From the Desk of Evan Yu: “Clinical Trial Updates of Single-Agent PARP Inhibitor Use in Homologous Recombination Deficient Prostate Cancer Populations.”

When this monthly Clinical Trials Portal first started at the beginning of 2017, I focused on what I thought to be one of the newest, hottest areas of clinical investigation in prostate cancer.  This was capitalizing on the discovery that 23% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor alterations in DNA repair genes that result in homologous recombination deficiency (HRD) e.g. BRCA1/2, etc.1  Coupling this information with the 11.8% of metastatic prostate cancer patients with germline alterations in DNA repair genes2 led to the conclusion that targeting the HRD patient population with poly-ADP ribose polymerase (PARP) inhibitors seemed to make much sense.  This was supported by early data with the PARP inhibitor, olaparib, in the TOPARP trial, which resulted in an 88% composite response rate.  This was defined by achieving either RECIST 1.1 soft tissue shrinkage, ³50% PSA decline and/or circulating tumor cell (CTC) count reduction to <5 cells per 7.5 ml of whole blood.3 

As a result of these findings, many trials were immediately launched and highlighted in that February 2017 Urotoday Clinical Trials Portal article.4  However, as biomarker enrichment was a mandatory inclusion criteria for enrollment onto the majority of these trials, eligible patient numbers have been limited and just about all of these initial trials are still actively accruing.  Fortunately, we have started to see the first hint of returns on this major investment, and I believe that there are many lessons to be learned from this early data. 

At ESMO 2018, we recently saw early data presented from the ongoing TRITON2 trial.5  This trial allows mCRPC patients with deleterious genetic alterations found in any one of 15 homologous recombination repair (HRR) genes detected by local or central testing of tumor or circulating tumor DNA in the blood to be enrolled to receive rucaparib 600 mg po bid.  It is also mandatory for patients to have had previous disease progression on a second-generation androgen receptor (AR)-directed therapy (e.g. abiraterone, enzalutamide or apalutamide) and 1 prior taxane-based chemotherapy, all for CRPC.  As of April 16, 2018, 85 patients were enrolled and evaluable for PSA response, while 46 patients were evaluable for radiographic response.  Focusing on soft-tissue response criteria by specific gene alterations, 11/25 (44%) of BRCA1/2, 0/5 (0%) of ATM, 0/8 (0%) of CDK12 and 2/8 (25%) of patients with other (BRIP1 and FANCA) HRR gene alterations achieved a response.  When evaluating confirmed PSA response of ³50% decline, 23/45 (51.1%) of BRCA1/2, 0/18 (0%) of ATM, 1/13 (7.7%) of CDK12, and 2/9 (22.2%) of patients with other (BRIP1 and FANCA) HRR gene alterations achieved that bar.  As a result of this early data, enrollment of patients with CDK12 gene alterations has been halted.  Although somewhat disappointing, there may be promising upcoming treatments for the CDK12 altered patients, as these patient tumors seem to be characterized by focal tandem duplications that lead to increased gene fusions, elevated neoantigen burden, and increased tumor T cell infiltration.6  Hence, these patients may benefit from immune-oncology therapeutics.6

The early data from TRITON2 may emphasize some very important lesson for us to heed carefully.  One natural reaction is to compare response rates from this trial with olaparib response rates, from the TOPARP trial, and conclude that response rates appear lower with rucaparib.  As usual, it is not appropriate to compare data from one single-arm, open-label trial with data from another such trial.  Additionally, the TOPARP trial utilized a composite response rate that extended beyond soft-tissue and PSA response to CTC normalization.  Another critical feature of the TOPARP trial is that biallelic alteration was mandated for a patient to be considered as having HRD.  It will be very important for the TRITON2 trial to attempt to discern between biallelic vs. monoallelic alterations, as likely only the former should lead to HRD.  It is possible that some patients enrolled in the TRITON2 trial may not have been enriched to respond to PARP inhibition due to flexibility in the assay allowance for eligibility.  Ultimately, this may become an issue in many of the trials highlighted below, and moving forward, deep dives into assay standardization and reporting will be helpful.  It will also be important to understand what proportion of patients had germline vs. somatic alterations.  As we learn more, we may find differences in response rates between the unique populations.

