Monotherapy For Prostate Cancer Research Articles

P087 Comprehensive evaluation of androgen receptor pathway inhibitor monotherapy in prostate cancer: Safety, oncologic outcomes, and quality of life – a systematic review and meta-analysis

P087 Comprehensive evaluation of androgen receptor pathway inhibitor monotherapy in prostate cancer: Safety, oncologic outcomes, and quality of life – a systematic review and meta-analysis

PPP06 Presentation Time: 11:15 AM: High-Dose-Rate (2 Fractions of 13,5 Gy)/Low-Dose-Rate Brachytherapy as Monotherapy in Prostate Cancer. Long Term Outcomes and Predictive Value of Nadir PSA

PPP06 Presentation Time: 11:15 AM: High-Dose-Rate (2 Fractions of 13,5 Gy)/Low-Dose-Rate Brachytherapy as Monotherapy in Prostate Cancer. Long Term Outcomes and Predictive Value of Nadir PSA

1161: HDR brachytherapy as monotherapy for prostate cancer: comparison of two fractionation schedules

1161: HDR brachytherapy as monotherapy for prostate cancer: comparison of two fractionation schedules

Population-based patient-reported quality of life outcomes following low-dose-rate versus high-dose-rate brachytherapy monotherapy for low-intermediate risk prostate cancer.

To evaluate patient reported quality of life outcomes (QoL) following low-dose-rate brachytherapy (LDR-BT) and high-dose-rate brachytherapy (HDR-BT) monotherapy for prostate cancer at a population-based setting. The study comprised men with low-intermediate risk prostate cancer in the Prostate Cancer Outcomes Registry Victoria (PCOR-Vic), who were treated with LDR-BT or HDR-BT monotherapy between 2015 and 2020 and completed the Expanded Prostate Cancer Index Composite (EPIC-26) questionnaire 12-month post-treatment. Men who had ADT were excluded (n = 12). Differences in substantial symptoms (i.e. 'moderate' or 'big' problem on a 5-point Likert scale) between LDR-BT and HDR-BT arms were evaluated using Pearson's chi-squared test. Multivariable linear regressions were used to estimate differences in EPIC-26 urinary, bowel and sexual functional domain scores between LDR-BT and HDR-BT arms. Overall, 198 men were included in this study, of which 167 (84%) had LDR-BT and 31 (16%) had HDR-BT. 9 (4.6%), 10 (5.1%) and 56 (28%) reported substantial symptoms for overall urinary, bowel and sexual function at 12-month post-treatment, with no significant difference between LDR-BT and HDR-BT arms. The adjusted mean differences in urinary incontinence, urinary obstructive, bowel and sexual function domain scores between LDR-BT and HDT-BT were: -3.53 (-8.21 to 1.14), -1.27 (-6.88 to 4.35), -0.01 (-5.63 to 5.63) and -8.68 (-21.44 to 4.07) respectively - these were not statistically significant and did not meet the minimal clinically important difference. This is the first Australian population-based study comparing QoL in men who had LDR-BT and HDR-BT, with no statistically or clinically significant differences in QoL observed at 12-month post-treatment.

Dosimetric Parameters Predictive of Treatment-Related Toxicity in High Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer.

