An Insight on Novel Molecular Pathways in Metastatic Prostate Cancer: A Focus on DDR, MSI and AKT

Prostate cancer is still one of the main causes of cancer-related death in the male population, regardless of the advancements in the treatment scenario. The genetic knowledge on prostate cancer is widely increasing, allowing researchers to identify novel promising molecular targets and treatment approaches. Genomic profiling has evidenced that DNA damage repair genes’ alterations are quite frequent in metastatic, castration resistant prostate cancer and specific therapies can interfere with this pathway, showing promising activity in this setting. Microsatellite instability is gaining attention as it seems to represent a predictive factor of the response to immunotherapy. Furthermore, the PTEN-PI3K-AKT pathway is another possible treatment target being investigated. In this review, we explore the current knowledge on these frequent genomic alterations of metastatic prostate cancer, their possible therapeutic repercussions and the promising future treatments under evaluation.

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Novel therapies are changing treatment paradigms in metastatic prostate cancer

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00978-z ◽

2020 ◽

Vol 13 (1) ◽

Cited By ~ 1

Author(s):

Eric Powers ◽

Georgia Sofia Karachaliou ◽

Chester Kao ◽

Michael R. Harrison ◽

Christopher J. Hoimes ◽

...

Keyword(s):

Prostate Cancer ◽

Treatment Options ◽

Parp Inhibitors ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Damage Repair ◽

Systemic Treatments ◽

Terminal Diagnosis ◽

Specific Membrane ◽

Repair Genes

Abstract Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.

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Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2020.7663 ◽

2021 ◽

Vol 19 (8) ◽

pp. 905-914

Author(s):

Baijun Dong ◽

Liancheng Fan ◽

Bin Yang ◽

Wei Chen ◽

Yonghong Li ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Cox Regression ◽

Dna Damage Repair ◽

Chinese Patients ◽

Castration Resistant Prostate Cancer ◽

Genomic Alterations ◽

Castration Resistant ◽

Damage Repair ◽

Repair Genes

Background: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. Patients and Methods: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer–Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. Results: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%–7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. Conclusions: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients’ response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.

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Platinum-based chemotherapy in metastatic prostate cancer with alterations in DNA damage repair genes.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5038 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5038-5038

Author(s):

Jose Mauricio Mota ◽

Ethan Barnett ◽

Jones Nauseef ◽

Konrad Hermann Stopsack ◽

Andreas Georg Wibmer ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Damage Repair ◽

Platinum Based Chemotherapy ◽

Before And After ◽

Repair Genes

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.

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Changing the History of Prostate Cancer with New Targeted Therapies

Biomedicines ◽

10.3390/biomedicines9040392 ◽

2021 ◽

Vol 9 (4) ◽

pp. 392

Author(s):

Susana Hernando Polo ◽

Diana Moreno Muñoz ◽

Adriana Carolina Rosero Rodríguez ◽

Jorge Silva Ruiz ◽

Diana Isabel Rosero Rodríguez ◽

...

Keyword(s):

Prostate Cancer ◽

Targeted Therapies ◽

Synthetic Lethality ◽

Castration Resistant Prostate Cancer ◽

Phosphatidylinositol 3 Kinase ◽

Castration Resistant ◽

Therapeutic Landscape ◽

Important Benefit ◽

History Of ◽

Repair Genes

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) is changing due to the emergence of new targeted therapies for the treatment of different molecular subtypes. Some biomarkers are described as potential molecular targets different from classic androgen receptors (AR). Approximately 20–25% of mCRPCs have somatic or germline alterations in DNA repair genes involved in homologous recombination. These subtypes are usually associated with more aggressive disease. Inhibitors of the enzyme poly ADP ribose polymerase (PARPi) have demonstrated an important benefit in the treatment of these subtypes of tumors. However, tumors that resistant to PARPi and wildtype BRCA tumors do not benefit from these therapies. Recent studies are exploring drug combinations with phosphatidylinositol-3-kinase (PI3K) or protein kinase B (AKT) inhibitors, as mechanisms to overcome resistance or to induce BRCAness and synthetic lethality. This article reviews various different novel strategies to improve outcomes in patients with prostate cancer.

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Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

International Journal of Cancer ◽

10.1002/ijc.33306 ◽

2020 ◽

Vol 148 (2) ◽

pp. 385-395

Author(s):

Peter H. J. Slootbeek ◽

Marleen L. Duizer ◽

Maarten J. Doelen ◽

Iris S. H. Kloots ◽

Malou C. P. Kuppen ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Damage Repair ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Damage Repair ◽

Aggressive Variant

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TALAPRO-1: An open-label, response rate phase II study of talazoparib (TALA) in men with DNA damage repair defects (DDR) and metastatic castration-resistant prostate cancer (mCRPC) who previously received taxane-based chemotherapy (CT) and progressed on ≥ 1 novel hormonal therapy (NHT)

Annals of Oncology ◽

10.1093/annonc/mdy284.068 ◽

2018 ◽

Vol 29 ◽

pp. viii301

Author(s):

J.S. de Bono ◽

C. Higano ◽

F. Saad ◽

K. Miller ◽

M. Casey ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Phase Ii ◽

Hormonal Therapy ◽

Response Rate ◽

Phase Ii Study ◽

Castration Resistant Prostate Cancer ◽

Open Label ◽

Castration Resistant ◽

Damage Repair

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Sex Hormones and Prostate Cancer

Annual Review of Medicine ◽

10.1146/annurev-med-051418-060357 ◽

2020 ◽

Vol 71 (1) ◽

pp. 33-45 ◽

Cited By ~ 6

Author(s):

Richard J. Auchus ◽

Nima Sharifi

Keyword(s):

Prostate Cancer ◽

Metastatic Prostate Cancer ◽

Current Treatment ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

History Of ◽

Prostate Cancer Research ◽

Prostate Cancers ◽

Androgen Independent ◽

Transition Studies

The prostate is an androgen-dependent organ that develops only in male mammals. Prostate cancer is the most common nonskin malignancy in men and the second leading cause of cancer deaths. Metastatic prostate cancer initially retains its androgen dependence, and androgen-deprivation therapy often leads to disease control; however, the cancer inevitably progresses despite treatment as castration-resistant prostate cancer, the lethal form of the disease. Although it was assumed that the cancer became androgen independent during this transition, studies over the last two decades have shown that these tumors evade treatment via mechanisms that augment acquisition of androgens from circulating precursors, increase sensitivity to androgens and androgen precursors, bypass the androgen receptor, or a combination of these mechanisms. This review summarizes the history of prostate cancer research leading to the contemporary view of androgen dependence for prostate cancers and the current treatment approaches based on this modern paradigm.

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