Almost two years removed from my original Clinical Trials Portal article on this topic, I am re-emphasizing the importance of completing accrual to both those trials, as well as to multiple newly open trials (see highlighted trials below).  The list of trials for prostate cancer patients with HRD has significantly expanded from the original list 2 years ago.  They include various PARP inhibitors, which offer unique biologic features, some offering more enzymatic activity and others offering more PARP trapping capabilities.  Ultimately, we may find that what matters the most is not which PARP inhibitor we are using, but how confident we are in the sequencing assays utilized, which DNA repair genes are altered, what alterations occur in those genes, whether those alterations are monoallelic or biallelic and/or whether the alterations are germline or somatic.  As more data emerges from these complex trials, we must continue to learn and adapt by incorporating newly garnered information into future analyses and trial design. 

Highlighted trials for prostate cancer patients with HRD

  • Phase 2 - Rucaparib (TRITON2) NCT02952534
  • Phase 3 - Rucaparib vs. patient choice (TRITON3) NCT02975934
  • Phase 2 – Rucaparib for germline HRD metastatic hormone-sensitive prostate cancer (TRIUMPH) NCT03413995
  • Phase 2 – Rucaparib for non-metastatic hormone-sensitive prostate cancer (ROAR) NCT03533946
  • Phase 2 – Rucaparib maintenance for mCRPC patients with HRD after induction docetaxel + carboplatin (PLATI-PARP) NCT03442556
  • Phase 2 - Niraparib (GALAHAD) NCT02854436
  • Phase 3 – Niraparib + abiraterone vs. abiraterone (cohort 1 with HRD enrichment only) NCT03748641
  • Phase 2 – Olaparib (TOPARP) NCT01682772
  • Phase 2 – Olaparib vs. abiraterone vs. abiraterone + olaparib (BRCAAway) NCT03012321
  • Phase 3 - Olaparib vs. enzalutamide or abiraterone acetate (PROfound) NCT02987543
  • Phase 2 - Talazoparib (TALAPRO-1) NCT03148795
Written by: Evan Yu, MD

1. Robinson D, Van Allen EM, Wu YM, et al.  Integrative clinical genomics of advanced prostate cancer.  Cell 2015; 161(5):1215-1228.
2. Pritchard CC, Mateo J, Walsh MF, et al.  Inherited DNA-repair gene mutations in men with metastatic prostate cancer.  N Engl J Med 2016; 375(5):443-453.
3. Mateo J, Carreira S, Sandhu S, et al.  DNA-repair defects and olaparib in metastatic prostate cancer.  N Engl J Med 2015; 373(18):1697-1708.
4. Yu EY.  From the desk of Evan Yu: Recent genome sequencing data in metastatic prostate cancer.  Urotoday Clinical Trials Portal.  February 12, 2017.
5. Abida W, Bryce AH, Vogelzang NJ, et al.  Preliminary results from TRITON2: A phase II study of rucaparib in patients with metastatic castration-resistant prostate cancer associated with homologous recombination repair gene alterations.  Ann Oncol 2018; 29 (suppl_8):793PD.
6. Wu YM, Cieslik M, Lonigro RJ, et al.  Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer.  Cell 2018; 173:1780-1782.e14

Further Related Content:
Watch: Results from TRITON2: Treatment of mCRPC with Rucaparib - Alan Bryce

Newsletter subscription

Free Daily and Weekly newsletters offered by content of interest

The fields of GU Oncology and Urology are rapidly advancing. Sign up today for articles, videos, conference highlights and abstracts from peer-review publications by disease and condition delivered to your inbox and read on the go.