Metastatic Castration-sensitive Prostate Cancer Research Articles

166P Comparative assessment of prognostic outcomes between vintage hormonal therapy and androgen deprivation therapy combined with novel androgen pathway inhibitor in Japanese patients with metastatic castration-sensitive prostate cancer

In recent years, therapeutic strategy for metastatic castration-sensitive prostate cancer (mCSPC) have been drastically changed since the introduction of combined treatment with conventional androgen-deprivation therapy (ADT) and novel androgen pathway inhibitor (ARPI). In Japanese real-world clinical practice, however, it remains common to perform vintage hormonal therapy (VHT) either by ADT alone or combined androgen blockade (CAB). The objective of this study was to analyze the impacts of upfront hormonal therapies on the prognostic outcomes in Japanese mCSPC patients. This study included 581 consecutive mCSPC patients consisting of 305 and 276 who received VHT (VHT group) and ADT plus ARPI (ARPI group), respectively, as first-line therapy. Potential parameters associated with PSA-progression free survival (PFS) and overall survival (OS) in these patients were investigated. Median PFS and OS of the 581 patients was 27 months and not reached, respectively. Multivariate analyses of several factors identified independent predictors associated with unfavorable PFS as follows: high alkaline phosphatase, high lactate dehydrogenase (LDH), number of bone metastasis ≥3, existence of symptoms, treatment with VHT, and those associated with unfavorable OS as follows: older age, poor performance status, high LDH, existence of symptoms. In LATITUDE low risk patients, the median PFSs were 36.6 months and not reached in the VHT and ARPI groups (P = 0.071), respectively, and the median OSs were not reached in both groups (P = 0.60). In LATITUDE high risk patients, the median PFSs were 12.4 months and not reached in the VHT and ARPI groups (P <0.001), respectively, and the median OSs were 40.2 months and not reached in the VHT and ARPI groups (P = 0.023), respectively. These findings suggest that it could be expected to achieve favorable prognostic outcomes in mCSPC patients, particularly those classified into LATITUDE high risk, by introducing ADT plus ARPI, rather than VHT, as first-line therapy.

Continuing enzalutamide with docetaxel in castration-resistant prostate cancer.

In metastatic prostate cancer, several life-prolonging therapeutics, such as novel androgen receptor pathway inhibitors, abiraterone acetate and second-generation antiandrogens, and the chemotherapeutic agent docetaxel, are available for both metastatic castration-sensitive prostate cancer and metastatic castration-resistant prostate cancer (mCRPC). Similarly, cabazitaxel, radioisotopes, and poly(ADP-ribose) polymerase inhibitors are available for the treatment of mCRPC. There is currently no evidence of a survival benefit of combination therapy in mCRPC, and life-prolonging drugs are administered sequentially for patients with mCRPC. However, the potential ability of combination therapy to delay progression has been shown in the CHEIRON (adding enzalutamide to docetaxel), 1 Caffo O Ortega C Nolè F et al. Docetaxel and prednisone with or without enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer: CHEIRON, a randomised phase II trial. Eur J Cancer. 2021; 155: 56-63 Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar ACIS (adding apalutamide to abiraterone plus prednisone), 2 Saad F Efstathiou E Attard G et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021; 22: 1541-1559 Summary Full Text Full Text PDF PubMed Scopus (18) Google Scholar IPATential150 (adding ipatasertib to abiraterone plus prednisone or prednisolone), 3 Sweeney C Bracarda S Sternberg CN et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021; 398: 131-142 Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar and PROpel (adding olaparib to abiraterone plus prednisone or prednisolone) trials. 4 Saad F Armstrong AJ Thiery-Vuillemin A et al. PROpel: phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Proc Am Soc Clin Oncol. 2022; 40: 11 Crossref Google Scholar Additionally, the survival benefit of combinations of androgen receptor pathway inhibitors, including the addition of abiraterone or the second-generation antiandrogen darolutamide to castration plus docetaxel, was shown in the PEACE-1 (adding abiraterone plus prednisone to docetaxel) 5 Fizazi K Foulon S Carles J et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022; 399: 1695-1707 Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar and ARASENS (adding darolutamide to docetaxel) trials. 6 Smith MR Hussain M Saad F et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022; 386: 1132-1142 Crossref PubMed Scopus (80) Google Scholar Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b studyPRESIDE met its primary endpoint and showed that continuing enzalutamide with docetaxel plus androgen deprivation therapy delayed time to progression compared with docetaxel plus androgen deprivation therapy alone, supporting the hypothesis that enzalutamide maintenance could control persistent androgen-dependent clones in men with mCRPC who progress after treatment with enzalutamide alone. Full-Text PDF

