Short-term Androgen Deprivation Research Articles

Short-Term Androgen Deprivation Therapy and High-Dose Radiotherapy in Intermediate- and High-Risk Localized Prostate Cancer: Results from the GETUG 14 Randomized Phase III Trial

Short-Term Androgen Deprivation Therapy and High-Dose Radiotherapy in Intermediate- and High-Risk Localized Prostate Cancer: Results from the GETUG 14 Randomized Phase III Trial

Effect of castration method on porcine skeletal muscle fiber traits and transcriptome profiles

This study examined the effects of immunocastration and surgical castration on the histomorphometric and transcriptome traits of the porcine skeletal muscle. We hypothesized that the differences in duration of androgen deprivation resulting from different castration methods influence skeletal muscle biology in a muscle-specific manner. This was tested by analyzing samples of m. longissimus dorsi (LD) and m. semispinalis capitis (SSC) from immunocastrated (IC; n = 12), entire male (EM; n = 12), and surgically castrated (SC; n = 12) pigs using enzyme/immunohistochemical classification and histomorphometric analysis of myofibers, quantitative PCR, and RNA sequencing. The results confirmed the distinctive histomorphometric profiles of LD and SSC and the castration method related muscle-specific effects at the histomorphometric and transcriptome levels. Long-term androgen deficiency (surgical castration) significantly reduced the proportion of fast-twitch type IIa myofibers in LD (P<0.05), whereas short-term androgen deprivation (immunocastration) reduced the cross-sectional area of oxidative type I myofibers in SSC (P<0.05). At the transcriptional level, glycolytic LD adapted to long- and short-term androgen deprivation by upregulating genes controlling myoblast proliferation and differentiation to maintain fiber size. In contrast, increased protein degradation through the ubiquitin ligase-mediated atrophy pathway (significantly increased TRIM63 and FBXO32 expression; P<0.05) could underly reduced cross-sectional area of type I myofibers in the oxidative SSC in IC. Potential candidate genes (HK2, ARID5B, SERPINE1, and SCD) linked to specific metabolic profiles and meat quality traits were also identified in IC, providing a foundation for studying the effects of immunocastration on skeletal muscle fiber and carcass/meat quality traits.

Abstract CT108: Phase I data from TENDU101, a first-in-human trial of a novel synthetic peptide conjugate cancer vaccine platform assessed in recurrent prostate cancer patients before salvage treatment

Abstract Synthetic peptides are explored in the clinic in cancer vaccine development for the purpose of inducing tumor-directed T cell responses. Their immunogenicity is dependent on the chosen adjuvant and target organ exposure (lymphoid organs). To improve peptide immunogenicity, we have developed a technology enabling cross-linking of endogenous, pre-existing circulating antibodies (Abs) by employing a three-dimensional chemistry design. Multiple identical tetanus toxin-derived B cell epitopes (MTTEs) are conjugated to synthetically made antigenic tumor peptides intended to induce T cell responses. Here we report the first clinical safety assessment of the vaccine platform in the trial TENDU101 (NCT04701021). The cancer vaccine candidate (TENDU) was designed to include longer synthetic peptides harboring prostate cancer derived epitopes (CD4 and CD8) from PAP and PSMA. The study was a 3+3 design and doses were 40, 400 and 960 microgram in patients with documented recurrent disease after radical prostatectomy. A tetanus toxoid (TTd) containing vaccine boost was followed by TENDU vaccination via subcutaneous injection in the abdomen (4 doses in total with a 2 week interval) in n=9 patients (gr 1, 2, 3.1). For group 3.2 (n=3) TENDU vaccination was administrated in the same arm as the TTd vaccination. Primary objective was safety and secondary objective assessment of immune responses and preliminary anti-tumor responses. A total of 52 adverse events (AEs) were reported, most mild and deemed unrelated to vaccination. Six treatment-related AEs were reported of which 50% were mild transient injection site reactions in a single patient (gr 3.1), and three events of increases in lipase levels in two patients (gr 2). No serious AEs was reported. T cell responses pre/post TENDU were assessed in a total of six patients of which five patients displayed increased response against vaccine-related CD8 and CD4 epitopes (ELISpot). The three patients with the greatest increase in T cell responses were found to display the highest anti-MTTE IgG responses. A trend towards decrease in circulating tumor cells from screening to the end of treatment visit was observed in the patients with the highest levels of anti-MTTE IgGs post TENDU vaccination. There were no trends for decrease in PSA and/or PAP at the end of treatment and follow-up measurements were affected by initiation of radiation and short-term androgen deprivation. The administration of TTd and TENDU to the same anatomical location although spaced in time appeared to negatively influence immune responses to TTd and TENDU. In conclusion, the novel synthetic peptide conjugate vaccine conjugate was found safe with no serious AEs reported and a positive correlation between anti-MTTE and T cell responses was noted in patients when TENDU was administrated in the abdomen. Citation Format: Wolfgang Lilleby, Anna Bergqvist, Aikaterini Nasi, Wenche Rasch, Sara Mangsbo. Phase I data from TENDU101, a first-in-human trial of a novel synthetic peptide conjugate cancer vaccine platform assessed in recurrent prostate cancer patients before salvage treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT108.

The effect of dose-escalation radiotherapy with simultaneous-integrated-boost on the use of short-term androgen deprivation therapy in patients with intermediate risk prostate cancer.

