PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations

Hussain, Maha; Mateo, Joaquín; Fizazi, Karim; Saad, Fred; Shore, Neal D.; Sandhu, Shahneen; N., Kim; Sartor, Oliver; Agarwal, Neeraj; Olmos, David; Thiery-Vuillemin, A.; Twardowski, Przemyslaw; Mehra, Niven; Goessl, Carsten; Kang, Jinyu; Burgents, Joseph E.; Wu, Weiwen; Kohlmann, Alexander; Adelman, Carrie A.; Bono, Johann de

doi:10.1093/annonc/mdz394.039

Cited by 67 publications

(54 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In advanced prostate cancer, however, the clinical utility of germline and somatic genetic testing is limited to the detection of mismatch repair (MMR) deficiency mutations (which may predict responsiveness to PD-1 inhibitors, eg, pembrolizumab) 1,2 or the detection of homologous recombination deficiency (HRD) mutations (which may predict sensitivity to investigational poly [ADP-ribose] polymerase [PARP] inhibitors, eg, olaparib, or platinum agents). [3][4][5] Furthermore, while immune checkpoint blockade has resulted in unprecedented gains in a growing number of tumor types, the use of CTLA-4-and/or PD-1-targeting agents in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) has been met with limited success. 6,7 To this end, identification of additional molecular subsets of mCRPC that may benefit from immune checkpoint inhibition is paramount.…”

Section: Introductionmentioning

confidence: 99%

CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors

Antonarakis

Velho

et al. 2020

JCO Precision Oncology

166

146

View full text Add to dashboard Cite

PURPOSE In prostate cancer, inactivating CDK12 mutations lead to gene fusion–induced neoantigens and possibly sensitivity to immunotherapy. We aimed to clinically, pathologically, and molecularly characterize CDK12-aberrant prostate cancers. METHODS We conducted a retrospective multicenter study to identify patients with advanced prostate cancer who harbored somatic loss-of-function CDK12 mutations. We used descriptive statistics to characterize their clinical features and therapeutic outcomes (prostate-specific antigen [PSA] responses, progression-free survival [PFS]) to various systemic therapies, including sensitivity to poly (ADP-ribose) polymerase and PD-1 inhibitors. RESULTS Sixty men with at least monoallelic (51.7% biallelic) CDK12 alterations were identified across nine centers. Median age at diagnosis was 60.5 years; 71.7% and 28.3% were white and nonwhite, respectively; 93.3% had Gleason grade group 4-5; 15.4% had ductal/intraductal histology; 53.3% had metastases at diagnosis; and median PSA was 24.0 ng/mL. Of those who underwent primary androgen deprivation therapy for metastatic hormone-sensitive disease (n = 59), 79.7% had a PSA response, and median PFS was 12.3 months. Of those who received first-line abiraterone and enzalutamide for metastatic castration-resistant prostate cancer (mCRPC; n = 34), 41.2% had a PSA response, and median PFS was 5.3 months. Of those who received a first taxane chemotherapy for mCRPC (n = 22), 31.8% had a PSA response, and median PFS was 3.8 months. Eleven men received a PARP inhibitor (olaparib [n = 10], rucaparib [n = 1]), and none had a PSA response (median PFS, 3.6 months). Nine men received a PD-1 inhibitor as fourth- to sixth-line systemic therapy (pembrolizumab [n = 5], nivolumab [n = 4]); 33.3% had a PSA response, and median PFS was 5.4 months. CONCLUSION CDK12-altered prostate cancer is an aggressive subtype with poor outcomes to hormonal and taxane therapies as well as to PARP inhibitors. A proportion of these patients may respond favorably to PD-1 inhibitors, which implicates CDK12 deficiency in immunotherapy sensitivity.

show abstract

Section: Introductionmentioning

confidence: 99%

CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors

Antonarakis

Velho

et al. 2020

JCO Precision Oncology

166

146

View full text Add to dashboard Cite

show abstract

“…This was a randomised phase III trial comparing the PARP inhibitor olaparib with physician's choice of enzalutamide or abiraterone in men with metastatic castrate-resistant prostate cancer with an alteration in one of 15 genes involved in homologous recombination repair. An impressive hazard ratio of 0.49 (0.38 to 0.63) in favour of olaparib was seen for the primary endpoint of radiographic progression free survival [32].…”

