ASCO 2019: TOPARP-B: A Phase II Randomized Trial of the Poly(ADP)-Ribose Polymerase Inhibitor Olaparib for Metastatic Castration Resistant Prostate Cancers with DNA Damage Repair Alterations - Medical Oncologist Perspective

Chicago, IL (UroToday.com) Currently, all FDA approved therapies for prostate cancer are tumor agnostic and approved regardless of the underlying genomic profile. However, recent insights have revealed that a subset of patients with DNA-repair defects may respond to poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) inhibition.
Initial results of PARP inhibition were described in a landmark paper in 2015 by Mateo et al,1 where 88% (14/16) of patients with a homozygous deletion or deleterious mutation in DNA-repair genes had a response to olaparib, an FDA approved PARP inhibitor for patients with recurrent ovarian cancer. In the prior published study, genes considered to be involved in DNA repair included BRCA1, BRCA2, ATM, FANCA, CHEK2, PALB2, HDAC2, RAD51, MLH3, ERCC3, MRE11, and NBN. The median survival of patients with a DNA repair defect was 13.8 months, compared with 7.5 months in the biomarker negative cohort. Subsequently, a number of trials are now ongoing investigating PARP inhibitor, both as a single agent (TRITON2, GALAHAD) as well as in combination with other therapies such as immune checkpoint inhibitors (KEYNOTE-365). Joaquin Mateo, MD, Ph.D. presented on the findings of TOPARP-B, the second stage of the trial where patients are pre-selected based on the detection of DNA repair defects.

ASCO2019_TOPARP-B.png

This abstract reports data on 98 patients with putatively pathogenic DNA damage repair (DDR) alterations who were randomized to either 300 mg or 400 mg of olaparib. Of note in TOPARP B, a second cohort was added at 300 mg given that this dose had been approved for other disease types. Also, unlike TOPARP A, circulating tumor cell (CTC) counts were not required at baseline. All patients had progressed after at least one line of taxane chemotherapy.

There was a combined primary endpoint which included objective response rate by RECIST 1.1, PSA50, and CTC conversion (from more than 5 to less than 5). This was a heavily pretreated population, almost all patients had prior abiraterone or enzalutamide, and 38% of patients had prior cabazitaxel.
 
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The response rate (combined primary endpoint) was 54% overall in the 400 mg cohort and 37% in the 300 mg cohort. The overall median PFS was 5.4 months. Responses were reported based on specific genomic alterations. Patients with a BRCA1/2 alteration had a response rate of 80%, PALB2 – 57%, ATM – 37%, and CDK12 - 25%. 73% of patients with a BRCA1/2 and 67% of the PALB2 cohort had a PSA50. A summary of the responses by gene variant are shown below: 

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Prescreening results are shown below. Of note, 89 patients did not have sufficient tumor for screening. This shows that obtaining tissue remains one of the barriers to our patients receiving targeted therapies – hopefully as ctDNA technology becomes more sensitive and specific, this number will decrease.

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The swimmer's plot below shows promising data for patients with BRCA1/2 loss. 1/3 of patients are without radiographic progression at 1 year with olaparib, which is phenomenal for these heavily pre-treated patients with metastatic castration resistant prostate cancer (mCRPC).

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Olaparib is active for patients with mCRPC who have a pathogenic alteration in DNA repair genes, specifically for patients with mutations in BRCA1/2, PALB2, ATM, and CDK12. Patients with BRCA1/2 variants appear to have the greatest benefit. It will be interesting to see how combination studies compare with single-agent PARP inhibition – early studies have shown that olaparib in combination with abiraterone may be beneficial regardless of mutational profile and checkpoint inhibitors may also represent a rational partner as well, with preclinical evidence showing that PARP inhibition may lead to adaptive upregulation of PD-L1 expression.2,3 Given the compelling body of work supporting the use of olaparib in certain genomic subsets of patients, it is only a matter of time before PARP inhibitors become one of the first biomarker-guided therapy for patients with mCRPC.

Presented by: Joaquin Mateo, MD, PhD, Prostate Cancer Translational Research Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain

Written by: Jason Zhu, MD, Fellow, Division of Hematology and Oncology, Duke University Twitter: @TheRealJasonZhu at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

References:
  1. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. New England Journal of Medicine 2015;373:1697-708.
  2. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Oncology 2018.
  3. Stewart RA, Pilié PG, Yap TA. Development of PARP and immune-checkpoint inhibitor combinations. Cancer research 2018;78:6717-25.
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