Biochemical Progression-free Survival Research Articles

A Prospective Randomized Trial of Neoadjuvant Chemohormonal Therapy vs Hormonal Therapy in Locally Advanced Prostate Cancer Treated by Radical Prostatectomy.

Benefits of docetaxel-based neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP) remain largely unknown. We explored whether docetaxel-based NCHT would bring pathological benefits and improve biochemical progression-free survival (bPFS) over neoadjuvant hormonal therapy (NHT) in locally advanced prostate cancer. A randomized trial was designed recruiting 141 locally advanced, high-risk prostate cancer patients who were randomly assigned at the ratio of 2:1 to the NCHT group (75 mg/m2 body surface area every 3 weeks plus androgen deprivation therapy for 6 cycles) and the NHT group (androgen deprivation therapy for 24 weeks). The primary end point was 3-year bPFS. Secondary end points were pathological response including pathological downstaging and minimal residual disease rates. The NCHT group showed significant benefits in 3-year bPFS compared to the NHT group (29% vs 9.5%, P = .002). At a median follow-up of 53 months, the NCHT group achieved a significantly longer median bPFS time than the NHT group (17 months vs 14 months). No significant differences were found between the 2 groups in pathological downstaging and minimal residual disease rates. NCHT plus RP achieved significant bPFS benefits when compared with NHT plus RP in high-risk, locally advanced prostate cancer. A larger cohort with longer follow-up duration is essential in further investigation.

Metastasis-Directed Stereotactic Body Radiotherapy in Prostate Cancer Patients Treated with Systemic Therapy and Undergoing Oligoprogression: Report on 11 Consecutive Cases

Background: Stereotactic body radiotherapy (SBRT) targeted at metastatic sites of disease progression is emerging as a potential therapeutic approach for managing oligoprogressive prostate cancer. However, a definitive benefit has yet to be demonstrated. Herein, we present our institution’s experience with this treatment approach. Methods: From April 2018 to March 2023, 11 patients affected by oligoprogressive prostate cancer were treated with SBRT targeting the nodal or bone sites of progression while maintaining the ongoing systemic therapy. Three patients were undergoing single-agent ADT (Androgen Deprivation Therapy), while the remaining eight were receiving a subsequent line of systemic therapy. All patients were evaluated with a pre-treatment 68Ga-PSMA-11 or 18F-fluorocholine PET/CT, which demonstrated between one and five localizations of disease. All the active sites were treated with SBRT in one (15–24 Gy) or three (21–27 Gy) fractions, except for one patient, who was treated in five fractions (35 Gy). PSA serum levels were tested at baseline, one month after RT and at least every three months; all patients underwent a post-treatment 68Ga-PSMA-11 or 18F-fluorocholine PET/CT. The evaluated endpoints were PSA response, defined as a post-treatment decrease >50% from baseline measured within 6 months, time to next-line systemic treatment (NEST), local control (LC), biochemical progression-free survival (bPFS), radiological progression-free survival (rPFS) and freedom from polymetastatic progression (FPP). Results: Nineteen lesions were treated (seven nodal and twelve bone). At a median follow-up of 19 months (7–63), 9 of the 11 patients had a PSA response; all patients had local control of the treated metastases. A total of six patients switched to a next-line systemic treatment, with a median NEST of 13 months. Six patients had polymetastatic progression with an FPP median time of 19 months. No patients died during the follow-up period. The SBRT-related toxicity was negligible. Conclusions: Our data support the use of SBRT targeting the sites of oligoprogressive disease before moving to a subsequent line of systemic treatment in patients with metastatic prostate cancer. Prospective studies to evaluate the potential impact of this approach on overall survival are warranted.

Prognostic utility of biopsy-based PTEN and ERG status on biochemical progression and overall survival after SBRT for localized prostate cancer.

Phosphatase and tensin homolog (PTEN) genomic deletions and transmembrane protease, serine 2/v-ets avian erthyroblastosis virus E26 oncogene homolog (ERG) rearrangements are two of the most common genetic abnormalities associated with prostate cancer. Prior studies have demonstrated these alterations portend worse clinical outcomes. Our objective is to evaluate the impact of biopsy-determined PTEN losses and TMPRSS2-ERG fusion on biochemical progression-free survival (bPFS) and overall survival (OS) in patients who receive SBRT for localized prostate cancer. Patients received SBRT for localized prostate cancer on a prospective quality-of-life (QoL) and cancer outcomes study. For each patient, the single biopsy core with the highest grade/volume of cancer was evaluated for PTEN and ERG abnormalities. Differences in baseline patient and disease characteristics between groups were analyzed using ANOVA for age and χ2 for categorical groupings. bPFS and OS were calculated using the Kaplan Meier (KM) method with Log-Rank test comparison between groups. Predictors of bPFS and OS were identified using the Cox proportional hazards method. For all analyses, p <0.05 was considered statistically significant. Ninety-nine consecutive patients were included in the analysis with a median follow-up of 72 months. A statistically significant improvement in bPFS (p = 0.018) was observed for wild type ERG patients with an estimated 5-year bPFS of 94.1% vs. 72.4%. Regarding PTEN mutational status, significant improvements in were observed in both bPFS (p = 0.006) and OS (p < 0.001), with estimated 5-year bPFS rates of 91.0% vs. 67.9% and 5-year OS rates of 96.4% vs. 79.4%. When including both ERG and PTEN mutational status in the analysis, there were statistically significant differences in both bPFS (p = 0.011) and OS (p < 0.001). The estimated 5-year bPFS rates were 100%, 76.6%, 72.9%, and 63.8% for patients with ERG+/PTEN+, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- phenotypes respectively. The estimated 5-year OS rates were 93.9%, 100%, 80.0%, and 78.7% for patients with ERG+/PTEN+, ERG-/PTEN+, ERG+/PTEN-, and ERG-/PTEN- phenotypes respectively. ERG rearrangements and PTEN deletions detected on biopsy samples are associated with poorer oncologic outcomes in prostate cancer patients treated with SBRT and merit further study in a dedicated prospective trial.