A Phase 1b Adaptive Androgen Deprivation Therapy Trial in Metastatic Castration Sensitive Prostate Cancer.

Background: We hypothesize that cancer survival can be improved through adapting treatment strategies to cancer evolutionary dynamics and conducted a phase 1b study in metastatic castration sensitive prostate cancer (mCSPC). Methods: Men with asymptomatic mCSPC were enrolled and proceeded with a treatment break after achieving > 75% PSA decline with LHRH analog plus an NHA. ADT was restarted at the time of PSA or radiographic progression and held again after achieving >50% PSA decline. This on-off cycling of ADT continued until on treatment imaging progression. Results: At data cut off in August 2022, only 2 of the 16 evaluable patients were off study due to imaging progression at 28 months from first dose of LHRH analog for mCSPC. Two additional patients showed PSA progression at 12.4 and 20.5 months and remain on trial. Since none of the 16 patients developed imaging progression at 12 months, the study succeeded in its primary objective of feasibility. The secondary endpoints of median time to PSA progression and median time to radiographic progression have not been reached at a median follow up of 26 months. Conclusions: It is feasible to use an individual’s PSA response and testosterone levels to guide intermittent ADT in mCSPC.

Development and Validation of a Multivariable Prognostic Model in De Novo Metastatic Castrate Sensitive Prostate Cancer: Exploring Potential Avenue for Risk Stratification and Treatment Personalization

<h3>Purpose/Objective(s)</h3> Metastatic castrate sensitive prostate cancer (mCSPC) is a heterogeneous disease state with patients having variable prognosis. Although several life-prolonging systemic agents are available, there is no robust multivariable model to predict prognosis and improve risk stratification in mCSPC. The purpose of our study was to investigate if baseline disease attributes, patient level characteristics, and blood-based markers are associated with overall survival in patients with de novo metastatic castrate sensitive prostate cancer. <h3>Materials/Methods</h3> We used data from LATITUDE, a phase III randomized controlled trial in which men with <i>de novo</i> mCSPC were randomly allocated to either ADT plus abiraterone or ADT with placebo. Patients with non-missing data (n=1,058) were randomly split in a 70:30 ratio to training (n=743) and testing (n=315) sets. Elastic net regression was used for variable selection. A multivariable Cox regression model for overall survival (OS) was then fitted using the selected variables. The predictive accuracy of the model was assessed on the testing set using the time-dependent area under curve (tAUC) with bootstrapped confidence intervals for OS and radiographic progression-free survival (rPFS). <h3>Results</h3> The 11 prognostic variables in the final model were performance status, number of skeletal metastases, Gleason score, presence of liver metastasis, baseline pain score, albumin, LDH, PSA, hemoglobin, and treatment arm (abiraterone vs placebo). The tAUC of the model for predicting OS at 2- and 3-years was 0.74 (95% confidence intervals [CI], 0.67-0.80) and 0.72 (95% CI, 0.65-0.77), respectively. The tAUC for progression-free survival at 2- and 3-years was 0.71 (95% CI, 0.64-0.76) and 0.76 (95% CI, 0.70-0.82), respectively. We stratified patients as high, intermediate, or low risk based on 33% and 67% quantiles of the risk score. The 3-year OS in the three risk groups were 34.2% (95%CI, 25.9-45.1), 56.6% (95%CI, 47.8-67.0), and 78.4% (95%CI, 70.2-87.5), respectively. <h3>Conclusion</h3> We developed a prognostic model for predicting OS in men with newly diagnosed mCSPC. We validated our 11-variable model and demonstrated a high level of prognostic accuracy, significantly exceeding that described in previous models in mCSPC patients The model consists of standard laboratory markers, patient characteristics, and disease attributes that are essential for guiding treatment decisions in this patient population and provides a way to tailor treatment and stratify patients for participation in future clinical trials.