High dose-rate (HDR) brachytherapy as monotherapy is an effective treatment for patients with low- and intermediate-risk prostate cancer and is increasingly being offered as a 2-fraction protocol. There is a lack of consensus on the optimal dosimetric planning parameters to use, or whether there is any benefit summating dosimetric parameters from more than one implant. Our goal is to determine planning parameters associated with disease control, toxicity and health-related quality of life (HRQOL). Data were collected on 83 patients with low- and intermediate-risk prostate cancer who received 2 fractions of 13.5 Gy HDR brachytherapy without androgen-deprivation therapy as part of a randomized phase II clinical trial. An in-house deformable, registration algorithm was used to co-register and dose-summate the plans from both implants for each patient. Acute and late GU and GI toxicities were measured using CTCAE 4.0 and HRQOL was measured in urinary, bowel, sexual and hormonal domains using the EPIC scores. Treatment efficacy was assessed through PSA measurement and imaging with or without biopsy where indicated. Covariates included baseline clinical factors, disease characteristics and treatment dosimetric parameters. Cox proportional hazards was performed to evaluate covariates impact on treatment toxicity and efficacy, and logistic regression analysis evaluated covariates impact on HRQOL. Among the 83 patients, median prostate volume was 46.7cm3. Median summated planning target volume receiving 100% prescription dose (PTV V100%) was 97.4%, median PTV V150% 42.4% and median PTV V200% 15.5%. Median highest dose to the 1cm3 rectum (D1cc) was 66.9% of the prescription dose and median rectum V80% was 0.008cm3. Median urethral D1cc was 99.0% of the prescription dose, median urethral Dmax 121.7% and median urethral D10% 116.2%. Grade ≥2 GI toxicity was uncommon (3.7% acute and 8.5% late), but grade ≥2 GU toxicity was reported in 73.2% (acute) and 46.3% (late) patients. Rectum D1cc and V80% were found to be significantly associated with grade 2 or higher acute GI toxicity, while use of a-blocker at baseline was associated with grade ≥2 acute GU toxicity. Similarly, use of a-blocker was associated with late grade ≥2 GU toxicity, but with no dosimetric associations. No other variables were associated with treatment-related toxicities. Only rectum D1cc was significantly associated with changes in bowel EPIC scores. Estimated 5-year biochemical disease-free survival was 93.9% and 5-year cumulative incidence of local failure was 3.8%. HDR monotherapy with 27 Gy delivered in 2 fractions in treatment of prostate cancer is well tolerated with high rates of disease control and minimal toxicity. Dose summation between 2 fractions of HDR brachytherapy is feasible, with rectal dose predicting acute GI toxicity. The lack of association between dose metrics and urinary toxicity raises the potential for further dose escalation.

44 Dosimetric Parameters Predictive of Treatment-Related Toxicity in High Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer

44 Dosimetric Parameters Predictive of Treatment-Related Toxicity in High Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer

PO59: Dosimetric Parameters Predictive of Treatment-Related Toxicity in High Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer

PO59: Dosimetric Parameters Predictive of Treatment-Related Toxicity in High Dose-Rate Brachytherapy as Monotherapy for Prostate Cancer

Abstract 6268: TT125-802 is a potent and highly selective CBP/p300 bromodomain inhibitor for the treatment of castration resistant prostate cancer and haematological malignancies

Abstract The paralogous lysine acetyltransferases CREB-binding protein (CBP) and p300 are key epigenetic regulators involved in diverse signaling pathways in cancer. The bromodomain (BRD) of CBP/p300 serves as an acetyl-lysine “reader” that allows CBP/p300 to bind chromatin at acetylated histone and non-histone proteins leading to the regulation of gene transcription. Indeed, CBP/p300 are critical co-activators of nuclear receptors, including the androgen receptor (AR) in castration resistant prostate cancer (CRPC). Thus, inhibition of CBP and p300 is an emerging therapeutic strategy to block the transactivation activity of the AR in CRPC. In addition, inhibition of the CBP/p300 BRD has been described as a potential therapeutic strategy to treat multiple myeloma (MM) through transcriptional suppression of interferon regulatory factor 4 (IRF4) and concomitant repression of its target genes MYC and MYB. TT125-802 is a highly selective and potent, oral small molecule inhibitor of the BRD of CBP/p300. In a BROMOscan assay against a panel of 40 BRD-containing proteins, TT125-802 revealed the unique selectivity to the BRD of CBP/p300 with a minimal off-target binding to all other BRDs, including BET proteins.TT125-802 shows selective anti-proliferative activity in AR-dependent prostate cancer cell lines (22Rv-1, C4-2, and LNCaP) and inhibits AR target gene expression (KLK2, KLK3, TMPRSS2, and MYC) in a dose-dependent manner (IC50 of 2 to 33 nM). AR-negative prostate cancer cell lines (DU-145 and PC-3) are insensitive to TT125-802 in vitro, pointing to an AR-selective mode of action. In an in vivo model of CRPC, TT125-802 inhibited tumor growth when administered orally to human C4-2 xenograft-bearing mice. Daily dosing of TT125-802 was well tolerated with stable bodyweights and platelet counts. In addition, preclinical studies in CRPC patient-derived xenograft (PDX)-bearing mice showed that the combination treatment of TT125-802 and enzalutamide had a synergistic effect on tumor growth inhibition compared to single agent treatments. TT125-802 reduced mRNA expression of the AR-target genes in tumor samples and decreased plasma PSA levels compared to enzalutamide alone, and the combination reduced levels even further. In a preclinical model of MM (OPM2), TT125-802 had a dose-dependent effect on tumor growth, inducing tumor regressions at the highest dose. Target genes such as MYC, MYB, and IRF4 were potently downregulated in tumors. We conclude that TT125-802 is a novel, highly selective inhibitor of the BRD of CBP/P300. It has therapeutic potential as monotherapy in prostate cancer and multiple myeloma and in combination with next-generation AR inhibitors for patients with lethal prostate cancer. A FIH study of TT125-802 in cancer patients is on track to start in 2023. Citation Format: Sara Laudato, Dorothea Gruber, Thomas Bohnacker, Martin Schwill, Charles-Henry Fabritius, Raquel Herrador, Katrin Westritschnig, Thushara Pattupara, Vikram Ayinampudi, Stefanie Flückiger-Mangual. TT125-802 is a potent and highly selective CBP/p300 bromodomain inhibitor for the treatment of castration resistant prostate cancer and haematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6268.