European association of urology risk stratification predicts outcome in patients receiving PSMA-PET-planned salvage radiotherapy for biochemical recurrence following radical prostatectomy

PurposeThe European Association of Urology (EAU) proposed a risk stratification (high vs. low risk) for patients with biochemical recurrence (BR) following radical prostatectomy (RP). Here we investigated whether this stratification accurately predicts outcome, particularly in patients staged with PSMA-PET. MethodsFor this study, we used a retrospective database including 1222 PSMA-PET-staged prostate cancer patients who were treated with salvage radiotherapy (SRT) for BR, at 11 centers in 5 countries. Patients with lymph node metastases (pN1 or cN1) or unclear EAU risk group were excluded. The remaining cohort comprised 526 patients, including 132 low-risk and 394 high-risk patients. ResultsThe median follow-up time after SRT was 31.0 months. The 3-year biochemical progression-free survival (BPFS) was 85.7 % in EAU low-risk versus 69.4 % in high-risk patients (p = 0.002). The 3-year metastasis-free survival (MFS) was 94.4 % in low-risk versus 87.6 % in high-risk patients (p = 0.005). The 3-year overall survival (OS) was 99.0 % in low-risk versus 99.6 % in high-risk patients (p = 0.925). In multivariate analysis, EAU risk group remained a statistically significant predictor of BPFS (p = 0.003, HR 2.022, 95 % CI 1.262–3.239) and MFS (p = 0.013, HR 2.986, 95 % CI 1.262–7.058). ConclusionOur data support the EAU risk group definition. EAU risk grouping for BCR reliably predicted outcome in patients staged lymph node-negative after RP and with PSMA-PET before SRT. To our knowledge, this is the first study validating the EAU risk grouping in patients treated with PSMA-PET-planned SRT.

Updated 5-year results for short course abiraterone acetate and LHRH agonist for unfavorable intermediate and favorable high-risk prostate cancer.

Combined androgen deprivation therapy (ADT) and radiotherapy (RT) improves outcomes for intermediate and high-risk prostate cancer. Treatment intensification with abiraterone acetate/prednisone (AAP) provides additional benefit for high-risk disease. We previously reported 3-year outcomes of a single-arm prospective multicenter trial (AbiRT trial) of 33 patients with unfavorable intermediate risk (UIR) and favorable high risk (FHR) prostate cancer undergoing short course, combination therapy with ADT, AAP, and RT. Here we report the final analysis demonstrating a high rate of testosterone recovery (97%) and excellent biochemical progression-free survival (97%) at 5 years. These data support comparative prospective studies of shorter, more potent ADT courses in favorable high-risk prostate cancer.

99m TcPSMA-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.

Does use of apalutamide enhance outcomes in combination with radiotherapy in metastatic hormone-sensitive prostate cancer? A real-world experience from the UK.

73 Background: Management of metastatic prostate cancer has undergone a significant change over the past decade, with the introduction of several novel agents and repurposing of others. Latest update from STAMPEDE trials shown prostate radiotherapy (RT) improves OS, without detriment in QoL in metastatic home sensitive prostate cancer mHSPC along with Docetaxel in those with low volume metastatic disease. There is no published data on impact of radiotherapy to prostate on Apalutamide treated mHSPC patients. Here we report our real-world experience of Apalutamide in mHSPC with radiotherapy. Methods: Patients with mHSPC (N = 266) from 5 UK centres, were treated with Apalutamide (240 mg) and ADT along with radiotherapy to prostate as per treating clinician’s discretion. The primary endpoint was objective rate (ORR) as determined by patients achieving a PSA decline of ≥90% (PSA90) and ≥50% (PSA50) and secondary endpoints included biochemical progression free survival (bPFS) and safety. Results: The median age for the whole cohort was 73.4 years (interquartile range 52 - 91), A total of 11.6% had received prior radical treatment (prostatectomy or radiotherapy for localised disease) and 88.4% had de novo metastatic disease. Median baseline PSA was 47 ng/ml (range 0.4-17100). The proportion of patients PSA90 and PSA50 at 3, 6 and 12 months is shown in the Table. Median PSA nadir was 0.1 ng/ml(rage 0.01- 48.2) and median time to reach nadir was 6 months (range 3-24 months). 13.5% (35) patients were treated with radiotherapy (RT) after at least 3 months (range 3 -6 months) of starting apalutamide. Patients received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) of radiotherapy (68 % vs 32%). Higher number of patients in RT group had achieved PSA90 compared to no radiotherapy cohort (97.14 % vs 87.3%, p =0.15). Patients treated with RT had median post treatment of PSA 0.01 ng/ml compared to 0.1 ng/ml in non RT group (p=0.0062). After median follow up of 8.4 months, proportion of patients shown biochemical progression in RT vs non RT group were 5.7 % vs 15 % respectively (p= 0.04). Patients with de novo metastatic disease have shown poor PSA response and higher chance of progression compared to patients who had initial radical treatment. Radiotherapy was well tolerated, with 17 % adverse events (Radiation Therapy Oncology Group grade 3–4) reported in radiotherapy group. Conclusions: Early experience of using apalutamide and radiotherapy in mHSPC showed improved PSA response and delayed progression. Treatment was well tolerated. Further follow up and clinical trials are needed to understand the impact on overall survival. [Table: see text]

Total and anatomically contextualized quantitative 18F-DCFPyL PET at biochemical recurrence to predict subsequent biochemical progression-free survival in patients with prostate cancer.

