Primary analysis of STARTAR: A phase 2 salvage trial of androgen receptor (AR) inhibition with androgen deprivation therapy (ADT) and apalutamide with radiation therapy (RT) followed by docetaxel in men with PSA recurrent prostate cancer (PC) after radical prostatectomy (RP).

5016 Background: ADT with salvage RT improves survival for men with PSA recurrence after RP. For high risk PSA recurrence, current standard ADT duration is up to 2 years with RT; shortening but intensifying systemic therapy may improve outcomes. The STREAM trial showed 6 mo enzalutamide with ADT/RT had 3-year progression free survival (PFS) of 53% in a high risk population, including lymph node (LN) positive. Given docetaxel (doce) improves survival in mHSPC, we evaluated the combination of salvage RT, ADT/apalutamide (apa) and doce in this setting. Methods: STARTAR is a multicenter investigator initiated phase 2 trial for salvage treatment of PSA recurrent PC post-RP, conducted in the DOD Prostate Cancer Clinical Trials Consortium. Key inclusion criteria included Gleason 7 with T3/positive margin/N1 or Gleason 8-10 PC, PSA relapse <4 years post-RP (inclusion PSA 0.2-4 ng/mL), and <4 positive LNs, standard imaging negative. Patients (pts) received ADT with apa for 9 months, RT (66-74 Gy to the prostate bed +/- pelvic LNs over 6-8 wks) starting wk 8, and then completed 6 cycles of concurrent doce 75mg/m2 q3 wks. The primary endpoint was 36 month PFS, defined as composite of freedom from PSA>0.2 + post-RT nadir with subsequent rise, clinical progression, other therapy start, or death, among pts with testosterone (T) recovery (>100ng/dL). Kaplan-Meier estimates for PFS were used to determine landmark 24 mo and 36 mo rates and compared to PFS rates from prior trials using a binomial test. Results: From 3/2018 to 2/2020, 39 pts were enrolled. As of 12/2022 data cutoff, median follow up was 36 months. Baseline characteristics: Gleason 7 in 54%; Gleason 8-10 in 46%; 23% LN positive; median PSA 0.58 ng/mL (range 0.21-3.40), and median time from RP 7.6 mo (range 2-98). 37 pts (95%) and 23 pts (62%) completed at least 1 and all 6 cycles doce, respectively. All pts achieved undetectable PSA nadirs. At 24mo and 36mo, PFS rates were 84% and 72%, respectively, with 95% pts recovering T at 36 mo. Compared to 40% historical PFS and 53% STREAM PFS rates, the 72% 36-mo PFS rate was statistically significantly improved (p<0.001 and p=0.013, respectively). Common any-grade adverse events (AEs) included 98% hot flashes, 88% fatigue, 77% alopecia, 57% dysgeusia, and 53% rash (28% grade 1; 15% grade 2, 10% grade 3), with 5% febrile neutropenia. Conclusions: In this first phase 2 trial of ADT, apa, salvage RT, and 6 cycles of doce for high risk PSA recurrence, the primary endpoint 3-year PFS rate improved to 72%, indicating durable remissions beyond historic controls. Intensifying systemic treatments in the non-metastatic hormone sensitive but high risk salvage setting may be feasible and efficacious, with fewer pts experiencing cancer progression over time. Clinical trial information: NCT03311555 .