To compare the biochemical failure (FFBF) and prostate cancer specific survival (PCSS) rates of patients with intermediate-risk prostate cancer (IR-PC) who were treated with 6 months of androgen deprivation therapy (ADT) with 78 Gy to the prostate, those treated with ADT and focal boost (FB) of 86 Gy to intraprostatic lesion (IPL) using the simultaneous-integrated boost (SIB) technique, and those treated with SIB alone. A retrospective analysis of 320 IR-PC patients treated between January 2012 and April 2021 was performed. Patients were divided into three groups based on their treatment arm: 78 + ADT (109 patients, 34.1%), 78/86 (102 patients, 31.8%), and 78/86 + ADT. Univariable and multivariable analyses were used to determine prognostic factors for FFBF and PCSS. Median follow-up was 8.8 years. The 8-year FFBF and PCSS rates were 88.6% and 99.0%. Patients who received ADT had significantly higher pretreatment PSA levels and clinical tumor stage. Disease progression occurred in 45 patients (7.3%) at a median of 41.9 months after definitive radiotherapy (RT). Younger age, positive core biopsy (PCB) ≥ 50%, and the absence of ADT were all independent predictors of poor FFBF in multivariate analysis, whereas patients with PCB < 50% who were also given ADT had better PCSS. Patients treated with 78/86 Gy alone had worse FFBF than those treated with 78 Gy and ADT (Hazard ratio [HR] = 3.39 [95% CI = 1.46-7.88]; p = 0.005), as well as than those treated with 78/86 Gy and ADT (HR = 3.21 [95% CI = 1.23-6.46]; p = 0.009). However, FB to IPL has no effect on PCSS in multivariable analysis. There was no significant difference between treatment groups in terms of acute and late Grade ≥2 genitourinary or gastrointestinal toxicity. Our findings demonstrated that patients who received 78/86 alone did worse than patients who received ADT with either 78 or 78/86 Gy. However, because IR-PC patients are so diverse, additional prospective trials are needed to validate our findings.

99mTcPSMA-radioguided surgery in oligorecurrent prostate cancer: the randomised TRACE-II trial.

To investigate whether combination treatment of prostate-specific membrane antigen (PSMA)-based radioguided surgery (RGS) with short-term androgen deprivation therapy (ADT) improves oncological outcomes in men with oligorecurrent prostate cancer (PCa) as compared to treatment with short-term ADT only. The TRACE-II study is an investigator-initiated, prospective, randomised controlled clinical trial. Patients (aged >18 years) with hormone-sensitive recurrent PCa after radical prostatectomy or radiotherapy (brachytherapy or external beam radiotherapy), with involvement of ≤2 lymph nodes or local oligorecurrent disease within the pelvis as determined by PSMA positron emission tomography (PET)/computed tomography (CT) are randomly assigned in a 1:1 ratio between 6-month ADT (Arm A) or 6-month ADT plus RGS (Arm B). The primary objective is to determine clinical progression-free survival (CPFS) at 24 months. After PSMA-RGS, CPFS is defined as the time between the start of treatment and the appearance of a re-recurrence (any N1 or M1) as suggested by PSMA-PET/CT or symptoms related to progressive PCa, or death from any cause. The secondary objectives include metastasis-free survival at 2, 5 and 10 years, biochemical progression-free survival at 2 years, and patient-reported quality of life at 2, 5 and 10 years. A total of 60 patients, 30 per arm, will be included. The trial is powered (80%) to detect at least a 30% absolute difference in CPFS between the two study arms in the period 2 years after randomisation. We expect to enrol the required participants in 3 years. The study has an expected duration of 5 years in total. Combining RGS with short-term ADT might be oncologically beneficial for patients with oligorecurrent PCa. In this first randomised controlled trial, we are investigating the potential oncological benefits of this combined treatment, while also focusing on maintaining quality of life.

Clinical Outcomes of Prostate SBRT Using Non-adaptive MR-Guided Radiotherapy.

Stereotactic body radiotherapy (SBRT) is widely used for localized prostate cancer and implementation of MR-guided radiotherapy has the advantage of tighter margins and improved sparing of organs at risk. Here we evaluate outcomes and time required to treat using non-adaptive MR-guided SBRT (MRgSBRT) for localized prostate cancer at our institution. From 9/2019 to 11/2021 we conducted a retrospective review of 80 consecutive patients who were treated with MRgSBRT to the prostate. Patients included low (LR) (5%), favorable intermediate (FIR) (40%), unfavorable intermediate (UIR) (49%), and high risk (HR) (6%). Short-term androgen deprivation therapy was used in 32% of patients. Target volumes included prostate gland and proximal seminal vesicles with an isotropic 3mm margin. Treatment was prescribed to 36.25 Gy in 5 fractions every other day with urethral sparing. Hydrogel spacer was used in 18% of patients. Time on the linac was recorded as beam on time (BOT) plus total treatment time (TTT) including gating. Analyzed outcomes included PSA response and patient reported outcomes scored by the American Urological Association (AUA) questionnaire and toxicity per CTCAE v5. General linear regression model was used to analyze factors affecting PSA and AUA in longitudinal follow up, and chi-square test was used to assess factors affecting toxicity. Median follow up was 19.3months (3.8 - 36.6). Median BOT was 4.6min (2.6 - 7.2) with a median TTT of 11 min (7.6 - 15.8). Pre-treatment vs post-RT median PSA was 6.36 (2.20 - 19.6) vs 0.85 (0.19 - 3.6), respectively (P < 0.001). PSA decrease differed significantly when patients were stratified by risk category, favoring LR/FIR vs UIF/HR group (P = 0.019). Four (5%) patients experienced a biochemical failure (BCF), with a median time to BCF of 20.4months (7.9 - 34.5). Median biochemical failure free survival (BCFFS) was not reached, with 2-yr and 4-yr BCFFS of 97.1% and 72.1%, respectively. Patients with LR/FIR disease had 100% 2-yr and 4-yr BCFFS, whereas patients with UIF/HR had 95% and 41% 2-yr and 4-yr BCFFS (P = 0.05). Mean pre-treatment AUA was 7.3 (1 - 25) vs 11.3 (1 - 26) at first follow-up; however, AUA normalized to baseline over time. Urethral Dmax ≥35Gy trended to lower AUA score at all follow-ups (P = 0.07). Forty-one (51%) patients reported grade 1-2 genitourinary toxicities at the 1 month follow up. Grade 3 toxicity (proctitis) was noted in 1 patient. There was no decrease in any grade rectal toxicity with use of hydrogel spacer (3 vs 6, P = 0.2). No grade ≥4 toxicities was observed. MRgSBRT has the potential for treatment adaptation but this comes at the cost of increased resource utilization. Our experience with non-adaptive MRgSBRT of the prostate highlights its short treatment times as well as efficacy with good PSA control and low toxicity profile.