33 Background: PSMA PET has been shown to detect more metastasis and alter management at biochemical recurrence (BCR), but it remains to be determined that it changes oncologic outcome. We assessed the quantitative parameters on 18F-DCFPyL PET at BCR and evaluated their association with tumor volume, metastatic locations with the subsequent biochemical progression free survival (bPFS). Methods: This is a retrospective image analysis and longitudinal follow up of a prospective study evaluating 18F-DCFPyL PET in BCR. Patients were treated with androgen deprivation therapy (ADT) and/or metastatic directed therapy (MDT) based on imaging findings. The 18F-DCFPyL PET images were quantitatively analyzed by the aPROMISE application, a semi-automated software for comprehensive analysis and structured reporting of PSMA PET/CT. aPROMISE uses deep learning to segment detailed anatomical information from the CT images and uses this information in combination with the PET image to detect and quantify candidates for prostate cancer lesions. The reader works in tandem with the software to vet the final list of lesions, from which the quantitative assessments and final report is created automatically. Based on the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. SUV mean, PSMA positive total tumor volume (PSMAttv) and aPSMA scores, a quantitative score for tumor burden measuring the interaction of tumor volume and uptake stratified by local tumors (aPSMA-miT), regional lymph nodes (aPSMA-miN) and distant metastases (aPSMA-miMa for extrapelvic metastases, miMb for bone metastases and miMc for other organ metastases) were obtained based on the miTNM classification. The association of these quantitative parameters with the subsequent bPFS was evaluated. Results: 143 patients (age 70.5 ± 7.9, range 50 -93 years; median PSA 2.8, range 0.12 – 1125.9 ng/mL) were included in the quantitative image analysis. 80 of 143 patients (56%) had nodal metastases 51/143 patients (36%) had bone metastases, only 16 of 143 patients (11%) had visceral metastases. With median follow up of 40 months, 82 of 143 patients (57%) have progressed again biochemically after MDT. The median bPFS was 26.9 months. Quantitative analysis of 18F-DCFPyL PET found that the subsequent bPFS is significantly associated with aPSMA-miMb ( P = 0.003), aPSMA-miN ( P = 0.005), aPSMA-miT ( P &lt; 0.001), and PSMAttv ( P = 0.006), but not with SUVmean, SUVmax or aPSMA-miMc. Conclusions: Quantitative image analysis of 18F-DCFPyL PET at BCR may be useful in predicting the subsequent bPFS. Given many patients were treated with MDT and/or ADT, clinical implication of the findings remains to be elucidated to guide treatment intensification based on findings on 18F-DCFPyL PET.

Dose-escalated Salvage Whole-pelvic Radiotherapy for Biochemical Recurrence After Radical Prostatectomy for High-risk Prostate Cancer.

To investigate the institutional experience of dose-escalated salvage whole-pelvic radiotherapy (WPRT) with the simultaneous integrated boost (SIB) technique in patients with biochemical recurrence (BCR) after radical prostatectomy for high-risk prostate cancer. This retrospective study included 21 patients with BCR who received radical prostatectomy for high-risk prostate cancer and underwent salvage RT. Clinical target volume (CTV) of the whole pelvis (CTV56) included the prostate bed, common iliac, external iliac, internal iliac, and obturator lymph node regions. The boost CTV (CTV66) included the prostate bed. Planning target volumes (PTV) were generated by adding a margin of 6-8 mm to CTV (PTV56 and PTV66). Doses of 56.1 and 66 Gy in 33 fractions were delivered to PTV56 and PTV66, respectively. The 5-year biochemical progression-free survival, overall survival, and cause-specific survival rates were 72%, 94%, and 94%, respectively. A grade 3 late genitourinary toxicity event of gross hematuria was observed in one patient (4%). Acute and late toxicities of grade ≥3, other than gross hematuria, were not observed in any patient. Dose-escalated salvage WPRT using the SIB technique provides appropriate tumor control without increasing the incident of significant toxicities.