Efficacy of Bicalutamide Monotherapy in Prostate Cancer: A Network Meta-Analysis of 10 Randomized Trials

<h3>Purpose/Objective(s)</h3> Bicalutamide, a first-generation androgen receptor antagonist, continues to be selectively used in the management of prostate cancer (PCa) in place of androgen deprivation therapy (ADT), often to avoid select ADT-specific side effects. However, none of the major American or European guidelines support the use of bicalutamide monotherapy (BICmono) without ADT for localized disease. Herein, we perform the first, to our knowledge, meta-analysis of randomized trials to assess the efficacy of BICmono in PCa. <h3>Materials/Methods</h3> A pre-specified protocol was registered with PROSPERO. MEDLINE, Embase, and Cochrane databases were searched for randomized trials testing the use of BICmono in PCa published before January 2022. The prescribed BICmono dose was 150 mg orally daily. The primary endpoint was overall survival (OS) with progression-free survival (PFS) as a secondary endpoint. Analyses were stratified into disease states defined by the Early Prostate Cancer (EPC) definition of localized (cT1-2, N0M0) and locally advanced (cT3-4, N0-1, M0). Patients with M1 disease were excluded. Standard of care (SOC) was defined as radical prostatectomy, radiotherapy, or watchful waiting. Comparisons of SOC +/- ADT was performed through an individual patient data meta-analysis in PCa randomized trials (MARCAP) consortium (5336 patients from NRG/RTOG 8610 and 9408, EORTC 22863 and 22991, TROG 9601, and PCS III). SOC +/- BICmono was compared through a study-level meta-analysis (9125 patients from EPC 23, 24, 25, PMH 9907, and NRG/RTOG 9601). SOC+BICmono versus SOC+ADT was compared through a random-effects network meta-analysis. Sensitivity analyses were conducted for the subset of patients who received RT as SOC. <h3>Results</h3> For localized PCa (n=9,897 patients), the addition of ADT to SOC significantly improved OS (HR 0.83, 95%CI 0.72-0.96). Conversely, BICmono did not significantly impact OS compared to SOC alone (HR 1.06, 95%CI 0.89-1.27). Results were similar for the subset of patients treated with radiotherapy as the SOC. Likewise, PFS was significantly improved with the addition of ADT to SOC (HR 0.69, 95%CI 0.61-0.77), but not from the addition of BICmono to SOC (HR 0.89, 95%CI 0.77-1.04). The network meta-analysis demonstrated that SOC+ADT was superior to SOC+BICmono for OS (HR 0.78, 95%CI 0.62-0.98) and PFS (HR 0.77, 95%CI 0.63-0.93). Similar trends were observed in locally advanced disease (n=4284 patients). <h3>Conclusion</h3> This study presents strong evidence for the superiority of ADT over BICmono for men with PCa. Furthermore, there was no improvement in outcomes from the use of BICmono compared to SOC alone without the use ADT in localized PCa. Thus, based on current randomized evidence, BICmono does not appear to have clinically meaningful activity in localized disease and SOC alone should be recommended if a patient declines ADT.