Changes in bone and mineral homeostasis after short-term androgen deprivation therapy with or without androgen receptor signalling inhibitor – substudy of a single-centre, double blind, randomised, placebo-controlled phase 2 trial

Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) have an increased fracture risk. Exploring biomarkers for early bone loss detection is of great interest. Pre-planned substudy of the ARNEO-trial (NCT03080116): a double blind, randomised, placebo-controlled phase 2 trial performed in high-risk PCa patients without bone metastases between March 2019 and April 2021. Patients were 1:1 randomised to treatment with gonadotropin-releasing hormone antagonist (degarelix)+androgen receptor signalling inhibitor (ARSI; apalutamide) versus degarelix+matching placebo for 12 weeks prior to prostatectomy. Before and following ADT, serum and 24-h urinary samples were collected. Primary endpoints were changes in calcium-phosphate homeostasis and bone biomarkers. Of the 89 randomised patients, 43 in the degarelix+apalutamide and 44 patients in the degarelix+placebo group were included in this substudy. Serum corrected calcium levels increased similarly in both treatment arms (mean difference+0.04mmol/L, 95% confidence interval, 0.02; 0.06), and parathyroid hormone and 1,25-dihydroxyvitamin D3 levels decreased. Bone resorption markers increased, and stable calcium isotope ratios reflecting net bone mineral balance decreased in serum and urine similarly in both groups. This exploratory substudy suggests that 12 weeks of ADT in non-metastatic PCa patients results in early bone loss. Additional treatment with ARSI does not seem to more negatively influence bone loss in the early phase. Future studies should address if these early biomarkers are able to predict fracture risk, and can be implemented in clinical practice for follow-up of bone health in PCa patients under ADT. Research Foundation Flanders; KU Leuven; University-Hospitals-Leuven.

Effects of Radiation Doses on Clinical Recurrence in Patients with Biochemically Recurrent Prostate Cancer after Prostatectomy.

Salvage radiotherapy (SRT) to the prostate bed is the only curative treatment for patients with biochemical recurrence (BCR) after radical prostatectomy (RP). Although several systematic reviews indicated that a dose escalation in the range of 60-70 Gy improved biochemical control, the effects of radiation doses on clinical relapse after SRT remain unclear. Our aim was to investigate the relationship between radiation doses and clinical relapse-free survival (cRFS) after SRT. We identified 295 eligible patients receiving SRT for biochemically recurrent prostate cancer after RP between 2005 and 2018 at 15 institutions. Sixteen patients (5%) received short-term (< 6 months) androgen deprivation therapy (ADT) following RP and/or concurrently with SRT. SRT was delivered to the prostate and seminal vesicle bed using photon beams at a median (range) dose of 66 Gy (61-85) in 1.8-3.0 Gy fractions. The primary outcome was cRFS. Clinical relapse was identified on radiological imaging and/or biopsy and included local recurrence, lymph node metastasis, and distant metastasis. In all analyses, doses were recalculated as an equivalent dose in 2-Gy fractions (EQD2) with α/β = 1.5 Gy. Clinical RFS between the EQD2 ≥ 66 Gy (n = 229) and EQD2 < 66 Gy (n = 66) groups were compared using the Log-rank test, followed by univariate and multivariate Cox regression analyses and a subgroup analysis. The median follow-up duration was 73 months. Among patients with BCR (n = 119), 79 of 96 (82%) in the EQD2 ≥ 66 Gy group and 21 of 23 (91%) in the EQD2 < 66 Gy group received second salvage ADT (p = 0.36). Among all patients (n = 295), clinical relapse was identified in 22 (7%) patients after SRT. Six-year biochemical relapse-free survival (bRFS), cRFS, cancer-specific survival (CSS), and overall survival (OS) rates were 58%, 93%, 98%, and 94%, respectively. Six-year cRFS rates were 94% (95% confidence interval [CI], 90-97) in the EQD2 ≥ 66 Gy group and 87% (95% CI, 75-93) in the EQD2 < 66 Gy group (p = 0.020). The multivariate analysis revealed that EQD2 < 66 Gy, Gleason score ≥ 8, seminal vesicle involvement, and PSA at BCR ≥ 0.5 ng/ml correlated with clinical relapse (p = 0.0016, 0.014, 0.011, and 0.027, respectively). The subgroup analysis showed the consistent benefit of EQD2 ≥ 66 Gy in patients across most subgroups including PSA at BCR after RP, extracapsular extension, and age at SRT. This large multi-institutional observational study demonstrated that a higher SRT dose (EQD2 ≥ 66 Gy) resulted in superior cRFS. The present result supports the dose recommendations in the 2023 National Comprehensive Cancer Network guidelines (64-72 Gy) even in terms of clinical relapse. Prospective trial is warranted to investigate an upper threshold for optimal SRT dose.

Biochemical Failure in Intermediate Risk Prostate Cancer: Then What? Long-Term Data from a Phase III Trial.