A Phase 1 Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy

NCT03253744 is a phase 1 trial with the primary objective to identify the maximum tolerated dose (MTD) of salvage stereotactic body radiation therapy (SBRT) in patients with local prostate cancer recurrence after brachytherapy. Additional objectives included biochemical control and imaging response. This trial was initially designed to test 3 therapeutic dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions. Intensity modulation was used to deliver the prescription dose to the magnetic resonance imaging and prostate-specific membrane antigen-based positron emission tomography imaging-defined gross tumor volume while simultaneously delivering 30 Gy to an elective volume defined by the prostate gland. This phase 1 trial followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until trial completion at 2 years post-SBRT using Common Terminology Criteria for Adverse Events version 5.0. Escalation was halted if 2 dose limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT or any grade ≥3 genitourinary (GU) or grade 4 gastrointestinal toxicity thereafter. Between August 2018 and January 2023, 9 patients underwent salvage SBRT and were observed for a median of 22 months (Q1-Q3, 20-43 months). No grade 3 to 5 adverse events related to study treatment were observed; thus, no dose limiting toxicities occurred during the observation period. Escalation was halted by amendment given excellent biochemical control in DL1 and DL2 in the setting of a high incidence of clinically significant late grade 2 GU toxicity. Therefore, the MTD was considered 42.5 Gy in 5 fractions (DL2). One- and 2-year biochemical progression-free survival were 100% and 86%, representing a single patient in the trial cohort with biochemical failure (prostate-specific antigen [PSA] nadir + 2.0) at 20 months posttreatment. The MTD of salvage SBRT for the treatment of intraprostatic radiorecurrence after brachytherapy was 42.5 Gy in 5 fractions producing an 86% 2-year biochemical progression-free survival rate, with 1 poststudy failure at 20 months. The most frequent clinically significant toxicity was late grade 2 GU toxicity.

Low-dose-rate brachytherapy and long-term treatment outcomes in patients younger than 60 years of age.

Low-dose-rate (LDR) brachytherapy in young men remains controversial amongst urologists due to their concerns regarding long-term biochemical control and treatment-related toxicities. The purpose of this study was to evaluate the treatment outcomes of men under 60 years of age who underwent LDR brachytherapy with iodine-125 (125I) for clinically localized low- to intermediate-risk prostate cancer. All consecutive patients with clinically localized prostate cancer treated at our institution from 2003 to 2016 with 125I monotherapy were included in the study. Prescription dose was 145.0 Gy modified peripheral loading (MPD). All patients were assessed for biochemical progression-free survival using Phoenix definition (nadir +2 ng/ml), clinical progression-free survival, overall survival (OS), and any associated treatment toxicity. A total of 161 patients were included, with a median follow-up of 6.8 years (range, 3-14.54 years). Median age at implant was 57 years (range, 53-59 years). Mean prostate specific antigen (PSA) level at diagnosis was 4.43 ng/ml (SD = 2.29). Majority of men had low-risk prostate cancer (70.2%). Biochemical progression-free survival at 8 years was 94% for the entire cohort. Median PSA at 4 years was 0.169 (IQR, 0.096-0.360), with 45% of patients having a PSA greater than 0.2. OS was 96.9%, with 5 deaths reported but only one was secondary to prostate cancer. Late grade > 2 genitourinary toxicities were reported in 18 patients (11.2%). Three patients (1.9%) developed secondary cancers, all considered unrelated to their LDR brachytherapy. With excellent long-term treatment outcomes and minimal associated toxicities, our results showed that LDR brachytherapy can be an effective treatment of choice in younger men.

Postradical prostatectomy prostate-specific antigen outcomes after 6 versus 18months of perioperative androgen-deprivation therapy in men with localized, unfavorable intermediate-risk or high-risk prostate cancer: Results of part 2 of a randomized phase 2 trial.

Patients with localized, unfavorable intermediate-risk and high-risk prostate cancer have an increased risk of relapse after radical prostatectomy (RP). The authors previously reported on part 1 of this phase 2 trial testing neoadjuvant apalutamide, abiraterone, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6months followed by RP. The results demonstrated favorable pathologic responses (tumor <5mm) in 20.3% of patients (n=24 of 118). Herein, the authors report the results of part 2. For part 2, patients were randomized 1:1 to receive either AAPL for 12months (arm 2A) or observation (arm 2B), stratified by neoadjuvant therapy and pathologic tumor classification. The primary end point was 3-year biochemical progression-free survival. Secondary end points included safety and testosterone recovery (>200ng/dL). Overall, 82 of 118 patients (69%) enrolled in part 1 were randomized to part 2. A higher proportion of patients who were not randomized to adjuvant therapy had a favorable prostatectomy pathologic response (32.3% in nonrandomized patients compared with 17.1% in randomized patients). In the intent-to-treat analysis, the 3-year biochemical progression-free survival rate was 81% for arm 2A and 72% for arm 2B (hazard ratio, 0.81; 90% confidence interval, 0.43-1.49). Of the randomized patients, 81% had testosterone recovery in the AAPL group compared with 95% in the observation group, with a median time to recovery of <12months in both arms. In this study, because 30% of patients declined adjuvant treatment, part B was underpowered to detect differences between arms. Future perioperative studies should be biomarker-directed and include strategies for investigator and patient engagement to ensure compliance with protocol procedures.

Biochemical progression free and overall survival among Black men with stage IV prostate cancer in South Africa: Results from a prospective cohort study.