Section: Parp Inhibitorsmentioning

confidence: 97%

“…They have also been shown to be effective in women with HER2 negative advanced/metastatic breast cancer with an inherited BRCA1/2 mutation [30,31] and have recently been approved by the US Food and Drug Administration (FDA) for use in this setting. Recent interim results from the PROfound study suggest these effects also hold true in prostate cancer patients with alterations in a number of homologous recombination repair genes beyond BRCA1/2 [32]. This was a randomised phase III trial comparing the PARP inhibitor olaparib with physician's choice of enzalutamide or abiraterone in men with metastatic castrate-resistant prostate cancer with an alteration in one of 15 genes involved in homologous recombination repair.…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Identifying Biomarkers to Pair with Targeting Treatments within Triple Negative Breast Cancer for Improved Patient Stratification

Tovey

Cheang

2019

Cancers

View full text Add to dashboard Cite

The concept of precision medicine has been around for many years and recent advances in high-throughput sequencing techniques are enabling this to become reality. Within the field of breast cancer, a number of signatures have been developed to molecularly sub-classify tumours. Notable examples recently approved by National Institute for Health and Care Excellence in the UK to guide treatment decisions for oestrogen receptors (ER)+ human epidermal growth factor receptor 2 (HER2)- patients include Prosigna® test, EndoPredict®, and Oncotype DX®. However, a population of still unmet need are those with triple negative breast cancer (TNBC). Accounting for 15–20% of patients, this population has comparatively poor prognosis and as yet no targeted treatment options. Studies have shown that some patients with TNBC respond favourably to DNA damaging drugs (carboplatin) or agents which inhibit DNA damage response (poly ADP ribose polymerase (PARP) inhibitors). Known to be a heterogeneous population, there is a need to identify further TNBC patients who may benefit from these treatments. A number of signatures have been identified based on association with treatment response or specific genetic features/pathways however many of these were not restricted to TNBC patients and as of yet are not common practice in the clinic.

show abstract

“…It is important to note that a predominant number of patients (94%, n = 31) who did not harbor these deleterious mutations had no response to olaparib (28). Based on TOPARP-A data, the multicenter randomized phase III clinical trial (PROfound study) evaluated the efficacy of olaparib (30). In this landmark trial, patients with metastatic CRPC who received prior novel hormonal therapy and harbored alterations in HRR genes were randomized in a 2:1 fashion to receive either olaparib (300 mg BID) or physician's choice of novel anti-androgen agents such as enzalutamide or abiraterone.…”

Section: Olaparib Monotherapymentioning

confidence: 99%

“…The most common adverse events with olaparib therapy were anemia, nausea, decreased appetite, and fatigue. At the time of data cutoff, there were no reports of myelodysplastic syndrome or leukemia (30).…”

Section: Olaparib Monotherapymentioning

confidence: 99%

PARP Inhibitors in Prostate and Urothelial Cancers

2020

View full text Add to dashboard Cite

Poly(ADP-ribose) polymerase (PARP) inhibitors targeting DNA repair gene mutations have shown significant clinical benefit in patients with ovarian and breast cancers. In metastatic prostate cancers, the prevalence of DNA repair gene mutations is up to 20%, and early phase studies have shown clinical activity of PARP inhibitors. Numerous clinical trials with either PARP monotherapy or in combination with other therapeutic agents are ongoing in prostate cancer. In this comprehensive review, we provide the rationale, efficacy, and safety data of PARP inhibitors in prostate as well as urothelial cancers.

show abstract

PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations

Cited by 67 publications

References 0 publications

CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors

CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors

Identifying Biomarkers to Pair with Targeting Treatments within Triple Negative Breast Cancer for Improved Patient Stratification

PARP Inhibitors in Prostate and Urothelial Cancers

Contact Info

Product

Resources

About