Aiming to determine long-term outcomes post biochemical failure (BF) in patients (pts) treated for intermediate-risk prostate cancer, we analyzed data from our prospective randomized trial (PCS III). From December 2000 to September 2010, 600 pts with intermediate risk prostate cancer (IRPC) received prostate radiotherapy (RT) with or without short-term (6 months) androgen deprivation therapy (ADT) on a Phase III trial. We report death rate from prostate cancer, rate and timing of BF plus the final clinical outcome of patients, alive or dead, with BF. Chi-squared test was used to compare BF and prostate cancer progression (PCP) rates between patient with or without ADT. Median age at randomization was 71 years (IQR 66-74). With a median follow-up (FU) of 13.5 years (IQR 11.2-17.0), 74.5% (447/600) were free from BF at last FU. Of these, 211 died, 79 stopped FU after 10 years, 9 were lost to FU, 6 withdrew from the study and 142 are still on FU, at a median follow-up of 13.2 years (IQR = 10.9 - 16.2). A total of 153 pts (25.5%) developed BF at a median time of 6.5 years post-randomization. Among BF pts, 82/153 died: we documented 32 deaths from prostate cancer (DPC) at a median time of 6 years post-BF and 50/153 pts died from other causes at a median time of 4.7 years from BF. 48/153 BF pts continue on FU: 34 show no clinical evidence of cancer, 9 developed a second cancer and 5 show clinical evidence of PCP. 20/153 pts stopped FU after 10 years: 3 of them with PCP. 3/153 pts were lost to FU: 1 after 3 years with prostate bone metastasis and 2 after 13 years of FU. In the first 5 years post-randomization, 47 pts (7.8%) presented BF with 1 (0.2%) DPC; between 6 and 10 years, there were another 84 (14%) BFs and 11 (1.8%) DPC. Finally, after 10 years and beyond, we recorded an additional 22 (3.7%) BFs and 20 (3.3%) DPC. The rate of patients who received ADT was significantly lower in patients with BF (74/153 = 48.4%) compared to patients without BF (324/447 = 72.5%), p<0.001. The rate of patients who received ADT was also significantly lower in patients with PCP (19/48 = 39.6%) compared to patients without PCP (379/552 = 68.7%), p<0.001. In our trial for intermediate-risk prostate cancer, a quarter of the pts developed BF. Most of the BFs occurred between 5- and 10- year post-randomization. Deaths due to prostate cancer post-BF occurred at a median time of 6 years, justifying the need for long-term FU. BF and PCP were significantly higher in patients not receiving ADT.

Association of Prostate Specific Antigen Kinetics after Testosterone Recovery with Subsequent Recurrence: Secondary Analysis of a Phase III Randomized Controlled Trial.

The combination of short-term androgen deprivation therapy (ST-ADT) with prostate radiotherapy (RT) is a standard of care for patients with localized prostate cancer (LPCa). After cessation of ST-ADT, it takes about 8 to 10 months for the testosterone (T) to recover to supracastrate levels, which could drive changes in PSA kinetics. It largely remains unknown whether early changes in PSA kinetics after T recovery could predict for subsequent biochemical relapse. We performed a secondary analysis of a phase III randomized controlled trial in which patients with newly diagnosed LPCa with Gleason score £7, clinical stage T1b to T3a, and PSA <30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate RT (76 Gy in 38 fractions over 7.5 weeks) or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate RT. Clinical assessment and laboratory investigations were repeated 1 month after completion of ADT, every 4 months for the first 2 years, every 6 months for the next 3 years, and annually thereafter. We calculated the PSA doubling time (PSADT) based on PSA values up to 18 months after recovery of T to a supracastrate level (>50 ng/dL). Patients with ³3 PSA measurements after T recovery to supracastrate level were included in this analysis. Fine and Gray cumulative incidence of biochemical recurrence (BCR) was calculated in patients with PSADT at or above median versus below median. Deaths were considered as competing events. All endpoints were calculated from the time of T recovery to supracastrate level. Subdistribution hazard ratios (sHR) with 95% confidence intervals (CI) were estimated for association of PSADT with relative incidence of recurrence using competing risk regression after adjusting for tumor stage, pre-treatment PSA, Gleason score, treatment regimen, and age at randomization. Overall, 311 patients were eligible for this analysis. Median PSADT was 8 months. Cumulative incidence of BCR at 10 years was 31.0% and 20.7% in patients with PSADT <8 months and ³8 months, respectively. Longer PSADT was associated with a significantly lower risk of cumulative incidence of BCR (sHR for PSADT as a continuous variable 0.43, 95% CI: 0.28-0.66; sHR for PSADT ³8 months 0.54, 95% CI: 0.30-0.99). After adjustment for time to recovery of T to supracastrate level in addition to the aforementioned variables, longer PSADT (³8 months) was associated with lower risk of cumulative incidence of BCR (sHR: 0.53, 95% CI: 0.27-1.01). These findings suggest that early PSA kinetics within 18 months of recovery of T to a supracastrate level predict for subsequent biochemical failure. Taking account of early changes in PSA after testosterone recovery may allow for recognition of potential failures earlier in the disease course and thereby permit greater personalization of management decisions.

Risk Factors Predicting Relapse 10 Years Following Extreme Dose-Escalated SBRT for Intermediate-Risk Prostate Cancer: Is De-Intensification Feasible in Unfavorable Subgroups?

