associated with longer OS (HR 0.62; p = 0.017 for both), as did AED and T levels in the highest 3 quartiles (HR 0.61 p = 0.025; HR 0.67, p = 0.069). OS did not differ by steroid levels in high volume patients. In low volume patients OS was longer for those in the highest 3 quartiles of progesterone (HR 0.52 p = 0.10), DHEA (HR 0.41 p = 0.03), AED (HR 0.39 p = 0.027), T (HR 0.36 p = 0.006) and estrone (HR 0.52 p = 0.10). In the ADT + Doc arm estrone levels < med associated with longer OS (HR 0.68; p = 0.05) as did AED levels in the lowest quartile (HR 0.67 p = 0.063). Estrone levels < med also associated with longer TTCRPC (HR 0.75; p = 0.097), as did AED and estrone in the lowest quartiles (HR 0.60 p = 0.009; HR 0.65 p = 0.05). There was no difference in OS in either the high or low volume patients based on steroid levels. In high volume patients, OS was particularly longer with ADT + Doc vs ADT in those with estradiol or estrone levels in the highest 3 quartiles (p = 0.018; 0.029) and in those with pregnenolone, AED, T, and DHT in the lowest quartile (p = 0.046, p = 0.018, p = 0.095; p = 0.066). In low volume patients, OS was also longer with ADT + Doc vs ADT in those with T levels in the lowest quartile (p = 0.055), but shorter with ADT + Doc vs ADT among those with progesterone, DHEA, AED, T and estrone levels in the top 3 quartiles (p = 0.095; p = 0.071; p = 0.091; p = 0.031; and p = 0.031). Conclusions: In men with mHNPC treated with ADT alone higher steroid levels at 24 weeks associate with longer OS (primarily in low volume disease), consistent with findings in the mCRPC setting (Mostaghel et al CCR 2021). In men treated with ADT + Doc lower levels of estrone and AED associate with longer OS and TTCRPC. The findings overall highlight that serum steroid levels associate with different patient outcomes depending on whether treated with ADT alone or with Doc, as well as the prognostic variable of high vs low volume disease. Clinical trial information: NCT00309985.