Bone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer

doi:10.1016/j.eururo.2014.10.001

European Urology

Volume 68, Issue 1, July 2015, Pages 42-50

https://doi.org/10.1016/j.eururo.2014.10.001 Get rights and content

Abstract

Background

Previous studies have reported on prognostic factors for castration-resistant prostate cancer (CRPC); however, most of these studies were conducted before docetaxel chemotherapy was approved for CRPC.

Objective

To evaluate the prognostic value of multiple parameters in men with bone metastases due to CRPC using a contemporary dataset.

Design, setting, and participants

The analysis included 1901 patients with metastatic CRPC enrolled in an international, multicenter, randomized, double-blind phase 3 trial conducted between May 2006 and October 2009.

Outcome measures and statistical analysis

We developed multivariate validated Cox proportional hazards models and nomograms to estimate 12-mo and 24-mo survival probabilities and median survival time.

Results and limitations

The median (95% confidence interval) overall survival was 20 (18, 21) mo. The final model included 12 of the 15 potential prognostic variables evaluated (concordance index 0.72). Seven bone-related variables were associated with longer survival in the final model: alkaline phosphatase ≤143 U/l (p < 0.0001); bone-specific alkaline phosphatase (BSAP) <146 U/l (p < 0.0001); corrected urinary N-telopeptide (uNTx) ≤50 nmol/mmol (p = 0.0008); mild or no pain (Brief Pain Inventory—Short Form [BPI-SF] score ≤4) (p < 0.0001); no previous skeletal-related event (SRE; p = 0.0002); longer time from initial diagnosis to first bone metastasis (p < 0.0001); and longer time from first bone metastasis to randomization (p < 0.0001). Other significant predictors of improved survival included prostate-specific antigen (PSA) level <10 ng/ml (p < 0.0001), hemoglobin >128 g/l (p < 0.0001), absence of visceral metastases (p < 0.0001), Eastern Co-operative Oncology Group (ECOG) score ≤1 (p = 0.017), and younger age (p = 0.008). Nomograms were generated based on the parameters included in the final validated models (with/without uNTx and BSAP). One limitation was that lactate dehydrogenase (LDH) levels, a known prognostic factor, were not available in this study.

Conclusions

Bone-related parameters are strong prognostic variables for overall survival in patients with bone metastases from CRPC.

Patient summary

Survival time is variable in patients with bone metastases from prostate cancer. We found that factors related to bone help to predict how long a patient will live.

Introduction

Worldwide, prostate cancer is the fifth most common cause of cancer death in men, with an estimated 307 000 deaths in 2012 [1]. Docetaxel plus prednisone has been the standard first-line therapy for symptomatic metastatic castration-resistant prostate cancer (CRPC) [2] since 2004, with a median overall survival of approximately 18 mo [3]. More recently, improved survival has been achieved with hormonal agents (abiraterone, enzalutamide), among other treatments [4], [5], [6], [7], [8].

Understanding prognostic factors for survival in metastatic CRPC is important for trial design as well as for informing patients about therapeutic options. Previous studies have identified prognostic variables based on disease characteristics such as prostate-specific antigen (PSA) level [9], PSA doubling time [10], PSA nadir [11], Gleason score [9], presence of visceral metastases [9], performance status [9], [12], and pain or analgesic use [12], [13]. Hemoglobin [9], [12], [14] and lactate dehydrogenase (LDH) [9], [12] have also been identified as independent prognostic factors. Of particular interest are bone-specific parameters, including history of previous skeletal-related event (SRE) [15], [16], pathologic fracture [17], urinary N-telopeptide (uNTx) [14], [18], [19], [20], alkaline phosphatase [9], and bone-specific alkaline phosphatase (BSAP) levels [14], [18], [19], which have demonstrated prognostic value. Notably, many of these factors were identified in datasets obtained prior to docetaxel approval, and the analyses were based on small sample sizes.

In this analysis, we examine the impact of baseline variables in a phase 3 trial [21] of bone-targeted agents (denosumab vs zoledronic acid). The objective of this study was to evaluate the risk reduction for time to first SRE between these agents; therefore, the study was not prospectively designed to collect all potential covariates for survival. The objective of this ad hoc analysis was to confirm and extend previously reported prognostic models in a large contemporary dataset.