Adding short-term androgen-deprivation therapy (ADT) to radiotherapy is recommended in unfavorable intermediate-risk (UIR) prostate cancer (PCa). Data supporting the addition of ADT to stereotactic body radiotherapy (SBRT) in intermediate-risk (IR) patients are limited. Given ADT has well-documented toxicities, we sought to identify the UIR prognostic factors that predict for relapse following SBRT without ADT. We combined results from two mature multicenter trials to determine if extreme dose-escalated SBRT yielded UIR subgroups in which the omission of ADT may be considered. Between 2008 and 2011, two prospective national trials enlisted 39 centers to enroll 285 patients with IR PCa: 182 had Memorial Sloan Kettering (MSK) favorable intermediate-risk (FIR) and 103 had MSK UIF PCa. All were treated with a non-coplanar robotic SBRT platform using real-time tracking of implanted fiducials. Two dose regimens were used: 40Gy in 5 fractions of 8Gy, and 38Gy in 4 fractions of 9.5Gy. ADT was not allowed. Univariate and multivariate analyses using a Cox proportional hazards model was performed for relapse free survival (RFS): relapse included pathologic or radiographic failure, initiation of salvage or systemic therapy, or biochemical relapse by the nadir + 2 definition. Insufficient events prevented similar analyses for local control, metastasis-free and PCa-specific survival. Examined risk factors included dose regimen, clinical T-stage, Gleason score, pre-treatment PSA, % positive biopsy cores, and number of unfavorable risk factors (URFs). All reported rates are actuarial, using Kaplan-Meier method. Median follow-up was 8.1 years. 71 patients were followed 10 years. There were no statistically significant differences in rates of toxicity, local failure, RFS, overall nor metastasis-free survival between the two dose regimens. For the entire group, 10-year overall survival was 82.9%, RFS was 83.2%, and the local failure rate was 3.6%. On univariate analysis, primary Gleason pattern 4 (PGP4) and >2 URFs predicted for RFS. On multivariate analysis, only PGP4 (hazard ratio: 3.71, p = 0.0053) was statistically significant. Examining the UIR subgroup, the only predictor for RFS was PGP4 (HR: 3.64, p = 0.0253). 10-year RFS was 88.4% for FIR and 89.1% for UIR without PGP4; this fell to 58.5% in patients with a PGP4. Following dose-escalated SBRT monotherapy, 10-year RFS rates were favorable in UIR patients without PGP4. Extreme dose escalation appeared to effectively address UIR factors correlating with tumor bulk (i.e., CS T2b, >50% cores+, PSA 10-20), but was less effective with biologically aggressive pathology (PGP4). A randomized trial, ideally including genomic classification, would be necessary to determine if dose-escalated SBRT allows de-intensification (omission of ADT) in such biologically less aggressive UIR subgroups. The high relapse rate observed in UIR patients with PGP4 affirms the need for adjuvant ADT in this subgroup.

Impact of Testosterone Recovery on Clinical Outcomes of Patients Treated with Salvage Radiotherapy and Androgen Suppression: A Secondary Analysis of the NRG/RTOG 0534 Sport Phase 3 Trial

Testosterone (T) kinetics and its relationship with clinical outcomes has not been studied in trials using salvage radiotherapy and androgen deprivation therapy (ADT). We performed a secondary analysis of the NRG Oncology/RTOG 0534 SPPORT trial, which compared prostate bed radiotherapy (PBRT) (arm 1), PBRT + short-term androgen deprivation therapy (ADT) (arm 2), or PBRT + pelvic lymph node radiotherapy (PLNRT) + short-term ADT (arm 3). We assessed longitudinal serum T levels and the impact of testosterone recovery (TR) on clinical outcomes. ADT was given for 4-6 months in arms 2 and 3, starting 2 months prior to radiotherapy. The trial excluded patients with baseline T < 40% of the lower limit of normal. TR was defined in 3 ways: 1) return to non-castrate level (>50 ng/dL), 2) return to normal level (>300 ng/dL), and 3) return to baseline level. Time to TR was estimated using cumulative incidence and death without an event considered a competing risk. Unadjusted and adjusted hazard ratios and 95% confidence intervals (CIs) were calculated using Cox proportional hazards model. Freedom from progression (FFP) was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A total of 1699 patients with T at baseline and at least 1 follow-up assessment were included. The median age was 64 years (IQR 59 - 69), 12.8% were black, 14.9% had diabetes, and 54.1% were former or current smokers. Median baseline T in arms 1, 2 and 3 was 320 ng/dL (IQR 239 - 424), 319 ng/dL (IQR 237 - 438) and 330 ng/dL (IQR 252 - 446), respectively. At 6 months, median T in arms 1, 2 and 3 was 290 ng/dL (IQR 210 - 390), 190.4 ng/dL (IQR 66 - 296) and 191 ng/dL (IQR 40.5 - 313). At 2 years, in arms 2 and 3, TR to non-castrate, normal and baseline levels were 95%, 55% and 23%, respectively. At 5 years, in arms 2 and 3, TR to non-castrate, normal and baseline levels were 98%, 73% and 42%, respectively. FFP was superior in arms 2 and 3 vs. arm 1 in patients with TR by all three definitions. In patients with recovered T to normal levels by 2 years (n = 904), the 5-year FFP rates were 71.8% (95% CI 66.9-76.6) in arm 1, 77.2% (72.1-82.2) in arm 2, and 86.3% (82.3-90.3) in arm 3 (arm 2 vs arm 1: HR 0.74, 95% CI 0.56-0.98, p = 0.034; arm 3 vs arm 1: HR 0.54, 95% CI 0.40-0.72, p<.0001). This work represents the largest study of T kinetics in patients treated with salvage radiation and ADT. Approximately half of patients did not normalize their T levels by 2 years. Our data validate an incremental and meaningful FFP benefit of adding short-term ADT and PLNRT to PBRT independent of T recovery.