High-dose-rate brachytherapy as monotherapy for prostate cancer: 5-year results

Objective: to evaluate clinical outcomes in patients with prostate cancer treated with high-dose-rate (HDR) brachytherapy (BT) as monotherapy.Materials and methods. From January 2015 to December 2017, 97 men with localized prostate cancer underwent HDR-BT as monotherapy, with a temporary implant on a MicroSelectron HDR device. The dose prescription was: 30 Gy in 2 fractions with an interval of 2 weeks. The overall and biochemical survival rate was assessed. The assessment of genitourinary and gastrointestinal toxicity was also carried out. The quality of life associated with urination before treatment and in dynamics during 5 years of observation, as well as the frequency and degree of development of erectile dysfunctionand its dynamics during the entire observation period were analyzed.Results. The median age was 65.2 (44 to 80) years. Overall, 29 patients had low risk prostate cancer, 63 patients had moderate risk, and 5 patients – high risk. The follow-up period was five years (range, 18 to 72 months). The median follow-up was 54.3 (95 % confidence interval 52.3–59) months. Overall survival and survival without biochemical recurrence were 96 and 99 %, respectively. Toxicity was assessed according to the RTOG/EORTC (Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer) scale for each event. Late genitourinary toxic reactions of grade 1 and 2 were noted in 23.9 and 6.3 %, respectively. Late gastrointestinal grade 2 toxicity was not observed. Genitourinary and gastrointestinal toxic reactions of grade 3 were not observed. The quality of life associated with urination after treatment was comparable to the level of quality of life at the time of inclusion of patients in the treatment protocol. Erectile dysfunction developed to a greater extentin the first 1–2 years after HDR-BT with a subsequenttendency to recovery.Conclusion. HDR-BT as monotherapy is a safe and highly effective treatment for localized prostate cancer. The fractionation mode in the form of 30 Gy for 2 fractions of 15 Gy with an interval of 2 weeks with or without dose modulation in the area of the tumor focus using a gel has a low toxicity profile from the side of critical organs.

Optimization of HIFU monotherapy for prostate cancer

Introduction. One of the most researched alternative treatments for localized prostate cancer (PCa) is ultrasound ablation (HIFU ¾ High-intensity Focused Ultrasound). Although the world history of the application of this method of PCa treatment is more than 15 years old, the scope of the application of the method has not finally been determined.Purpose of the study. To study the results of the application of ultrasound ablation in the treatment of patients with localized and locally advanced PCa.Materials and methods. The study included 147 patients with PCa who underwent HIFU treatment using the AblathermÒ device («EDAP TMS», Vaulx-en-Velin, Lyon, France). Group 1 included patients with localized and locally advanced PCa treated at the stage of gaining experience and evaluating the results of treatment (n = 82). Group 2 consisted of patients with localized PCa of low and moderate oncological risk (n = 65). The number of sessions in group 1 varied from 1 (65) to 2 (17). The need to perform a second session was associated with the ineffectiveness of the first. HIFU was also performed after the failure of external beam radiation (2), and photodynamic (1) therapy. In group 2, 61 patients received one treatment session, 4 patients received 2 sessions each. The mean follow-up time for the patients in group 1 was 17.4 ± 5.2 (3 – 29) months, for group 2 was 18.2 ± 7.3 (3 – 29) months.Results. In group 1 of patients with a low degree of oncological risk, a decrease in blood prostate-specific antigen (PSA) below the threshold value and the absence of its significant increase during the observation period was noted in 87.5% of cases (28 patients), with an average degree of oncological risk in 65.6% of cases (21 patients), with a high degree in 27.7% of cases (5 patients). In 34.1% (28 patients), the treatment was ineffective, 21 of them underwent repeated ultrasound ablation of the prostate, and 7 patients received subsequent external beam radiation therapy. These results led us to abandon the use of HIFU in patients with baseline blood PSA levels greater than 20 ng/ml and locally advanced disease. In group 2, biochemical recurrence was noted in 9 patients. A control biopsy in 6 patients confirmed local recurrence, which became the basis for a second HIFU session (4). Five patients received adjuvant hormonal therapy. The total effectiveness of the treatment in group 2 was 86.2%.Conclusion. The results support the notion that HIFU is a treatment option for localized PCa only. The evaluation of the initial results led us to abandon treatment with this method in patients with locally advanced and high-risk localized PCa.

Phase 2 trial of immunotherapy in tumors with CDK12 inactivation (IMPACT): Results from cohort A of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) receiving dual immune checkpoint inhibition (ICI).