Section snippets

Study design and patients

The trial was a randomized, double-blind, phase 3 study comparing denosumab and zoledronic acid in 1901 men (clinicaltrials.gov identifier NCT00321620) [21]. Patients had CRPC (defined as rising PSA levels despite circulating testosterone levels of <0.50 ng/ml), radiological evidence of bone metastasis, but no known brain metastases, and an ECOG score ≤ 2. Baseline demographic and disease characteristics were similar between treatment groups and no differences in overall survival were observed

Patients

Baseline demographics and disease characteristics for the overall study population are shown in Table 1. Median (95% confidence interval [CI]) overall survival time was 20 (18, 21) mo.

Univariate analyses

Point estimates for each variable are shown in Table 2. The bone-specific markers alkaline phosphatase, BSAP, and uNTx were each found to be predictors of survival (all p < 0.0001; Fig. 1). Two other bone parameters, pain and history of SRE, were also significant in the univariate analysis (both p < 0.0001). PSA <10

Discussion

In this analysis from the largest prospective clinical trial of CRPC patients with bone metastases (n = 1901), we demonstrate that bone-related parameters are good prognostic variables for overall survival. The analyses reported here both confirm previously identified variables and identify two new prognostic factors. As a whole, this analysis emphasizes the compelling prognostic value of bone-related factors in patients with bone metastases from CRPC. It is well recognized that the population of

Conclusions

In conclusion, bone-related parameters were found to be strong predictors of overall survival in addition to established disease stage factors in multivariate analyses using a large contemporary trial population of metastatic CRPC patients. The main utility of these findings is in the stratification of prospective clinical trials, although survival prediction in routine clinical practice is also feasible.

Presented at the annual meeting of the American Society of Clinical Oncology 2012.