Quality of Life Results of Addition of Androgen Deprivation Therapy and Pelvic Lymph Node Treatment to Prostate Bed Salvage Radiotherapy: NRG Oncology/RTOG 0534 SPPORT

Report the quality of life (QOL) analysis of the SPPORT trial of men with a detectable prostate specific antigen (PSA) after prostatectomy for prostate cancer randomized to (Arm 1) salvage prostate bed radiotherapy (PBRT), (Arm 2) 4-6 months of short-term androgen deprivation therapy (STADT) + PBRT, and (Arm 3) pelvic lymph node radiotherapy (PLNRT) + STADT + PBRT. Primary analysis established a benefit of adding PLNRT and STADT to PBRT. There was higher short term but no statistically significant difference in long term adverse events with the exception of blood or bone marrow events. QOL endpoints were assessed at baseline, 6 weeks after RT start, 1 and 5 years, including Expanded Prostate Cancer Index Composite (EPIC) (bowel, urinary, sexual, and hormonal domains), Hopkins Symptom Checklist (HSCL-25) (depressive symptoms), and the EuroQol (EQ-5D) (health state weights used in quality adjusted life years (QALYs). In addition to statistical significance, differences in scores were assessed using 0.5 standard deviation (SD) as the criterion for clinical importance. Difference among arms was assessed using pairwise t-tests, Fisher's exact test, and mixed effects regression modeling. To control for multiplicity, the p-value required for statistical significance is p<0.025. Six hundred forty-four patients consented to QOL, about 210 on each arm. Baseline characteristics were not significantly different among arms: 81% were white and 54% <65 years. For EPIC, bowel domain scores decreased at 6 weeks post-RT then increased by years 1 and 5, although not to baseline levels. One clinically significant difference in bowel scores was Arm 3 vs. Arm 1 at 6 weeks. For the urinary domain, scores decreased at 6 weeks post-RT and remained below baseline at 1 and 5 years, but there were no significant differences among arms. For the sexual domain, there were statistically significant differences between arms at 6 weeks and 1 year with patients receiving STADT exhibiting poorer sexual QOL scores. By year 5 the differences were no longer significant. A similar pattern was seen for the hormonal domain. For HSCL-25, differences at 6 weeks were statistically but not clinically significant, and there were no significant differences at the later time points. Comparisons of QALYs for overall survival over an 8-year horizon showed no significant group differences, with a mean of about 7.8 in each arm. Regarding freedom from progression, QALY means were 5.7, 6.5, and 7.4 years for Arms 1, 2, and 3, respectively, with a significant difference between Arms 3 and 1 (p = <.001) favoring the more intensive treatment. While QOL generally declined among all arms at 6 weeks post RT, there were no clinically significant differences in QOL among arms at 5 years. QALYs for freedom from progression favored STADT + PLNRT + PBRT for salvage treatment of prostate cancer.

Re: Dose-escalated Radiotherapy Alone or in Combination with Short-term Androgen Deprivation for Intermediate-risk Prostate Cancer: Results of a Phase III Multi-institutional Trial

Re: Dose-escalated Radiotherapy Alone or in Combination with Short-term Androgen Deprivation for Intermediate-risk Prostate Cancer: Results of a Phase III Multi-institutional Trial

Neurocognitive function outcomes in NRG/RTOG 0534, the SPPORT trial.

12022 Background: RTOG 0534 established the benefit of adding of short term androgen deprivation therapy (PBRT+STADT, Arm 2) to prostate bed salvage radiotherapy (PBRT, Arm 1), and demonstrated that elective pelvic lymph node irradiation combined with STADT (PBRT+STADT+PLNRT, Arm 3) results in further reductions in progression. Longitudinal monitoring of neurocognitive function (NCF) was conducted to evaluate the hypothesis that patients treated with STADT will demonstrate greater decline in NCF compared to patients receiving PBRT alone. Methods: Patients were administered the Clinical Trial Battery [Hopkins Verbal Learning Test – Revised (HVLT-R), Trail Making Test (TMT), and the Controlled Oral Word Association (COWA) test] by certified test administrators at baseline, and at 6 weeks (6w), 1 year (1yr), and 5 years after the end of RT (5yr). Raw NCF tests scores were converted to standardized z-scores adjusted for age and education when necessary. Analyses included z-score change and reliable change index (RCI) determined decline compared to baseline, and longitudinal mixed effect regression models using z-scores. To control for multiplicity, p &lt; 0.025 is required for statistical significance. Results: Among the 1716 analyzable patients, 429 consented to NCF monitoring. There were no significant differences in sociodemographic or clinical characteristics between arms. NCF test completion was 82, 76, 63 and 30% at baseline, 6w, 1yr, and 5yr, respectively. RCI-based NCF deterioration was more frequent in Arm 3 compared to Arm 1 at 6 weeks on Delayed Recall (16% vs. 7%, p = 0.023). Patients in Arm 3 evidenced greater z-score decline compared to patients in Arm 1 at 6w on HVLT-R Total Recall [M(SD) Z-score∆ = -0.1(1.0) vs 0.2(0.9), (p = 0.020)] and Delayed Recall [M(SD) Z-score∆ = -0.4(1.5) vs 0.1(1.2), (p = 0.012)]. Mixed effects models identified statistically significant differences in z-scores between Arm 3 and 1 at 6w on Delayed Recall [-0.541 (SE 0.178, p = 0.002)]. A statistically significant difference was observed between Arm 2 and 1 at 6w on TMTB [1.498 (SE 0.626, p = 0.017) favoring Arm 2]. Between arm differences were not seen at any other time point, or on other NCF outcomes. Conclusions: Compared to patients treated with PBRT alone, patients treated with PBRT+STADT+PLNRT exhibited greater worsening in episodic verbal learning and memory processes at 6 weeks after the end of RT, while patients treated with PBRT+STADT exhibited greater improvement in processing speed. The absence of long term or progressive cognitive decline associated with STADT-containing regimens is promising but limited by substantial missing data at year 5. FUNDING This project was supported by grants 10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), CTEP from the National Cancer Institute (NCI). Clinical trial information: NCT00567580 .

