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PROfound: Phase 3 Study of Olaparib vs. Enzalutamide or Abiraterone for Metastatic Castration-Resistant Prostate Cancer with Homologous Recombination Repair Gene Alterations

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Not all patients with metastatic castration-resistant prostate cancer (mCRPC) have sufficient tumor tissue available for multigene molecular testing. Furthermore, samples may fail because of difficulties within the testing procedure.

PROfound is the largest poly(ADP-ribose) polymerase (PARP) inhibitor Phase III study to date to conduct central, prospective tissue next-generation sequencing (NGS) to screen patients with metastatic castration-resistant prostate cancer (mCRPC) for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) genes.

Based on PROfound, olaparib is approved for patients with metastatic castration-resistant prostate cancer following disease progression on at least enzalutamide or abiraterone and who carry relevant alterations in DNA repair genes.

The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control.

Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future molecularly targeted therapies.

Olaparib is a poly(ADP-ribose) polymerase inhibitor approved for metastatic castration-resistant prostate cancer (mCRPC). Olaparib is approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with deleterious or suspected deleterious germline or somatic HRR gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone

We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent.

Multiple loss-of-function alterations in genes that are involved in DNA repair, including homologous recombination repair, are associated with response to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition in patients with prostate and other cancers.

Conference Coverage
Conference Highlights Written by Physician-Scientist
Presented by Fred Saad, MD, FRCS

In a podium presentation at the American Urologic Association (AUA) Virtual Annual Meeting, Dr. Fred Saad and colleagues presented an exploratory analysis of the efficacy of olaparib versus either abiraterone or enzalutamide, given a potential difference in the efficacy of NHA sequencing.

 

Presented by Johann de Bono, MB ChB FRCP MSc Ph.D. FMedSci
At the 2021 ASCO GU meeting, Dr. Johann De Bono and colleagues presented results of gene-by-gene analysis of olaparib antitumor activity among the 15 prespecified homologous recombination repair genes. Patients in PROfound were randomized to olaparib (300 mg BID; n=256) or physician’s choice of enzalutamide or abiraterone (control; n=131). The following is a summary of the trial design and endpoints:
Presented by Nobuaki Matsubara, MD
In the plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Matsubara and colleagues performed a retrospective assessment of ctDNA to identify alterations in BRCA1, BRCA2, and ATM among men in the PROfound trial.
Presented by Kim N. Chi, MD, FRCPC
In plenary abstract presentation in the Poster Highlights Session: Prostate Cancer session at the 2021 ASCO GU Cancers Symposium, Dr. Kim Chi and colleagues evaluated the utility of plasma-derived ctDNA to identify deleterious BRCA and ATM mutations in screened patients from PROfound.
Presented by Maha H.A. Hussain, MD, FACP, FASCO
AT the 2020 SUO annual meeting, Dr. Hussain discussed the role of PARP inhibitors, particularly Olaparib, in mCRPC. Dr. Hussain began by reviewing the rationale for targeting PARP-1 in advanced prostate cancer given its implicated role in many aspects of prostate cancer including its role in mediating DNA repair response to alkylating agents,
Presented by Karim Fizazi, MD, Ph.D
In an oral presentation in the New Trials Update session at the 12th European Multidisciplinary Congress on Urological Cancers (EMUC), Dr. Karim Fizazi presented a discussion of the results of PROfound Study, Study of Olaparib (Lynparza™) Versus Enzalutamide or Abiraterone Acetate in Men With Metastatic Castration-Resistant Prostate Cancer (PROfound), examining the role of olaparib among patients with metastatic castration-resistant prostate cancer (mCRPC) and DNA defect repair (DDR) mutations.
Presented by Henrik Grönberg, MD, PhD
(UroToday.com) Following the presentations from Dr. de Bono and Dr. Joaquin Mateo of the data from IPATential150 and PROfound, respectively, Dr. Henrik Grönberg provided an invited discussion of these data.  He began by laying out a number of important topics to consider: 1. study population: is this representative of patients seen in the clinic today? 2. control group: are these patients getting the best treatment available?
Presented by Joaquin Mateo, MD
In 2016, Pritchard and colleagues reported that mutations in DNA-damage repair genes, particularly homologous recombination repair genes, were relatively common among patients with advanced metastatic castration-resistant prostate cancer (mCRPC).
(UroToday.com) In the phase III PROfound study, olaparib lead to significantly longer radiographic progression-free survival compared with physician’s choice of next-generation hormonal agent (control) in patients with previously treated metastatic castration-resistant prostate cancer (mCRPC) and alterations in homologous recombination repair (HRR) genes.
(UroToday.com) In 2016, Pritchard and colleagues reported that mutations in DNA-damage repair genes, particularly homologous recombination repair genes, were relatively common among patients with advanced metastatic castration-resistant prostate cancer (mCRPC).
Presented by Fred Saad, MD, FRCS
In the Phase III PROfound study, olaparib significantly improved radiographic progression-free survival (primary endpoint) versus physician’s choice of new hormonal agent (enzalutamide or abiraterone) in patients with mCRPC and homologous recombination repair (HRR) gene alterations.
Presented by  Antoine Thiery-Vuillemin, MD, PhD
The randomized Phase 3 PROfound trial showed that olaparib significantly prolonged radiographic progression-free survival compared with physician’s choice of new hormonal agent (enzalutamide or abiraterone) in men with mCRPC and HRR gene alterations, whose disease had progressed on prior new hormonal agent.
San Francisco, California (UroToday.com) The PROfound Study is the first positive randomized Phase 3 study in a molecularly-defined population of patients with metastatic castration-resistant prostate cancer (mCRPC).
Presented by Elena Castro, MD, PhD
San Francisco, CA (UroToday.com) In this talk, Dr. Elena Castro gave an overview of the genomic landscape of advanced prostate cancer. It has been shown that in over 70%
San Francisco, California (UroToday.com) Metastatic castration-resistant prostate cancer (mCRPC) is a molecularly heterogeneous disease, with between 20 and 25% of patients with mCRPC harboring deleterious alterations in DNA damage repair genes, including those with direct or indirect roles in homologous recombination repair (HRR).
Presented by Maha Hussain, MD
Barcelona, Spain (UroToday.com) Despite significant progress in systematic therapy, metastatic castration-resistant prostate cancer (mCRPC) continues to be a lethal disease.
Presented by Eleni Efstathiou, MD, PhD
Barcelona, Spain (UroToday.com) Following oral presentation of the PROfound study of olaparib in metastatic castration-resistant prostate cancer (mCRPC) patients with selected homologous recombination repair defects in their tumors, Dr. Eleni Efstathiou discussed the findings and posed the question of whether this study should be considered practice-changing.
Barcelona, Spain (UroToday.com) A proportion of patients with metastatic castration-resistant prostate cancer (mCRPC) have tumor cells harboring homologous recombination repair gene mutations that may confer sensitivity to poly ADP-ribose polymerase (PARP) inhibition.