Survival outcomes and characterization of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT) who do not achieve an optimal PSA response (PSA ≤0.2 ng/mL).

By Nicolas Sayegh, Nishita Tripathi & 13 more. A study on survival outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC) undergoing intensified androgen deprivation therapy (ADT)

Progression-free survival (PFS) and overall survival (OS) in patients (pts) with de-novo, high-volume metastatic castration-sensitive prostate cancer (dn-hv-mCSPC) undergoing intensified androgen deprivation therapy (ADT)

Progression-free survival (PFS) and overall survival (OS) in patients (pts) with de-novo, high-volume metastatic castration-sensitive prostate cancer (dn-hv-mCSPC) undergoing intensified androgen deprivation therapy (ADT)

Transcriptomic profiling of patients (pts) with de-novo metastatic castration-sensitive prostate cancer (DN-mCSPC) versus those with mCSPC that have relapsed from prior localized therapy (PLT-mCSPC)

Transcriptomic profiling of patients (pts) with de-novo metastatic castration-sensitive prostate cancer (DN-mCSPC) versus those with mCSPC that have relapsed from prior localized therapy (PLT-mCSPC)

Triple therapy for metastatic castration sensitive prostate cancer: PEACE-1 trial.

Triple therapy for metastatic castration sensitive prostate cancer: PEACE-1 trial.

Early prostate-specific antigen response among Black and non-Black patients with advanced prostate cancer treated with apalutamide.

Aim: To assess reduction in prostate-specific antigen (PSA) levels among Black and non-Black patients treated with apalutamide for non-metastatic castration-resistant prostate cancer (nmCRPC) or metastatic castration-sensitive prostate cancer (mCSPC). Patients & methods: Patients were identified from electronic medical data. PSA reduction (≥50%, ≥90%or below 0.2 ng/ml) after apalutamide initiation was assessed. Results: A total of 313 patients with nmCRPC and 260 patients with mCSPC were identified. The majority of patients treated with apalutamide achieved a 90% reduction in PSA regardless of indication or race. The proportion of patients achieving a PSA reduction at any level was similar among Black and non-Black patients and was consistent with apalutamide phase III trials. Conclusion: In routine clinical practice, apalutamide consistently produced reduction in PSA levels in Black and non-Black men with nmCRPC or mCSPC.

4MO Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer

De novo metastatic castration-sensitive prostate cancer (mCSPC) is highly aggressive, but the lack of routine tumour tissue in this setting hinders genomic stratification and jeopardizes precision oncology efforts. Accurate molecular profiling at diagnosis is imperative for genomics-informed risk stratification and biomarker-guided treatment. Currently, it is unclear the extent that intrapatient heterogeneity impacts clinical cancer genotyping.

First-line Therapy for Metastatic Castration-sensitive Prostate Cancer

First-line Therapy for Metastatic Castration-sensitive Prostate Cancer

Association of dynamic change in patient-reported pain with survival in metastatic castrate sensitive prostate cancer-exploratory analysis of LATITUDE study.