Phase III study of local or systemic therapy intensification directed by PET in prostate cancer patients with post-prostatectomy biochemical recurrence (INDICATE): ECOG-ACRIN EA8191.

TPS5118 Background: Salvage radiation therapy (sRT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). PET imaging with recently FDA-approved agents in this setting (18F-Fluciclovine, 18F-DCFPyL and 68Ga-PSMA-11), have shown improved accuracy for detection of metastases not identified with conventional imaging (CIM). Given the greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for different treatment intensification approaches. In metastatic prostate cancer, metastasis-directed RT (MDT) has been used to avoid or delay systemic therapy in men with oligometastatic disease. Apalutamide (Apa) is an androgen receptor signaling inhibitor that has been shown to improve outcomes when added to ADT in mCSPC. This study will evaluate whether patients with PET-detected lesions outside the pelvis will benefit from addition of MDT to treatment intensification with STAD/Apa, and whether patients with no PET-detected lesions outside the pelvis will benefit from addition of Apa to standard sRT/STAD. Methods: PC pts with post-RP BCR (PSA &gt; 0.5ng/mL; &gt; 0.2ng/mL if first detectable within 12 mos of RP) and no extrapelvic metastases on CIM who are candidates for SOC ST (sRT to prostate bed and pelvic nodes with STAD) are eligible. Pts will undergo SOC baseline PET using a FDA-approved tracer. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic metastases). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- MDT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death, whichever occurs first. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of MDT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 76.5% in the experimental arm from 61.5% in the control arm. Secondary endpoints include overall and event-free survival, toxicity, PET progression and quality of life. Clinical trial registry number: NCT04423211. Clinical trial information: NCT04423211 .

Phase III study of local or systemic therapy intensification directed by PET in prostate cancer patients with post-prostatectomy biochemical recurrence (INDICATE): ECOG-ACRIN EA8191.

TPS402 Background: Salvage radiation therapy (sRT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). PET imaging with recently FDA-approved agents in this setting (18F-Fluciclovine, 18F-DCFPyL and 68Ga-PSMA-11), have shown improved accuracy for detection of metastases not identified with conventional imaging (CIM). Given the greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for different treatment intensification approaches. In metastatic prostate cancer, metastasis-directed RT (MDT) has been used to avoid or delay systemic therapy in men with oligometastatic disease. Apalutamide (Apa) is an androgen receptor signaling inhibitor that has been shown to improve outcomes when added to ADT in mCSPC. This study will evaluate whether patients with PET-detected lesions outside the pelvis will benefit from addition of MDT to treatment intensification with STAD/Apa, and whether patients with no PET-detected lesions outside the pelvis will benefit from addition of Apa to standard sRT/STAD. Methods: PC pts with post-RP BCR (PSA&gt;0.5ng/mL; &gt;0.2ng/mL if first detectable within 12 mos of RP) and no extrapelvic metastases on CIM who are candidates for SOC ST (sRT to prostate bed and pelvic nodes with STAD) are eligible. Pts will undergo SOC baseline PET using a FDA-approved tracer. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic metastases). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- MDT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death, whichever occurs first. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of MDT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 76.5% in the experimental arm from 61.5% in the control arm. Secondary endpoints include overall and event-free survival, toxicity, PET progression and quality of life. Clinical trial information: NCT04423211 .

Results of a multicenter, randomized, phase 3 trial of trimodality therapy with I-125 brachytherapy, external beam radiation therapy, and long- versus short-term androgen deprivation therapy for localized high-risk prostate cancer (TRIP/TRIGU0907).

305 Background: The TRIP trial was a multicenter, phase 3 randomized investigation designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiotherapy (EBRT) for localized high-risk prostate cancer. Methods: The trial was done in 37 hospitals in Japan. Men between 40 to 79 years old with stage T2c-3a, or a prostate-specific antigen (PSA) &gt;20 ng/ml or a Gleason score &gt;7 received 6 months of ADT combined with I-125 brachytherapy at a prescription dose of 110 Gy, followed by EBRT of 45 Gy. Patients were randomly assigned either no further treatment (short arm) or 24 months of adjuvant ADT (long arm) after stratification. The primary endpoint was biochemical progression-free survival using the Phoenix definition of failure. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific survival, overall survival, and grade 3 or higher of adverse events. An intention-to-treat analysis was conducted with survival estimates determined using competing risk analyses. Results: Of 332 patients, 165 were randomized to the short and 167 to the long arm. The median follow-up periods were 9.43 and 9.24 years, respectively. 24 patients have died in each arm. The cumulative incidence for biochemical progression in the short vs. long arm were 10.4% (95% confidence interval [CI] 6.62-16.42) vs 9.5% (5.85-15.46) at 9 years, respectively (p=0.647). The cumulative incidences for clinical progression, distant metastases, salvage treatment, and disease-specific mortality events were not significantly different between the two arms. The overall survival rates of the short arm vs long arm were 87.2% (82.13-92.63%) and 85.9% (80.41-91.77%) at 9 years, respectively (p=0.914). Endocrine-related grade 3 morbidity for short arm vs long arm was 0.6% vs 1.8% (p=0.623), and radiation-related grade 3 morbidity was 1.2% vs 0.6% (p=0.622). Conclusions: In localized high-risk prostate cancer, TRIP did not demonstrate the superiority of 30 months vs. 6 months of ADT when combined with brachytherapy and EBRT. These data suggest that ultra-high radiation doses can be combined with a shorter course of ADT without compromising survival. Clinical trial information: UMIN000003992 .