103 Background: Prostate cancer with CDK12 inactivation represents a distinct subtype in mCRPC, tumors are characterized by excessive tandem duplications, genomic instability, gene fusion-caused putative neoantigens and increased tumor T cell infiltration. Retrospective experiences with ICI in CDK12 inactivation CRPC pts reported PSA and radiographic responses. We conducted a prospective multi-site clinical trial of ipilimumab and nivolumab in CDK12 inactivation or mutated cancers. Herein, we report our findings in the completed cohort A of men with mCPRC. Methods: Eligible pts had mCRPC (ongoing androgen deprivation therapy with serum testosterone £ 50 ng/dL) and putative CDK12 inactivation of function aberrations on any commercial or institutional CLIA/CAP approved next generation sequencing assay. Archival tumor tissue was requested for correlative biomarker analysis. Pts received nivolumab 3 mg/kg IV and ipilimumab 1 mg/kg IV q3 weeks for up to 4 cycles, followed by maintenance nivolumab at 480 mg IV q4 weeks until disease progression, intolerable toxicity, or consent withdrawal. The primary endpoint was PSA response, defined as a greater than or equal to 50% decline in PSA from baseline. Secondary endpoints included safety/toxicity, secondary efficacy measures including QoL and overall survival. Exploratory objectives included baseline tumor whole exome analysis and changes in circulating immune profiles with therapy. Results: As of data cut-off in Aug 2021, 28 mCRPC pts enrolled in Cohort A; median ECOG PS was 1 (0-2 range), 22/28 had Gleason 8-10 cancer, mean baseline PSA at study entry was 231 ng/dL, all pts had received ≥1 prior oral androgen signaling inhibitor and ≥1 cytotoxic chemotherapy. Unconfirmed PSA ≥30% decline was seen in 6/28 pts (21.4%) and PSA ≥50% decline in 4/28 pts (14.2%). Grade ≥3 possible/probable/definite adverse events were noted in 7/28 (25%) and SAEs in 10/28 pts (35.7%). Six pts (21.4%) experienced a rapid PSA increase by ≥ 10-fold over baseline. Conclusions: Combination immunotherapy was reasonably tolerated in this heavily pre-treated population and was associated with unconfirmed PSA responses in a subset of pts. Ongoing correlative analyses could explain responses mechanistically. Enrollment in Cohort B of non-prostate cancers and Cohort C of nivolumab monotherapy in prostate cancer are still ongoing. Clinical trial information: NCT03570619.

The CAPRA-S Score and Immune Dysfunction as a Guide to Outcome in Men Treated with Prostatectomy Radical as Mono-Therapy for Prostate Cancer.

Incorporate the immune function as determined by the absolute lymphocyte count (ALC) into the CAPRA-S risk stratification score to determine if predictive values could be improved. The clinical pathological findings in the surgical specimen and total PSA were used to define the three CAPRA-S risk groups. One month after surgery and at each follow up total PSA and the ALC were determined, until biochemical failure (BF) or the end of the study period. A cut off value of <1,000 lymphocytes/mm3 was used to define lymphocytopenia (LCP). Each CAPRA-S group was sub-divided based on the presence or absence of LCP. Kaplan-Meier biochemical failure free survival (BFFS) curves and restricted mean biochemical failure free survival times were calculated for each group. 404 patients participated of whom 103 (25.5%) underwent BF. 270 men were CAPRA-S low risk (LR), 89 intermediate risk (IR) and 45 high risk (HR), of whom LCP was found in 22 (8%) of low risk, 24 (27%) of intermediate risk and 17 (38%) of high risk men. LCP was significantly associated with a higher PSA, higher Gleason and CAPRA-S scores and BF. HRs were 1.76 for IR, 2.49 for HR and 1.29 for LCP. Five-year BFFS for men without LCP, LR 93.5%, IR 61% and HR 36%, for those with LCP, LR 55%, IR 25% and HR 6%. All patients with LCP and IR or HR scores relapsed within 6 years. 10 year BFFS for men without LCP were 71% LR, 43% IR and 23% HR, LR with LCP 16%. Men with BF had increasing LCP approximately 18 months before BF. The incorporation of the ALC taken one month after surgery with the CAPRA-S improves risk stratification; decreases in the ALC suggest that BF is occuring. These results need to be confirmed with larger studies.