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Health-related quality of life and pain outcomes with [<sup>177</sup>Lu]Lu-PSMA-617 plus standard of care versus standard of care in patients with metastatic castration-resistant prostate cancer (VISION): a multicentre, open-label, randomised, phase 3 trial
2023, The Lancet Oncology
In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [¹⁷⁷Lu]Lu-PSMA-617 (vipivotide tetraxetan) improved radiographic progression-free survival and overall survival when added to protocol-permitted standard of care in patients with metastatic castration-resistant prostate cancer. Here, we report additional health-related quality of life (HRQOL), pain, and symptomatic skeletal event results.
This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [¹⁷⁷Lu]Lu-PSMA-617 plus protocol-permitted standard of care ([¹⁷⁷Lu]Lu-PSMA-617 group) or standard of care alone (control group) using permuted blocks. Randomisation was stratified by baseline lactate dehydrogenase concentration, liver metastases, ECOG performance status, and androgen receptor pathway inhibitor inclusion in standard of care. Patients in the [¹⁷⁷Lu]Lu-PSMA-617 group received intravenous infusions of 7·4 gigabecquerel (GBq; 200 millicurie [mCi]) [¹⁷⁷Lu]Lu-PSMA-617 every 6 weeks for four cycles plus two optional additional cycles. Standard of care included approved hormonal treatments, bisphosphonates, and radiotherapy. The alternate primary endpoints were radiographic progression-free survival and overall survival, which have been reported. Here we report the key secondary endpoint of time to first symptomatic skeletal event, and other secondary endpoints of HRQOL assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-5L, and pain assessed with the Brief Pain Inventory-Short Form (BPI-SF). Patient-reported outcomes and symptomatic skeletal events were analysed in all patients who were randomly assigned after implementation of measures designed to reduce the dropout rate in the control group (on or after March 5, 2019), and safety was analysed according to treatment received in all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, NCT03511664, and is active but not recruiting.
Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [¹⁷⁷Lu]Lu-PSMA-617 group (n=385) or control group (n=196) on or after March 5, 2019, and were included in analyses of HRQOL, pain, and time to first symptomatic skeletal event. The median age of patients was 71 years (IQR 65–75) in the [¹⁷⁷Lu]Lu-PSMA-617 group and 72·0 years (66–76) in the control group. Median time to first symptomatic skeletal event or death was 11·5 months (95% CI 10·3–13·2) in the [¹⁷⁷Lu]Lu-PSMA-617 group and 6·8 months (5·2–8·5) in the control group (hazard ratio [HR] 0·50, 95% CI 0·40–0·62). Time to worsening was delayed in the [¹⁷⁷Lu]Lu-PSMA-617 group versus the control group for FACT-P score (HR 0·54, 0·45–0·66) and subdomains, BPI-SF pain intensity score (0·52, 0·42–0·63), and EQ-5D-5L utility score (0·65, 0·54–0·78). Grade 3 or 4 haematological adverse events included decreased haemoglobin (80 [15%] of 529 assessable patients who received [¹⁷⁷Lu]Lu-PSMA-617 plus standard of care vs 13 [6%] of 205 who received standard of care only), lymphocyte concentrations (269 [51%] vs 39 [19%]), and platelet counts (49 [9%] vs five [2%]). Treatment-related adverse events leading to death occurred in five (1%) patients who received [¹⁷⁷Lu]Lu-PSMA-617 plus standard of care (pancytopenia [n=2], bone marrow failure [n=1], subdural haematoma [n=1], and intracranial haemorrhage [n=1]) and no patients who received standard of care only.
[¹⁷⁷Lu]Lu-PSMA-617 plus standard of care delayed time to worsening in HRQOL and time to skeletal events compared with standard of care alone. These findings support the use of [¹⁷⁷Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer who received previous androgen receptor pathway inhibitor and taxane treatment.
Advanced Accelerator Applications (Novartis).
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Talazoparib has shown antitumor activity with a manageable safety profile in men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR)/homologous recombination repair (HRR) alterations.
To evaluate patient-reported health-related quality of life (HRQoL) and pain in patients who received talazoparib in the TALAPRO-1 study, with a special interest in patients harboring breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations.
TALAPRO-1 is a single-arm, phase 2 study in men with mCRPC DDR alterations either directly or indirectly involved in HRR, who previously received one to two taxane-based chemotherapy regimens for advanced prostate cancer and whose mCRPC progressed on one or more novel hormonal agents.
Men completed the European Quality-of-life Five-dimension Five-level scale (EQ-5D-5L), EQ-5D visual analog scale (VAS), and Brief Pain Inventory—Short Form at predefined time points during the study. The patient-reported outcome (PRO) population included men who completed a baseline and one or more postbaseline assessments before study end. Longitudinal mixed-effect models assuming an unstructured covariance matrix were used to estimate the mean (95% confidence interval [CI]) change from baseline for pain and general health status measurements among all patients and patients with BRCA1/2 mutations.
In the 97 men in the PRO population treated with talazoparib (BRCA1/2, n = 56), the mean (95% CI) EQ-5D-5L Index improved (all patients, 0.05 [0.01, 0.08]; BRCA1/2 subset, 0.07 [0.03, 0.10]), as did the EQ-5D VAS scores (all patients, 5.42 [2.65, 8.18]; BRCA1/2 subset, 4.74 [1.07, 8.41]). Improvements in the estimated overall change from baseline (95% CI) in the mean worst pain were observed in all patients (–1.08 [–1.52, –0.65]) and the BRCA1/2 subset (–1.15 [–1.67, –0.62]). The probability of not having had experienced deterioration of worst pain by month 12 was 84% for all patients and 83% for the BRCA1/2 subset.
