Benjamin Maughan shares his perspectives on clinical practice-changing data for prostate cancer in this conversation with Petros Grivas. The conversation includes discussions of the data from the ARCHES and TITAN trials for treatment on nonmetastatic prostate cancer and how the combination hormone therapies may impact treatment decisions. New data was also discussed from ENZAMET where the addition of docetaxel to the hormone combination therapy did not improve overall survival from the combination hormone therapies alone and did increase toxicities. Ben also discusses results presented from Alliance A031201, a phase III trial of enzalutamide versus enzalutamide, abiraterone, and prednisone for metastatic castration-resistant prostate cancer (mCRPC). The trial was supported by the Alliance for Clinical Trials in Oncology and the findings presented by Michael J. Morris demonstrate that the addition of abiraterone acetate to enzalutamide did not prolong survival in men with mCRPC. The combination resulted in more AEs than enzalutamide alone. Dr. Maughan also highlights the results from the prospective TAXOMET study which is a French Prospective Multicenter Randomized Controlled Phase II Study Comparing Docetaxel Plus Metformin Versus Docetaxel Plus Placebo in mCRPC. In the clinical setting, retrospective data is mixed. Two large retrospective studies have not found any prostate cancer-specific survival benefit. Prospective data in this setting is lacking. In this study, Marc Martin, MD, and colleagues describe the results of a prospective multicenter randomized controlled phase II study comparing docetaxel plus metformin versus docetaxel plus placebo in mCRPC.For patients with mCRPC without diabetes, the addition of metformin to docetaxel chemotherapy does not improve PSA50, objective response rates, mPFS, or OS.

In the mCRPC patient population, TOPARP-B data was presented which is a phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration-resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations. The researchers initially screened the tumors of 592 men and found 27% had alterations in one or more genes linked to repairing damaged DNA. After screening and evaluation, they enrolled 98 patients with DNA repair mutations onto the trial. BRCA mutations were by far the most common mutation—found in 33% of the tumors with a DNA repair mutation. Other common DNA repair mutations were found in ATM, CDK12, CHEK2, and PALB2. Overall, 47% of men with DNA repair defects in their tumors responded to olaparib, and the drug delayed disease progression for a median of 5.5 months—2.7 months longer than the previous trial, TOPARP-A, found in men with advanced prostate cancer who weren’t selected for treatment based on gene mutations. Approximately 80% of men with BRCA1/2-mutated prostate cancer responded to olaparib, and even though men in the trial had advanced, heavily pretreated prostate cancer, olaparib delayed progression of the disease in these patients for a median of 8.3 months. About 35% were free of progression for more than 1 year. Among patients with mutations in the PALB2 gene, 57% responded to olaparib—the next highest response after those with BRCA1 or BRCA2 mutations—and 25% of men with CDK12 mutations experienced a response.

Phase III trials of the drug are now underway. The trial is assessing olaparib versus enzalutamide or abiraterone acetate in men with metastatic castration-Prostate Cancer (PROfound Study).  This is a prospective, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of olaparib versus enzalutamide or abiraterone in subjects with metastatic castration-resistant prostate cancer (mCRPC) who have failed prior treatment with a new hormonal agent and have a qualifying tumor mutation in one of 15 genes involved in the homologous recombination repair (HRR) pathway. Subjects will be divided into two cohorts based on HRR gene mutation status.  Approximately 340 subjects will be randomized 2:1 (olaparib: investigator choice of enzalutamide or abiraterone acetate) into the trial.

A second phase III trial is also underway: A Randomised, Double-blind, Placebo-controlled, Multicentre Phase III Study of Olaparib Plus Abiraterone Relative to Placebo Plus Abiraterone as First-line Therapy in Men With Metastatic Castration-resistant Prostate Cancer (PROpel Study)


Biographies:

Benjamin L. Maughan, MD, PharmD, Assistant Professor in the Division of Medical Oncology at Huntsman Cancer Institute, the University of Utah, Salt Lake City, Utah, United States

Petros Grivas, MD, Ph.D., Clinical Director, Genitourinary Cancers Program, University of Washington Medicine Associate Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine