Novel metastatic burden‐stratified risk model in de novo metastatic hormone‐sensitive prostate cancer

PURPOSE The STAMPEDE trial recruits men with newly diagnosed, high-risk, hormone-sensitive prostate cancer. To ascertain the feasibility of targeted next-generation sequencing (tNGS) and the prevalence of baseline genomic aberrations, we sequenced tumor and germline DNA from patients with metastatic prostate cancer (mPCa) starting long-term androgen-deprivation therapy (ADT). METHODS In a 2-stage approach, archival, formalin-fixed, paraffin-embedded (FFPE) prostate tumor core biopsy samples were retrospectively subjected to 2 tNGS assays. Prospective enrollment enabled validation using tNGS in tumor and germline DNA. RESULTS In stage 1, tNGS data were obtained from 185 tumors from 287 patients (65%); 98% had de novo mPCa. We observed PI3K pathway aberrations in 43%, due to PTEN copy-number loss (34%) and/or activating mutations in PIK3 genes or AKT (18%) and TP53 mutation or loss in 33%. No androgen receptor ( AR) aberrations were detected; RB1 loss was observed in < 1%. In stage 2, 93 (92%) of 101 FFPE tumors (biopsy obtained within 8 months) were successfully sequenced prospectively. The prevalence of DNA damage repair (DDR) deficiency was 14% (somatic) and 5% (germline). BRCA2 mutations and mismatch repair gene mutations were exclusive to high-volume disease. Aberrant DDR (22% v 15%), Wnt pathway (16% v 4%), and chromatin remodeling (16% v 8%) were all more common in high-volume compared with low-volume disease, but the small numbers limited statistical comparisons. CONCLUSION Prospective genomic characterization is feasible using residual diagnostic tumor samples and reveals that the genomic landscapes of de novo high-volume mPCa and advanced metastatic prostate cancer have notable similarities (PI3K pathway, DDR, Wnt, chromatin remodeling) and differences ( AR, RB1). These results will inform the design and conduct of biomarker-directed trials in men with metastatic hormone-sensitive prostate cancer.

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Cost-effectiveness of upfront therapeutic options in low-volume de novo metastatic hormone-sensitive prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.211 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 211-211

Author(s):

Neil Rohit Parikh ◽

Eric M. Chang ◽

Nicholas George Nickols ◽

Matthew Rettig ◽

Ann C. Raldow ◽

...

Keyword(s):

Prostate Cancer ◽

Radiation Therapy ◽

Cost Effectiveness ◽

Systemic Therapy ◽

De Novo ◽

Cost Effective ◽

Therapeutic Options ◽

Oral Drug ◽

Hormone Sensitive ◽

Low Volume

211 Background: Low-volume de novo metastatic hormone-sensitive prostate cancer (mHSPC) has historically been treated with lifelong androgen deprivation therapy (ADT). Recently, however, the addition of several advanced therapeutic options – radiation therapy (RT) to the primary, advanced hormonal therapy agents such as abiraterone acetate/prednisone (AAP), and chemotherapy – to ADT have been shown to improve survival in low-volume mHSPC. The objective of this study was to compare the cost-effectiveness of treating low-volume mHSPC patients upfront with RT+ADT, AAP+ADT, or docetaxel+ADT. Methods: A Markov-based cost-effectiveness analysis was constructed comparing three treatment strategies for low-volume mHSPC patients: (1) upfront RT+ADT --> salvage AAP+ADT --> salvage docetaxel+ADT; (2) upfront AAP+ADT --> salvage docetaxel+ADT, and (3) upfront docetaxel+ADT --> salvage AAP+ADT. Transition probabilities were calculated using data from STAMPEDE arms C/G/H, COU-AA-301, COU-AA-302, and TAX-327. RT was delivered via five-fraction stereotactic body radiation therapy. The analysis utilized a 10-year time horizon, and a $100,000/quality adjusted life year (QALY) willingness-to-pay threshold. Utilities were extracted from the literature; costs were taken from Medicare fee schedules and VA oral drug contracts. Results: At 10 years, total cost was $140K, $259K, and $189K, with total QALYs of 4.66, 5.03, and 3.72 for strategies (1) upfront RT+ADT, (2) upfront AAP+ADT, and (3) upfront docetaxel+ADT, respectively. Compared to upfront RT+ADT, upfront AAP+ADT was not cost-effective (ICER: $321K/QALY). This result remained unchanged even after modification of various model inputs in 1-way sensitivity analysis. Upfront docetaxel+ADT was both more costly and less effective than upfront RT+ADT (ICER: -$53K/QALY). Conclusions: At 10 years, RT+ADT is cost-effective compared to other advanced systemic therapy options alone, and should be considered as a viable treatment strategy in all patients with a low-burden of metastatic disease. Additional studies are needed to determine whether any benefit exists in combining RT to the primary with upfront advanced systemic therapy.

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A single-arm phase II study of ADT with PD-1 blockade and docetaxel in men with metastatic hormone-sensitive prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.tps271 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. TPS271-TPS271

Author(s):

Jessica Hawley ◽

Timothy Geoffrey Bowler ◽

Xinzheng Victor Guo ◽

Matthew Dallos ◽

Emerson A. Lim ◽

...

Keyword(s):

Prostate Cancer ◽

Phase Ii ◽

De Novo ◽

Phase Ii Study ◽

Castration Resistant Prostate Cancer ◽

Castration Resistance ◽

Tumor Cell Death ◽

Serum Samples ◽

Open Label ◽

Hormone Sensitive

TPS271 Background: Overall survival of men with de novo metastatic, hormone-sensitive prostate cancer (mHSPC) is improved by treatment intensification with docetaxel and hormone therapy compared to androgen deprivation therapy (ADT) alone. However, castration-resistant prostate cancer (CRPC) invariably develops. Reprogramming the immune system in the mHSPC setting is a novel approach to delay progression to CRPC. In the hormone-sensitive setting, ADT induces a robust and functional immune infiltrate into the tumor microenvironment (TME), with upregulation of immune checkpoint molecules (PD-1 and PD-L1). These effects diminish as castration resistance emerges. Docetaxel causes immunogenic tumor cell death and stimulates antigen presentation. We hypothesize that leveraging the immunogenic effects of ADT with PD-1 blockade and docetaxel will promote antitumor immune killing and improve clinical outcomes. Methods: This is an open-label, single-arm, phase II study of ADT, cemiplimab, and docetaxel in patients with de novo mHSPC (N=20). Subjects will receive continuous ADT, followed by a two-cycle lead-in of cemiplimab prior to the standard six cycles of docetaxel. Cemiplimab will be continued q3weeks for one year or until disease progression or intolerable side effect. The primary endpoint is undetectable PSA at 6 months. Secondary endpoints include time to development of CRPC and radiographic response. Subjects will be monitored for toxicity using a Bayesian adaptive study design with an early stopping rule for toxicity. Correlative studies will determine the effects of ADT and PD-1 blockade on the TME by comparing baseline and on-treatment biopsies using transcriptional data from single-cell RNA-sequencing and standard immunohistochemistry (IHC). Serum samples will also be collected to quantify the effects of therapy on circulating levels of immunosuppressive cytokines. The study is open with 3 patients currently enrolled at the time of submission. Clinical trial information: NCT03951831.

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Docetaxel vs. Novel Hormonal Agent for Upfront Management of De Novo Metastatic Hormone-Sensitive Prostate Cancer: A Comprehensive Report of a Single-Center Experience

10.21203/rs.3.rs-659032/v1 ◽

2021 ◽

Author(s):

Sunny Guin ◽

Bobby K. Liaw ◽

Tomi Jun ◽

Kristin Ayers ◽

Bonny Patel ◽

...

Keyword(s):

Prostate Cancer ◽

Prognostic Value ◽

Proportional Hazards ◽

De Novo ◽

Standard Of Care ◽

Cox Proportional Hazards ◽

Post Treatment ◽

Real World Data ◽

Significant Difference ◽

Hormone Sensitive

Abstract Background: Upfront docetaxel or novel hormonal agents (NHA) such as abiraterone and enzalutamide have become the standard of care for metastatic hormone sensitive prostate cancer (mHSPC). However, data comparing the efficacy of docetaxel and NHAs in this setting are limited.Patients and Methods: This was a retrospective cohort study of patients with de novo mHSPC treated with upfront docetaxel or an NHA between January 1, 2014 and April 30, 2019 within the Mount Sinai Health System. Clinical data were extracted from the medical record. The primary outcome was failure-free survival (FFS), defined as the time to next treatment. The primary predictor was treatment with docetaxel or NHA. FFS was compared between the two groups using the Kaplan Meier method and multivariable Cox proportional hazards models. We additionally assessed the prognostic value of post-treatment PSA.Results: We identified 94 de novo mHSPC patients; 52 and 42 treated with upfront docetaxel and NHAs, respectively. NHAs were associated with significantly longer FFS compared to docetaxel (20.7 vs. 10.1 months, p=0.023). In a multivariable model adjusting for demographics and clinical factors, docetaxel was independently associated with worse FFS compared to NHAs (HR 1.96, 95% CI 1.12−3.45, p=0.019). High metastasis burden patients had a significantly longer FFS with NHAs than docetaxel (25.12 vs. 9.63 months, p=0.014), while there was no significant difference in FFS among low metastasis burden patients (NHA 20.71 vs. Docetaxel 26.5 months, p=0.9). Regardless of treatment, lower post-treatment PSA levels were associated with improved FFS (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, >0.4ng/ml, respectively; p<0.001) Conclusion: Comparative analysis of real-world data demonstrated longer FFS in de novo mHSPC treated with NHA compared to docetaxel. In addition, the depth of PSA response following combination treatment may hold prognostic value for mHSPC outcomes.

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Why Chemotherapy Should be Given Early for Men with Metastatic Prostate Cancer

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2015.35.e263 ◽

2015 ◽

pp. e263-e269 ◽

Cited By ~ 1

Author(s):

Leonel F. Hernandez-Aya ◽

Maha Hussain

Keyword(s):

Prostate Cancer ◽

De Novo ◽

High Volume ◽

High Response Rate ◽

Phase Iii ◽

Incurable Disease ◽

Castration Resistant ◽

Castrate Resistant Prostate Cancer ◽

Hormone Sensitive ◽

Castrate Resistant

Metastatic hormone-sensitive prostate cancer (mHSPC) is an incurable disease, and despite a high response rate to androgen-deprivation therapy (ADT), outcomes have not significantly changed for many decades. Earlier attempts at multitargeted strategies with the addition of cytotoxic chemotherapy to ADT did not affect survival. As more effective therapies are emerging, including cytotoxic therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC), there is increasing interest for testing these drugs earlier in the disease course. The premise is that agents with clinical benefit in advanced mCRPC may have a better effect if used preemptively before the development of significant resistance and to attack earlier de novo androgen resistant/independent clones. The recent results of the phase III clinical trial E3805 investigating ADT with or without docetaxel in mHSPC provide compelling support for this strategy. Docetaxel combined with ADT significantly improved overall survival from 44 to 57.6 months (p = 0.0003), particularly in patients with high-volume disease (from 32.2 to 49.2 months; p = 0.0006). Longer follow-up is needed to assess the effect on patients with low disease burden. Further studies are needed to further maximize the antitumor effect in patients with mHSPC and to investigate the effects of advancing therapy to this disease setting on the efficacy of respective agents in the castration-resistant setting.

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The prognostic significance of homologous recombination repair pathway alterations in metastatic hormone-sensitive prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.150 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 150-150

Author(s):

Justin Shaya ◽

Aaron Lee ◽

Angelo Cabal ◽

Justine Panian ◽

James Michael Randall ◽

...

Keyword(s):

Prostate Cancer ◽

Homologous Recombination ◽

Cox Regression ◽

De Novo ◽

Prognostic Significance ◽

Parp Inhibitors ◽

Homologous Recombination Repair ◽

Significant Difference ◽

Recombination Repair ◽

Hormone Sensitive

150 Background: Little is known about the clinical course of patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) who harbor alterations in the homologous recombination repair (HRR) pathway. Here, we examine the outcomes of men with mHSPC with HRR alterations. Methods: Single center, retrospective analysis of men with mHSPC who underwent next generation sequencing from 2015-2020. The primary endpoint was to assess the time from diagnosis of mHSPC to onset of castrate resistance (mCRPC), as defined by PCWG3 criteria, in pts with HRR alterations vs wild type (WT). Both somatic and germline HRR alterations were permitted. Univariate and multivariate Cox regression were used to assess the effect of HRR alterations on time to mCRPC. Secondary endpoints included time to mCRPC stratified by HRR gene and time to treatment failure (TTF) in HRR altered vs WT pts, stratified by therapy. Results: We identified 151 men with mHSPC for the study. Median age was 66 years and 62% (n = 93) had de novo metastatic disease. 25% (n = 37) had HRR alterations detected and the most common alterations were in BRCA2 (n = 15), ATM (n = 10), CDK12 (n = 7). 78.4% (n = 29) of alterations were somatic and 13.5% (n = 5) of pts had co-alterations in 2 HRR genes. Time to mCRPC was significantly decreased in pts with HRR alterations vs WT (12.7 vs 16.1 mos, HR- 1.95, p- 0.02). In multivariate analysis, the effect of HRR alterations on time to mCRPC remained statistically significant when adjusting for age, mHSPC therapy, presence of visceral metastases, and PSA (adjusted HR- 1.69, p-0.02). Stratified by individual HRR gene, pts with BRCA2, CDK12, or co-occurring alterations had significantly decreased time to mCRPC compared to other HRR alterations (Table). In terms of mHSPC therapy, 45.7% were treated with ADT alone, 27.8% with an androgen receptor signaling inhibitor (ARSI), and 26.5% with docetaxel. TTF was inferior in HRR altered vs WT pts (10.8 vs 13.8 mos, p-0.004, HR- 1.84). Stratified by therapy, TTF was inferior in HRR altered vs WT pts treated with ADT alone (8.9 vs 13.3 mos, p- 0.019, HR-1.94) and there was no significant difference in TTF in HRR altered vs WT pts treated with either the addition of an ARSI or docetaxel. Conclusions: HRR alterations are associated with worsened outcomes in mHSPC patients. Given the established role of PARP inhibitors in mCRPC, these data highlight an opportunity to explore the use of PARP inhibitors in mHSPC to potentially improve outcomes. [Table: see text]

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Impact of Cerebrovascular Disease on Survival Benefits from Local Treatment in Patients with De Novo Metastatic Hormone-Sensitive Prostate Cancer

Yonsei Medical Journal ◽

10.3349/ymj.2019.60.12.1129 ◽

2019 ◽

Vol 60 (12) ◽

pp. 1129 ◽

Cited By ~ 1

Author(s):

Tae Jin Kim ◽

Young Dong Yu ◽

Dong Soo Park ◽

Koon Ho Rha ◽

Sung Joon Hong ◽

...

Keyword(s):

Prostate Cancer ◽

Cerebrovascular Disease ◽

De Novo ◽

Local Treatment ◽

Hormone Sensitive

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Outcomes of prechemotherapy (pCHT) abiraterone (AA) or enzalutamide (E) for metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) + docetaxel (D) or ADT alone for metastatic hormone sensitive prostate cancer (mHSPC) in a hospital-based registry.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16515 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e16515-e16515

Author(s):

Edoardo Francini ◽

Kathryn P. Gray ◽

Carolyn Evan ◽

Marina D. Kaymakcalan ◽

Grace Katherine Shaw ◽

...

Keyword(s):

Prostate Cancer ◽

De Novo ◽

Small Sample Size ◽

Small Sample ◽

Castration Resistant Prostate Cancer ◽

Start Time ◽

Time To Death ◽

Castration Resistant ◽

Kaplan Meier ◽

Hormone Sensitive

e16515 Background: The E3805: CHAARTED trial noted use of D at time of commencing ADT for mHSPC was associated with an improvement in time to CRPC (PSA rise or clinical progression [CP]) or time to CP and resulted in a prolongation of overall survival (OS). Therefore, we postulated that pCHT AA or E maintained activity after ADT+D. Methods: A cohort of CRPC patients (pts) treated with pCHT AA or E for CRPC between 2010 and 2016 was selected from the Dana-Farber Cancer Institute IRB approved database. Patients were grouped by use of D and whether they had prior localized therapy (PLT) or de novo (DN) metastatic disease, at time of ADT start for mHSPC. The analysis endpoints included OS (time to death from all causes) from ADT start, time to AA/E start from ADT start, OS from AA/E start. Kaplan-Meier method estimated the time to events distribution with median (95% CI). Results: Of the 147 pts selected, 134 (91.2%) had previously received ADT alone, while 13 (8.8%) had ADT+D. Once stratified by PLT or DN, the distributions of the 4 groups are 33.3% (ADT/PLT), 57.8% (ADT/DN), 0.7% (ADT+D/PLT), and 8.2% (ADT+D/DN). In the ADT alone group, the median OS with pCHT AA or E for CRPC was approximately 3 years from the AA/E start, regardless of PLT or DN. In the smaller cohort of pts selected for treatment with ADT+D, both the OS from ADT start and from AA/E start were shorter than the ADT alone cohort. However, even in this group with shorter time to AA/E start, the median OS from AA/E start was still 1.5 years despite prior chemotherapy. Conclusions: Within limitations of a hospital-based registry, small sample size for ADT+D and lack of volume of metastases data, pts selected for ADT+D show poorer outcomes but still have an OS of 1.5 yrs from AA/E start. [Table: see text]

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Prostate Cancer: 2021 ASCO Annual Meeting Highlights for the Advanced Practitioner

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.6.7 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Morgane C. Diven, PharmD, BCOP

Keyword(s):

Prostate Cancer ◽

Health Care ◽

Combination Therapy ◽

Annual Meeting ◽

Small Molecule ◽

Metastatic Prostate Cancer ◽

De Novo ◽

Advanced Practitioner ◽

Hormone Sensitive ◽

Va Health Care System

Morgane C. Diven, PharmD, BCOP, of Phoenix VA Health Care System, evaluates research on an investigational radiolabeled small molecule, combination therapy in the treatment of de novo metastatic prostate cancer, and a CYP17-lyase inhibitor in metastatic hormone-sensitive prostate cancer. Coverage provided by The ASCO Post.

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