In heavily pretreated men with mCRPC and DDR/HRR alterations, talazoparib was associated with improved HRQoL in all patients and the BRCA1/2 subset. In both patient groups, worst pain improved from baseline and the probability of not experiencing a deterioration in worst pain with talazoparib was high.
We show that talazoparib was associated at least with no change or improvements in health-related quality of life (HRQoL) and pain burden in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair gene alterations in the TALAPRO-1 study. These findings in patient-reported HRQoL and pain complement the antitumor activity and tolerability profile of talazoparib.
A Novel Radiographic Pattern Related to Poor Prognosis in Patients with Prostate Cancer with Metastatic Spinal Cord Compression
2023, European Urology Open Science
Prostate cancer spinal bone metastases can have a radiographic profile that mimics multiple myeloma.
To analyse the presence and prognostic value of myeloma-like prostate cancer bone metastases and its relation to known clinical, molecular, and morphological prognostic markers.
A cohort of 110 patients with prostate cancer who underwent surgery for metastatic spinal cord compression (MSCC) was analysed. Spinal bone metastases were classified as myeloma like (n = 20) or non–myeloma like (n = 90) based on magnetic resonance imaging prior to surgery. An immunohistochemical analysis of metastasis samples was performed to assess tumour cell proliferation (percentage of Ki67-positive cells) and the expression levels of prostate-specific antigen (PSA) and androgen receptor (AR). The metastasis subtypes MetA, MetB, and MetC were determined from transcriptomic profiling.
Survival curves were compared with the log-rank test. Univariate and multivariate Cox proportional hazard models were used to assess the effects of prognostic variables. Groups were compared using the Mann-Whitney U test for continuous variables and the chi-square test for categorical variables.
Patients with the myeloma-like metastatic pattern had median survival after surgery for MSCC of 1.7 (range 0.1–33) mo, while the median survival period of those with the non–myeloma-like pattern was 13 (range 0–140) mo (p < 0.001). The myeloma-like appearance had an independent prognostic value for the risk of death after MSCC surgery (adjusted hazard ratio 2.4, p = 0.012). Postoperative neurological function was significantly reduced in the myeloma-like group. No association was found between the myeloma-like pattern and morphological markers of known relevance for this patient group: the transcriptomic subtypes MetA, MetB, and MetC; tumour cell proliferation; and AR and PSA expression.
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Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident bone metastases from primary solid tumors between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients received ≥ 2 consecutive 120 mg denosumab doses on a 4-week (± 14 days) schedule with a minimum follow-up of ≥ 1 year after the last denosumab dose, or an SRE occurring between days 84 and 365 after denosumab discontinuation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential factors for SRE risk using Shapley Additive Explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted.
A total of 1,414 adult cancer patients (breast: 40%, prostate: 30%, lung: 13%, other: 17%) were eligible, of whom 1,133 (80%) were assigned to model training and 281 (20%) to model evaluation. The median age at inclusion was 67 (range, 19–89) years with a median duration of denosumab treatment of 253 (range, 88–2,726) days; 490 (35%) patients experienced ≥ 1 SRE 83 days after denosumab discontinuation. Meaningful model performance was evaluated by an area under the receiver operating curve score of 77% and an F1 score of 62%; model precision was 60%, with 63% sensitivity and 78% specificity. SHAP identified several significant factors for the tumor-agnostic and tumor-specific models that predicted an increased SRE risk following denosumab discontinuation, including prior SREs, shorter denosumab treatment duration, ≥ 4 clinic visits per month with at least one hospitalization (all-cause) event from the baseline period up to discontinuation of denosumab, younger age at bone metastasis, shorter time to denosumab initiation from bone metastasis, and prostate cancer.
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Platinum Priority – Prostate CancerEditorial by Peter I. Croucher, Belinda S. Parker, Niall Corcoran and Michael J. Rogers on pp. 51–52 of this issueBone-related Parameters are the Main Prognostic Factors for Overall Survival in Men with Bone Metastases from Castration-resistant Prostate Cancer

Abstract

Background

Objective

Design, setting, and participants

Outcome measures and statistical analysis

Results and limitations

Conclusions

Patient summary

Introduction

Section snippets

Study design and patients

Patients

Univariate analyses

Discussion

Conclusions

Ann Oncol

Ann Oncol

Lancet Oncol

Ann Oncol

J Urol

Ann Oncol

Lancet

Pain

Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer

N Engl J Med

Targeting continued androgen receptor signaling in prostate cancer

Clin Cancer Res

Increased survival with enzalutamide in prostate cancer after chemotherapy

N Engl J Med

Sipuleucel-T immunotherapy for castration-resistant prostate cancer

N Engl J Med