Pain is an important dimension of quality-of-life in patients with metastatic castrate-sensitive prostate cancer (mCSPC). However, it is unclear if dynamic change in pain over time can predict for overall survival (OS) or progression-free survival (PFS) in these patients. This is an exploratory analysis of LATITUDE, a phase III randomized study, in which men with de novo mCSPC were randomized to receive either ADT plus abiraterone versus ADT alone. Information was collected on patient-reported worst pain score (WPS) and pain-interference score (PIS) from the Brief Pain Inventory-Short Form. A Bayesian joint modelling approach was used determine the association of dynamic change in WPS and PIS with OS and PFS. Overall, 1125 patients with at least 3 measurements on pain scores were eligible. On Cox multivariable regression, increase in baseline WPS was associated with inferior OS (hazard ratio [HR] 1.049 [95% confidence intervals [CI] 1.015-1.085]; time dependent area under curve [tAUC] 0.64) and PFS (HR 1.045 [1.011-1.080]; tAUC: 0.64). Increase in baseline PIS was associated with inferior OS (HR 1.062 [1.020-1.105]; tAUC: 0.63) but not with PFS (HR 1.038 [0.996-1.08]). On independent joint models, an increase in the current value of WPS by 1-unit was associated with inferior OS (HR 1.316 [1.258-1.376]; tAUC 0.74) and PFS (HR 1.319 [1.260-1.382]; tAUC 0.70). Similar association was seen for increase in the current value of PIS with OS (HR 1.319 [1.261-1.381]; tAUC 0.73) and PFS (HR 1.282 [1.224-1.344]; tAUC 0.73). The above findings highlight the potential dynamic interplay between patient-reported pain with OS and PFS in mCSPC. Compared to baseline pain, such dynamic assessment of pain was found to have superior predictive ability and thus has the potential to tailor subsequent treatment based on response to initial therapy beyond its role as a very important dimension of quality-of-life.

SPOP Mutations as a Predictive Biomarker for Androgen Receptor Axis-Targeted Therapy in De Novo Metastatic Castration-Sensitive Prostate Cancer.

Intensification of androgen deprivation therapy (ADT) with either docetaxel or androgen receptor axis-targeted therapies (ARAT) are the current standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC). However, biomarkers guiding treatment selection are lacking. We hypothesized that ADT intensification with ARAT, but not with docetaxel, would be associated with improved outcomes in patients with de novo (dn)-mCSPC harboring SPOP mutations. Patient-level data from a deidentified nationwide (U.S.-based) prostate cancer clinico-genomic database between January 2011 and December 2021 were extracted. Eligibility criteria: diagnosis of metastatic disease within 30 days of original prostate cancer diagnosis, genomic profiling of a tissue biopsy collected within 90 days of original diagnosis, and initiation of ARAT or docetaxel within 120 days of initial diagnosis. The log-rank test and Cox proportional hazards models were used to compare time to castration-resistant prostate cancer (TTCRPC) and overall survival (OS) for patients with and without SPOP mutations undergoing ADT intensification with ARAT or docetaxel. In the ARAT cohort, presence of SPOP mutation compared with wild-type was associated with more favorable TTCRPC [not reached (NR) vs. 16.7 months; adjusted HR (aHR), 0.20; 95% confidence interval (CI), 0.06-0.63; P = 0.006] and OS (NR vs. 27.2 months; aHR, 0.19; 95% CI, 0.05-0.79; P = 0.022). In contrast, SPOP mutation status was not associated with TTCRPC or OS in docetaxel-treated cohort. In real-world settings, SPOP mutations were associated with improved outcomes to ADT plus ARAT (but not ADT plus docetaxel) in patients with dn-mCSPC. This may serve as a predictive biomarker to guide treatment selection for patients with mCSPC.

1417P Mixed treatment comparisons evaluating contemporary therapies in metastatic castration sensitive prostate cancer (mCSPC): A living systematic review

Results from recent trials (PEACE-1, and ARASENS), the disease heterogeneity in mCSPC and lack of direct comparisons between triplets and novel hormonal therapy (NHT) doublets prompted us to assess the comparative effectiveness of contemporary treatments accounting for volume of disease.

1376P Association of dynamic change in patient-reported pain with survival in metastatic castrate sensitive prostate cancer: Exploratory analysis of LATITUDE study

Pain is an important dimension of quality-of-life in patients with metastatic castrate-sensitive prostate cancer (mCSPC). However, it is unclear if dynamic change in pain over time can predict for overall survival (OS) or time to radiographic progression (TTRP) in these patients.