Dosimetric Predictors of Toxicity and Quality of Life Following Single Fraction High Dose-Rate Prostate Brachytherapy

<h3>Purpose/Objective(s)</h3> Little is known about optimal dose constraints when high dose rate (HDR) brachytherapy is used as monotherapy for prostate cancer. Most dose constraints for HDR monotherapy were extrapolated from predictors of toxicity when HDR brachytherapy was combined with external beam radiotherapy as a boost. We sought to determine clinical and dosimetric predictors of toxicity and health related quality of life (HRQOL) in men treated with HDR brachytherapy as monotherapy. <h3>Materials/Methods</h3> Eligible patients were treated with single fraction HDR brachytherapy as monotherapy on two prospective clinical trials at a single institution. Patients in the first trial (HDR-mono) received a single fraction of 19 Gy without a dominant intraprostatic lesion (DIL) boost, and patients from the second trial (MARS) received 19 Gy in a single fraction with an MRI-guided DIL boost to ≥ 23 Gy. ADT was not used. Univariable and multivariable logistic regression was used to evaluate clinical (age, IPSS score, prostate volume, alpha blocker use at baseline, and receipt of a DIL boost) and dosimetric (prostate V100, V150, V200, D90, Urethral Dmax and D10, and Rectal Dmax and V80) predictors of CTCAE v4 acute/late toxicity and HRQOL changes measured with expanded prostate index composite (EPIC). Three classifications of late minimally clinically important changes (MCICs) were evaluated: small (> 0.5 standard deviation [SD]), moderate (> 1.0 SD) and severe (> 2.0 SD) declines compared to baseline. <h3>Results</h3> 147 patients were included (87 from HDR-mono, 60 from MARS). Median follow-up was 62.8 months. Only increasing prostate size predicted acute GU toxicity ≥ grade 2 (OR 1.05, 95% CI 1.01–1.09, <i>P</i> = 0.021). On multivariable regression, predictors of late GU toxicity ≥ grade 2 were not receiving a DIL boost (OR 3.78, 95% CI 1.88–7.83, <i>P</i> < 0.001) and higher baseline IPSS score (OR 1.89, 95% CI 1.89–3.18, <i>P</i> = 0.015). Rectal and urethral dose constraints were not associated with late GU/GI toxicity ≥ grade 2. Contrary to our hypothesis, small (OR 0.91, 95% CI 0.81–0.98, <i>P</i> = 0.032) and moderate (OR 0.91, 95% CI 0.80–0.98, <i>P</i> = 0.037) urinary MCICs were less frequent in those with higher urethral Dmax. No impact of urethra D10 on urinary MCICs was seen. Rectal Dmax and V80 did not predict bowel MCIC changes at any threshold. <h3>Conclusion</h3> We were unable to identify dose constraints that were predictive of late toxicity or relevant HRQOL changes in single fraction HDR brachytherapy. This suggests dose parameters used in these trials were safe, and that minor variability in plan dosimetry likely has little clinical significance. While increasing urethral Dmax paradoxically predicted for less frequent urinary MCICs, we do not believe this finding is clinically relevant. Further research exploring optimal dose constraints to be used in HDR brachytherapy as monotherapy for prostate cancer is warranted.

Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells.

Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel‐based therapy remains the first‐line treatment for metastatic castration‐resistant prostate cancer. However, dose‐limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high‐throughput kinome‐wide loss‐of‐function screen. Further drug‐gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA‐approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel‐induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)–negative DU145 and PC3 cells, but not in the AR‐positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2‐specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.

Research work of Prof. Yoshioka on high-dose-rate brachytherapy monotherapy for prostate cancer

Prostate cancer is one of the most common types of cancer. If identified early, treatment can be very effective, but morbidity rates are higher in older patients and in cases where the cancer is identified in the later stages. Three main treatment options are surgery, external beam radiotherapy and brachytherapy. Professor Yasuo Yoshioka, Radiation Oncology Department, Cancer Institute Hospital of Japanese Foundation for Cancer Research, believes brachytherapy to be the most effective treatment option for prostate cancer patients and is working to improve the methods by which brachytherapy is performed in order to further enhance its effectiveness, while reducing the amount of damage to the patient during the course of treatment. Yoshioka and his team are focused on high-dose-rate (HDR) brachytherapy as they believe it has advantages over low-dose-rate (LDR) brachytherapy, including its ability to treat advanced-stage patients, the ability to adjust the strength of radiation at each source position and the fact that no radiation sources will be left in the patient's body after treatment. Yoshioka reported the world's first HDR monotherapy experience for prostate cancer and, over the past decade, he and his team have been refining the procedure in order to maximise the effect of the treatment while minimising damage to the patient.