Men of African descent are disproportionately affected by prostate cancer (PCa), and many have metastatic disease at presentation. In South Africa (SA), androgen deprivation therapy (ADT) is the first-line treatment for stage IV PCa. To identify predictors of overall survival (OS) in Black South African men with stage IV PCa treated with ADT. Men diagnosed with prostate cancer (3/22/2016-10/30/2020) at Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, were recruited for the Men of African Descent with Cancer of the Prostate study. We included men with newly diagnosed stage IV PCa treated with ADT who had a prostate-specific antigen (PSA) level drawn prior to initiation of ADT and had ≥1 PSA drawn ≥12 weeks after ADT start. We used Kaplan-Meier statistics to estimate OS and Cox regression models to identify predictors of OS. Of the 1097 men diagnosed with prostate cancer, we included 153 men with stage IV PCa who received ADT and met PSA requirements. The median age was 68.0 years (interquartile range 64-73 years). Median OS from time of ADT initiation was 3.39 years (95% confidence interval (CI): 3.14%-noncalculable), while biochemical progression-free survival was 2.36 years (95% CI: 2.03%-3.73%). Biochemical progression (HR 3.52, 95% CI: 1.85%-6.70%), PSA nadir level >4 ng/mL (HR 3.77, 95% CI: 1.86%-7.62%), alkaline phosphatase level at diagnosis >150 IU/dL (HR 3.09, 95% CI: 1.64%-5.83%), and hemoglobin at diagnosis <13.5 g/dL (HR 2.90, 95% CI: 1.28%-6.56%) were associated with worse OS. In this study, we identified factors associated with poor OS among Black South African men with stage IV PCa treated with ADT. These factors may be useful in identifying patients for upfront treatment escalation, including the use of docetaxel chemotherapy or escalation of therapy at the time of biochemical progression. In this study, we found that high alkaline phosphatase level, anemia at diagnosis, and high PSA nadir after initiation of androgen deprivation therapy are associated with worse overall survival among Black South African men treated with androgen deprivation therapy for metastatic prostate cancer.

Co-occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer

Background and objectiveBRCA2 mutations in metastatic castration-resistant prostate cancer (mCRPC) confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. However, additional factors predicting PARP inhibitor efficacy in mCRPC are needed. Preclinical studies support a relationship between speckle-type POZ protein (SPOP) inactivation and PARP inhibitor sensitivity. We hypothesized that SPOP mutations may predict enhanced PARP inhibitor response in BRCA2-altered mCRPC. MethodsWe conducted a multicenter retrospective study involving 13 sites. We identified 131 patients with BRCA2-altered mCRPC treated with PARP inhibitors, 14 of which also carried concurrent SPOP mutations. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate (≥50% PSA decline). The secondary endpoints were biochemical progression-free survival (PSA-PFS), clinical/radiographic progression-free survival (PFS), and overall survival (OS). These were compared by multivariable Cox proportional hazard models adjusting for age, tumor stage, baseline PSA level, Gleason sum, prior therapies, BRCA2 alteration types, and co-occurring mutations. Key findings and limitationsBaseline characteristics were similar between groups. PSA responses were observed in 60% (70/117) of patients with BRCA2mut/SPOPwt disease and in 86% (12/14) of patients with BRCA2mut/SPOPmut disease (p = 0.06). The median time on PARP inhibitor treatment was 24.0 mo (95% confidence interval [CI] 19.2 mo to not reached) in this group versus 8.0 mo (95% CI 6.1–10.9 mo) in patients with BRCA2 mutation alone (p = 0.05). In an unadjusted analysis, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (hazard ratio [HR] 0.33 [95% CI 0.15–0.72], p = 0.005) and clinical/radiographic PFS (HR 0.4 [95% CI 0.18–0.86], p = 0.02), and numerically longer OS (HR 0.4 [95% CI 0.15–1.12], p = 0.08). In a multivariable analysis including histology, Gleason sum, prior taxane, prior androgen receptor pathway inhibitor, stage, PSA, BRCA2 alteration characteristics, and other co-mutations, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (HR 0.16 [95% CI 0.05–0.47], adjusted p = 0.001), clinical/radiographic PFS (HR 0.28 [95% CI 0.1–0.81], adjusted p = 0.019), and OS (HR 0.19 [95% CI 0.05–0.69], adjusted p = 0.012). In a separate cohort of patients not treated with a PARP inhibitor, there was no difference in OS between patients with BRCA2mut/SPOPmut versus BRCA2mut/SPOPwt disease (HR 0.97 [95% CI 0.40–2.4], p = 0.94). In a genomic signature analysis, Catalog of Somatic Mutations in Cancer (COSMIC) SBS3 scores predictive of homologous recombination repair (HRR) defects were higher for BRCA2mut/SPOPmut than for BRCA2mut/SPOPwt disease (p = 0.04). This was a retrospective study, and additional prospective validation cohorts are needed. Conclusions and clinical implicationsIn this retrospective analysis, PARP inhibitors appeared more effective in patients with BRCA2mut/SPOPmut than in patients with BRCA2mut/SPOPwt mCRPC. This may be related to an increase in HRR defects in coaltered disease. Patient summaryIn this study, we demonstrate that co-alteration of both BRCA2 and SPOP predicts superior clinical outcomes to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors than BRCA2 alteration without SPOP mutation.