Effects of Androgen Deprivation Therapy on Prostate Cancer Outcomes According to Competing Event Risk: Secondary Analysis of a Phase 3 Randomised Trial

BackgroundPrevious studies indicate that the benefit of short-term androgen deprivation therapy (ADT) with radiotherapy (RT) for prostate cancer depends on competing risks. ObjectiveTo determine whether a quantitative method to stratify patients by risk for competing events (omega score) could identify subgroups that selectively benefit from ADT. Design, setting, and participantsAn ancillary analysis of NRG/RTOG 9408 phase 3 trial (NCT00002597) involving 1945 prostate cancer patients was conducted. InterventionShort-term ADT. Outcome measurements and statistical analysisWe applied generalised competing event regression models incorporating age, performance status, comorbidity, T category, Gleason score (GS), and prostate-specific antigen (PSA), to stratify patients according to relative hazards for primary cancer-related events (distant metastasis or prostate cancer death) versus competing noncancer mortality. We tested interactions between ADT and subgroups defined by standard risk criteria versus relative risk (RR) using the omega score. Results and limitationsT2b, higher GS, and higher PSA were associated with an increased RR for cancer-related versus competing mortality events (a higher omega score); increased age and comorbidity were associated with a decreased omega score. Of 996 patients with low-risk/favourable intermediate-risk (FIR) disease, 286 (28.7%) had a high omega score (≥0.314). Of 768 patients with unfavourable intermediate-risk disease, 175 (22.8%) had a low omega score. The overall discordance in risk classification was 26.1%. Both standard criteria and omega score identified significant interactions for the effect of ADT on cancer-related events and late mortality in low- versus high-risk subgroups. Within the low-risk/FIR subgroup, a higher omega score identified patients in whom ADT significantly reduced cancer events and improved event-free survival. Limitations are the need for external/prospective validation and lower RT doses than contemporary standards. ConclusionsStratification based on competing event risk is useful for identifying prostate cancer patients who selectively benefit from ADT. Patient summaryWe analysed the effectiveness of androgen deprivation therapy (ADT) for localised prostate cancer among patients, defined by the relative risk (RR) for cancer versus noncancer events. Among patients with traditional low-risk/favourable intermediate-risk disease, those with a higher RR benefitted from short-term ADT.

GETUG-AFU 22 Phase II Randomized Trial Evaluating Outcomes of Post-Operative Immediate Salvage Radiation Therapy with or without ADT for Patients with Persistently Elevated PSA Level

<h3>Purpose/Objective(s)</h3> Radical prostatectomy (RP) is one of the recommended option for localized prostate cancer (PCa) treatment but no clear recommendations guide post-operative treatment patients with persistently elevated prostate-specific antigen (PSA) after RP. The aim of this trial was to compare immediate salvage radiation therapy (iSRT) with or without short-term androgen deprivation therapy (ADT) in these patients. <h3>Materials/Methods</h3> RP patients with nonmetastatic PCa on conventional preoperative imaging, and with a post-RP PSA level between 0.2 and 2 ng/mL were randomized (1:1) to iSRT alone (iSRT arm) or 6 months of ADT (degarelix) with iSRT (iSRT+ADT arm). ISRT consisted of pelvic irradiation (46 Gy in 23 Fr) with a boost on the prostate bed (66 Gy in 33 Fr). The primary endpoint was event-free survival (EFS). Biochemical progression-free survival (bPFS), metastates-free survival (MFS), overall survival (OS), quality of life, and toxicities were evaluated as secondary endpoints. <h3>Results</h3> From Jan-2013 to Sept-2015, 125 pts were included (iSRT arm: 64 pts; iSRT+ADT arm: 61). Median follow up was 75.0 months (95% CI: 74.1-76.6). The baseline characteristics were well-balanced between the two arms. Median PSA was 0.6 ng/mL (0.12-3.65) at randomization. All patients received the planned iSRT and 98.4% in the arm iSRT+ADT received ADT as planned. The efficacy results were analyzed at 5 years. EFS was 62.3% (95% CI: 48.9-73.2) in iSRT arm and 63.5% (95% CI: 49.9-74.2) in iSRT+ADT arm (HR=0.83; 95%CI: 0.47-1.47; p=0.528). bPFS was 62.3% (95% CI: 48.9-73.2) in iSRT arm and 66% (95% CI: 52.3-76.6) in iSRT+ADT arm (HR=0.76; 95%CI: 0.44-1.31; p=0.322). MFS was in favor of the iSRT+ADT arm with HR=0.51 (95% CI: 0.26-0.99; p=0.048). OS data were not mature at the time of analysis. Multivariate analysis demonstrated that PSA level <0.6 ng/ml at randomization and tumor ≤pT3a were associated with increased bPFS (HR=1.84; 95%CI: 1.02-3.33; p=0.05 and HR=2.96; 95%CI: 1.66-5.25; p=0.0002, respectively). PSA level <0.6 ng/ml at randomization was associated with improved MFS (HR=2.82; 95%CI: 1.14-6.95; p=0.019). No grade 4 toxicities were observed. Overall, no difference in acute toxicity were observed between the 2 arms and more late toxicities (≥6 months after iSRT) were observed in the iSRT+ADT than the iSRT arm (53.1% vs 70.5%; p=0.046). At 12 months ADT-related symptoms were more important in the iSRT+ADT arm (QLQ-PR25; p=0.04). At 24 months, no difference in QLQ-C30 or QLQ-PR25 analysis was reported. After an initial 25-fold decrease in blood testosterone level, all patients recovered to normal level 12 months after starting ADT. <h3>Conclusion</h3> Despite the lack of differences in terms of EFS between the two arms, this study demonstrated that iSRT+ADT improved MFS without impaired quality-of-life for patients with persistently elevated PSA after RP.