PRSOR12 Presentation Time: 12:55 PM: Dosimetric Predictors of Toxicity and Quality of Life Following Single Fraction High Dose-Rate Prostate Brachytherapy

Purpose: Little is known about optimal dose constraints when high dose rate (HDR) brachytherapy is used as monotherapy for prostate cancer. Most dose constraints for HDR monotherapy were extrapolated from predictors of toxicity when HDR brachytherapy was combined with external beam radiotherapy as a boost. We sought to determine clinical and dosimetric predictors of toxicity and health related quality of life (HRQOL) in men treated with HDR brachytherapy as monotherapy.

PP-0121 HDR Brachytherapy as Monotherapy for Prostate Cancer: Early Toxicity of a Randomized Phase II Trial

PP-0121 HDR Brachytherapy as Monotherapy for Prostate Cancer: Early Toxicity of a Randomized Phase II Trial

HDR brachytherapy as monotherapy for prostate cancer: A systematic review with meta-analysis

PurposeThe effectiveness and safety of high dose brachytherapy as monotherapy (HDR-BRT-M) in prostate cancer is limited to retrospective studies. We performed a meta-analysis to summarize existing data and identify trends in biochemical recurrence-free survival (bRFS) and toxicity after HDR-BRT-M in patients with prostate cancer. Methods and MaterialsRetrospective, prospective, or randomized clinical trials were identified on electronical databases through June 2020. We followed the PRISMA and MOOSE guidelines. A meta-regression analysis was performed to assess if there is a relationship between moderator variables and bRFS. A p-value < 0.05 was considered significant. ResultsFourteen studies with a total of 3534 patients treated were included. The cumulative size of the bRFS at 5 years was 0.92 (95% confidence interval (CI) 0.48–0.61). The five-year bRFS for low, intermediate, and high risk was 97.5% (95% CI 96–98%), 93.5% (95% CI 91–96%), and 91% (95% CI 88–93%), respectively. The total biological effective dose (BED) (p = 0.02), the BED per fraction (p = 0.001), androgen deprivation therapy usage (p = 0.04), and the number of fractions of HDR-BRT-M (p = 0.024) were significantly associated with bRFS rate. The rate of late Grade 2/3 or > genitourinary and gastrointestinal toxicity was 22.4% (95% CI 9–35,2%)/1.4% (95% CI 0.8–2.1%) and 2.7% (95% CI 0–6.8%) and 0.2% (95% CI 0.1%–0.4%), respectively. ConclusionsHDR-BRT-M is safe with excellent rates of bRFS for all risk groups. The total BED, the BED per fraction, and number of fractions were the key factors associated with the biochemical control. These data can be useful to choose the size and number of BRT fractionation.

Prostate high dose-rate brachytherapy as monotherapy for prostate cancer: Late toxicity and patient reported outcomes from a randomized phase II clinical trial

Background and PurposeLong-term toxicity of high dose-rate brachytherapy as monotherapy for prostate cancer is not well defined. We report late toxicity and health related quality of life (HRQOL) changes from a randomized phase II clinical trial of two different fractionation schemes. Materials and MethodsEligible patients had NCCN low or intermediate risk prostate cancer. 170 patients were randomized to receive either a single 19 Gy or two-fractions of 13.5 Gy one week apart. Toxicity was measured using Common Terminology for Adverse Events (CTCAE) v4.0, and HRQOL was measured using the Expanded Prostate Index Composite (EPIC). ResultsMedian follow-up was 63 months. The 5-year cumulative incidence of Grade 2 or higher genitourinary (GU) and gastrointestinal (GI) toxicity was 62% and 12% in the single-fraction arm, and 47% and 9% in the two-fraction arm, respectively. Grade 3 GU toxicity was only seen in the single fraction arm with a cumulative incidence of 2%. The 5-year prevalence of Grade 2 GU toxicity was 29% and 21%, in the single- and two-fraction arms, respectively, with Grade 2 GI toxicity of 1% and 2%. Beyond the first year, no significant differences in mean urinary HRQOL were seen compared to baseline in the two-fraction arm, in contrast to the single-fraction arm where a decline in urinary HRQOL was seen at 4 and 5 years. Sexual HRQOL was significantly reduced in both treatment arms at all timepoints, with no changes in the bowel domain. ConclusionsHDR monotherapy is well tolerated with minimal impact on HRQOL.