Fixed Duration Combination Therapy with Carfilzomib, Lenalidomide, and Dexamethasone Followed By Lenalidomide Maintenance Leads to High Rates of Sustained MRD Negativity in Patients with High-Risk Smoldering Multiple Myeloma: Long Term Follow up of an Investigator Initiated Phase 2 Trial

Background: Patients with high-risk smoldering multiple myeloma (HR-SMM) have a 5-year risk of progression to symptomatic multiple myeloma of approximately 75% and a median time to progression of less than 2 years (Lakshman et al., Blood Cancer J 2018) (Rajkumar et al., Blood 2015). We previously reported the primary results of our phase 2 trial of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance (KRd-R) as prevention of symptomatic multiple myeloma in patients with HR-SMM (Kazandjian et al., JAMA Onc 2021). Herein, we present follow-up data after all patients have completed lenalidomide maintenance to evaluate the durability of responses off therapy. Methods: Patients with HR-SMM based on the Mayo Clinic, PETHEMA, and/or Rajkumar, Mateos, and Landgren criteria were eligible for enrollment in this single-center phase 2 investigator-initiated study. Patients received eight 28-day cycles (induction) of carfilzomib, 20/36 mg/m 2, with dexamethasone 20/10 (days 1,2, 8, 9, 15, 16) and lenalidomide 25 mg (days 1-21), followed by 2 years of maintenance therapy with lenalidomide 10 mg (days 1-21). The primary endpoint was the rate of minimum residual disease negative complete responses (MRD negative CR) at the end of induction as assessed by multicolor flow cytometry (MRD sensitivity 10 -5). Secondary objectives included progression to overt clinical multiple myeloma (end-organ damage or myeloma-defining event) or death (clinical PFS) and biochemical progression (PD) by IMWG criteria (biochemical PFS). Results: A total of54 patients were enrolled and started treatment between May 29, 2012 and July 23, 2020. Full patient demographics and baseline disease characteristics were previously reported. (Kazandjian et al., JAMA Onc 2021) At the data cut-off of July 17, 2023, the median follow-up time was 60.2 months (range: 33.7 - 127.8). As previously reported, 38 patients (70.4%) achieved MRD negative CR by the end of induction. The median duration of MRD negative CR was 57.4 months (95% CI: 44.6 - 97.2). To date, durability of MRD negative CR has been observed up to 120.6 months and 21 patients (39%) have remained MRD negative for over 2 years (95% CI: 25.9 - 53.1%). (Figure 1) All patients attained a PR or better and the median duration of response has still not been reached. At 60 months, 75.1% of patients maintained their response (95% CI: 59.9 - 85.2%). The median clinical PFS has also not been reached. Only 5 out of 54 (9.3%; 95% CI: 3.1-20.3%) patients have progressed to clinical multiple myeloma. At 60 months, 92.7% of patients were free from clinical progression (95% CI: 78.1 - 97.9%). The probability of being free of clinical progression at 100 months was 78.9% (95% CI: 51.9 - 91.8%). While the median biochemical PFS has not been reached, patients who were MRD negative by the end of induction had significantly less risk of having biochemical progression compared to patients who still had measurable disease at completion of induction (median biochemical PFS NR vs. 41.8 (HR 0.168 (95% CI: 0.060 - 0.474) (P value &amp;lt; 0.0001) (Figure 2). As previously reported, KRd-R was well tolerated, with no grade 4 non-hematologic adverse events and manageable low-grade toxicities. Discussion: Treatment of patients with HR-SMM with KRd-R has led to deep and durable remissions. At a median of 5 years of follow-up, this trial has yet to reach a median clinical PFS, indicating success in preventing serious end organ damage. However, it is still unclear if the beneficial outcomes seen in HR-SMM interventional studies are due to treatment of more susceptible disease or inherently less aggressive disease. An abstract evaluating the genomic profile of patients from this trial has been submitted to the meeting separately. Future prospective trials must capture and eventually select HR profiles based on validated genomic signatures. This study suggests that patients who achieve MRD negative remissions after induction therapy have prolonged biochemical PFS. However, further follow-up time is needed to fully understand the rates of clinical PFS and OS. To evaluate if additional treatment duration to achieve MRD negativity would be beneficial we have designed a trial using daratumumab, carfilzomib, and dexamethasone utilizing an adaptive treatment duration based on MRD status for patients with HR-SMM which is currently enrolling participants (NCT04933539).

Salvage Cryoablation for Recurrent Prostate Cancer Following Primary External Beam Radiotherapy or Primary Cryotherapy: A Propensity Score Matched Analysis of Mid-term Oncologic and Functional Outcomes.

Local prostate cancer recurrence following radiotherapy (XRT) or cryoablation (CRYO) may be addressed with salvage cryotherapy (SCT), although little is known about how the primary treatment modality affects SCT results. Oncologic and functional outcomes of patients who underwent SCT after primary XRT (XRT-SCT) or cryoablation (CRYO-SCT)were studied. Data was collected using the Duke Prostate Cancer database and the Cryo On-Line Data (COLD) registry. The primary outcome was biochemical progression-free survival (BPFS). Urinary incontinence, rectourethral fistula, and erectile dysfunction were secondary outcomes. The Kaplan-Meier log-rank test and univariable/multivariable Cox proportional hazards (CPH) models were utilized to evaluate BPFS between groups. 419 XRT-SCT and 63 CRYO-SCT patients met inclusion criteria, that was reduced to 63 patients in each cohort after propensity matching. There was no difference in BPFS at 2 and 5 years both before (P=.5 and P=.7) and after matching (P=.6 and P=.3). On multivariable CPH, BPFS was comparable between treatment groups (CRYO-SCT, HR=1.1, [0.2-2.2]). On the same analysis, BPFS was lower in D'Amico high-risk (HR 3.2, P < .01) and intermediate-risk (HR 1.95, P < .05) categories compared to low-risk. There was no significant difference in functional outcomes between cohorts. Following primary cryotherapy, salvage cryoablation provides comparable intermediate oncological outcomes and functional outcomes compared to primary radiotherapy.