1384P Treatment patterns and overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) from 2010 to 2019

1384P Treatment patterns and overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) from 2010 to 2019

1361MO 8-month PSA strongly predicts outcomes of men with metastatic castration-sensitive prostate cancer in the PEACE-1 phase III trial

1361MO 8-month PSA strongly predicts outcomes of men with metastatic castration-sensitive prostate cancer in the PEACE-1 phase III trial

1421P Effect of abiraterone-prednisone in metastatic castration-sensitive prostate cancer (mCSPC) with neuroendocrine and very high-risk features in the PEACE-1 trial

The PEACE-1 trial demonstrated improved overall survival (OS) in de novo mCSPC patients treated with a combination of androgen deprivation therapy, docetaxel, and abiraterone (AA) plus prednisone. Prostate cancers with neuroendocrine differentiation (NEPC) are rare. Most trials exclude de novo NEPC, thus their standard of care remains uncertain. As NEPC was allowed in PEACE-1, we aimed to assess the effect of AA in NEPC and those with very high-risk factors (Gleason >8, liver metastases).

1413P Tumor transcriptomic profiling of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) who do not achieve optimal PSA response to intensified androgen deprivation therapy (ADT-I)

Pts with mCSPC undergoing ADT-I and achieving a PSA nadir ≤0.2 ng/mL (PSA-L) any time after start of therapy was associated with improved overall survival (OS) versus those with a PSA nadir >0.2 ng/mL (PSA-H) (HR: 0.17, P<0.0001) (Chi AUA 2021, abstract 1281). We hypothesized that tumor gene expression profiling in PSA-H would be distinct from PSA-L. Eligibility: confirmed mCSPC on ADT-I with Androgen Receptor Axis Targeted Therapy (ARAT) and availability of RNAseq profiling performed by a CLIA-certified lab using primary prostate biopsies collected before treatment. DEseq2 package was used to identify differentially expressed genes in PSA-H versus PSA-L cohorts. Gene Set Enrichment Analysis (GSEA) was used to identify pathways enriched in each cohort. All analyses were done using R v4.2. Eligible pts= 33 (11 PSA-H, 22 PSA-L) had a median age 65 years, median baseline PSA of 23.3 ng/ml, Gleason ≥8 ∼79%, de novo 55% and high-volume disease per CHAARTED criteria ∼52%. Pts with PSA-H had downregulation of the androgen response, estrogen response, and TNF-α signaling pathway, and upregulation of the interferon-alpha and coagulation pathway (Table).Table: 1413PGSE Scores contrast PSA-H versus PSA-LPathwayNormalized enrichment score (NES)P-valueQ-valuesTNFA_Signaling via_NFKB-2.04632<<<0.001<<<0.001Androgen response-1.67726<0.0010.005Estrogen response late-1.64446<<0.0010.001Coagulation1.5609930.0010.005Interferon-alpha response1.890529<<0.0010.001Positive NES = upregulation in PSA-H pts, and negative NES = downregulation in PSA-H pts Open table in a new tab Positive NES = upregulation in PSA-H pts, and negative NES = downregulation in PSA-H pts mCSPC pts not achieving an optimal response to ADT-I have downregulated pre-treatment tumor AR signaling and TNF-α signaling and upregulation of inflammatory molecular pathways characterized by increased angiogenesis, adhesiveness, and invasiveness (PMIDs: 34696780, 12429291). After external validation, these data may provide upfront identification of patients who may not respond to intensified ADT, and aid with counselling, prognostication, and trial enrollment.

1373P SPOP mutations (mtSPOP) are a treatment-selection biomarker in patients (pts) with de novo metastatic castration-sensitive prostate cancer (dn-mCSPC)

Intensification of androgen deprivation therapy (ADT) with docetaxel or androgen receptor axis-targeted therapy (ARAT: abiraterone, apalutamide, enzalutamide) is the current standard of care for pts with mCSPC. However, biomarkers to guide treatment selection are lacking. We previously showed that dn-mCSPC pts with mtSPOP had improved survival outcomes with ADT (PMID: 32624276). Here, we hypothesized that mtSPOP would be associated with improved outcomes with ARAT + ADT but not with docetaxel + ADT.