Outcomes in Locally Advanced Non-Metastatic Prostate Cancer Presenting with Low PSA at Diagnosis.

Men with low serum prostate-specific antigen (PSA) and high Gleason grade group (GGG) are thought to have poor outcomes compared to high PSA secretors. However, there is limited outcome data to support this. We report clinical outcomes from a single-institutional cohort of men presenting with locally advanced prostate cancer but low serum PSA. Data from electronic database of a UK tertiary cancer center was acquired for men with histological diagnosis of prostate adenocarcinoma, GGG 4 or 5, stage ≥cT3a, and PSA <10ug/L at diagnosis. Men with metastatic disease, or prior androgen deprivation therapy (ADT) were excluded. Biochemical progression was defined as per Phoenix criteria (PSA > nadir+2) for primary radiotherapy, or PSA >0.2 ug/L after primary prostatectomy (and post-operative radiotherapy, if received). Overall survival (OS, from date of diagnosis to death), metastasis-free survival (MFS, from diagnosis to first recorded metastasis or death), and biochemical progression free survival (bPFS, from diagnosis to biochemical progression or death) were estimated by Kaplan Meier method, and multivariable analysis performed using Cox proportional hazards method. Medical records of 7,200 men presenting with non-metastatic prostate cancer from 2013 to 2021 were screened, of which 270 men satisfying the eligibility criteria were included for this study. Initial analysis of 123 men shows median PSA at presentation 7.1 ug/L (IQR 5.6-8.5), and median age 70 years (IQR 65-75). Histology was GGG 4 in 47.6% and 5 in 52.4%. Tumor stage was cT3a in 56.6%, cT3b in 36.9%, and T4 in 6.6%. Pelvic nodes were involved in 5% patients. Majority (83.7%) were treated with radical radiotherapy (external beam alone 64.2%, brachytherapy boost 19.5%), with 24 months ADT; 11.4% underwent radical prostatectomy, and 4.9% received ADT alone. Three men (2.4%) received docetaxel, and one received abiraterone. At a median follow up of 66 months (IQR 27-77), 36 (29.3%) patients had biochemical failure. Total 23 (18.6%) patients had metastases at recurrence, which were visceral in 4%, bone-only in 10%, and nodal-only in 4%. Total 38 (30.6%) patients had died, 23% with prostate cancer and 11% due to other causes. Five-year bPFS was 65.9%, MFS 69.0%, and OS was 77.4%. GGG 5 (versus 4) was associated with significantly worse 5-year bPFS (59.4% vs 73.9%, HR 1.8, 95% CI 1.0-3.2, p = 0.05) and MFS (59.2% vs 81.6%, HR 2.2, 1.2-4.2, p = 0.02). On multivariable analysis including age and PSA at diagnosis, only GGG 5 was associated with worse bPFS (HR 1.8, 1.0-3.3, p = 0.05) and MFS (HR 2.42, 1.25-4.67, p = 0.009). Men with low secreting but high Gleason grade group prostate cancer are a relatively rare group with poor clinical outcomes despite being non-metastatic. Ongoing work (expected completion June 2023) will analyze remaining cases, and compare outcomes within an expanded multicentric cohort with matched controls having elevated PSA at presentation.

Three Months PSA Response after PSMA-Guided Approach for Biochemical Relapse after Prostatectomy (PSICHE Trial).

Prostate bed salvage radiotherapy (SRT) is currently the main approach for early biochemical relapse (BR) after radical prostatectomy (RP). Nonetheless, 68Ga-PSMA-11 PET/CT implementation in this scenario prompted significant changes in patients' management. Our trial is aimed to prospectively assess the oncological outcomes after a pre-defined, 68Ga-PSMA-11 PET/CT based treatment strategy. In this analysis, we present early results focusing on three-months biochemical outcomes after treatment. Inclusion criteria were BR after RP (PSA ≥0.2 ng/ml; < 1 ng/ml) +/- postoperative SRT. All patients with PSA persistence after RP (PSA >0.2 ng/ml within 16 weeks from surgery) were excluded from the trial. After centralized 68Ga-PSMA PET/CT, a pre-defined treatment approach was proposed, consisting in Observation and re-staging at further PSA progression in case of negative 68Ga-PSMA PET/CT and previous postoperative RT, prostate bed SRT in case of negative imaging or positive imaging within prostate bed, Stereotactic body radiotherapy (SBRT) to all sites of disease in patients with pelvic nodal recurrence or oligometastatic disease (defined as (< 3 non-visceral metastatic lesions) or Androgen deprivation therapy +/- other systemic treatment indicated for hormone sensitive prostate cancer for widespread metastatic disease. PSA ≤0.2 ng/ml or ≤ 50% of baseline were defined as Complete or partial biochemical response (CBR or PBR), respectively. At present, 135 patients were enrolled within the protocol. Current analysis is focused on a cohort of patients with at least three months of follow up and excludes all patients who underwent only observation after re-staging due to previous prostate bed SRT (n = 42). In this subgroup, PBR or CBR were detected in 28 (66.7%) and 25 (59.5%) patients, respectively. PSA reduction if compared to baseline was detected in 34 patients, for an overall biochemical response rate of 80.9%. Biochemical progression after treatment was reported in 3 patients, who underwent a second 68Ga-PSMA PET/CT re-staging with detection of distant metastases. Promising results after a 68Ga-PSMA PET/CT targeted salvage treatment strategy were reported in terms of early biochemical response. This approach may allow to defer systemic treatment in this setting. Biochemical relapse free and progression free survival will be the objects of further analysis after longer follow-up.

Multi-Institutional Analysis of Metastasis Directed Therapy with or without Androgen Deprivation Therapy in Oligometastatic Castration Sensitive Prostate Cancer.

Several prospective trials in oligometastatic castration sensitive prostate cancer (omCSPC) have shown metastasis-directed therapy (MDT) can delay time to progression and initiation of androgen deprivation therapy (ADT) compared to observation. However, the optimal integration of ADT with MDT remains unclear. Here we report a multi-national, multi-institutional retrospective cohort of omCSPC treated with MDT to characterize the long-term outcomes of patients treated with MDT alone or in combination with ADT. Patients with a controlled primary site and omCSPC (defined as ≤ 5 lesions on conventional imaging) treated with MDT with or without concurrent ADT and with at least 36 months follow-up were retrospectively screened across 13 institutions. The primary endpoints included biochemical progression free survival (bPFS) and radiographic progression free survival (rPFS) calculated using Kaplan-Meier method and stratified by treatment group (MDT alone vs MDT + ADT). Multivariable Cox regression was performed adjusted for variables found to be prognostic on univariate analysis. Among 414 patients screened, a total of 263 patients treated between 2003 and 2018 met inclusion criteria and included. Of these, 105 received MDT alone and 158 received MDT+ADT, with median follow-up of 49.5 and 54.5 months, respectively. The majority were metachronous (90%) and had bone lesions (60%). Median ADT duration was 21.3 months (IQR 12.0- 31.9). Patients who received ADT vs. no ADT had poorer prognostic features including 23% vs. 1% synchronous (p<0.001), and 55% vs 40% Gleason 8-10 (p = 0.012). ADT use was associated with a better 5-year bPFS 24% vs 11% (p<0.0001) and rPFS 41% vs 29% (p<0.001). On multivariable Cox regression adjusting for post-MDT PSA nadir and salvage therapy, ADT use maintained significance for both bPFS (HR 0.51 (0.36, 0.71), p<0.001) and rPFS (HR 0.67, 95% CI 0.46-0.96, p = 0.03). Long-term outcomes with MDT alone suggest a small proportion of patients experience sustained disease control. The addition of ADT appears to improve rPFS, however prospective studies are needed in order to allow for personalization of care in patients with omCSPC.

Patterns of Recurrence Following Radiation and ADT for Pathologic Lymph Node Positive Prostate Cancer: A Multi-Institutional Study

Retrospective studies have suggested that post-operative radiation therapy (RT) can reduce the risk of cause-specific mortality in men with pathologic nodal involvement (pN1) after radical prostatectomy (RP). We evaluated prognostic factors and patterns of recurrence in patients who received post-operative RT +/- androgen deprivation therapy (ADT) for pN1 disease in a multicentric cohort of 4 academic centers. Data from patients with pN1 prostate cancer after RP who subsequently received RT with short term (< = 6 mo) or long term (>6 mo) ADT were obtained from 4 academic institutions. Patterns of recurrence, biochemical progression free survival (bPFS) and distant metastasis free survival (DMFS) were evaluated. A total of 270 patients with a median follow-up of 48 months were included. Gleason grade group (GG) 2 was present in 20 patients (7.5%), GG 3 in 81 (30%), GG4 in 36 (13.5%), GG5 in 130 (49%) patients. 256 (95%) patients had extracapsular extension, 70% had seminal vesicle invasion, 59% had positive surgical margins, and 66% had a detectable post-operative PSA. The number of positive nodes at surgery were 1 in 59%, 2 in 19% and >2 in 22% of patients. Of the 83 patients that had pre-RT imaging, 46 (55%) had a PET scan (PSMA, or fluciclovine); 25 (30%) of those had lymph nodes detected on imaging prior to RT. Median time from RP to RT was 6 mo (IQR 4.5-9.1 mo). 96% received radiation to both the prostate bed (median dose 68.4Gy) and pelvic lymph nodes (median dose 46Gy). ADT was prescribed short-term (20%) or long-term (68%), while 26 (10%) received no ADT, and 7 (3%) had an unknown duration. Biochemical failure (bF) was observed in 29% of men, with 5% having pelvic nodal failure and 11.5% having distant metastases (majority in bones, followed by paraaortic nodes) at last follow up. Of 59 patients who had normal baseline testosterone levels, 37% recovered their testosterone by last follow-up. The 4-year bRFS was 72% for all patients and was 83% for those with a pre-RT PSA of <0.1 ng/mL, 76% for PSA 0.1-<0.5 ng/mL, 60% for PSA 0.5-2 ng/mL, and 35% for PSA >2 ng/mL. On multivariable analysis, maximum pre-RT PSA ≥0.5 (0.5 to 2.0 vs <0.1 HR = 3.19; >2.0 vs <0.1 HR = 9.00), use of LTADT (HR = 0.47), and percent pN1 (HR = 1.03) were significantly associated with bF. Pre-RT PSA >2 (HR = 4.10), use of LT ADT (HR = 0.33) and percent pN1 (HR = 1.03) were also significantly associated with DM. In pN1 patients, pelvic RT and ADT at low PSA levels is associated with improved oncologic outcomes compared to treatment at higher levels, suggesting that PSA may have prognostic value for pN1 prostate cancer.