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Can PARP Inhibitors Make It into the Metastatic Castration-Sensitive Prostate Cancer Disease State?

I’m continuing this series focused on metastatic castration-sensitive prostate cancer (mCSPC), as it is a disease state with many upcoming potential changes to standard of care.  A couple of months ago, I briefly summarized what is known about the PEACE-1 trial, and I highlighted ongoing chemohormonal therapy trials.1  Since then, there has been a press release that the ARASENS trial with androgen deprivation therapy (ADT) plus docetaxel and darolutamide is superior in overall survival compared to ADT plus docetaxel.  We eagerly await the data to be presented at the upcoming 2022 ASCO Genitourinary Cancers Symposium.  Additionally, just last month, I summarized the trials that are ongoing using PD-1/PD-L1 antibody inhibition for patients with mCSPC.2  Although single agent PD-1/PD-L1 inhibitors have not shown definitive promise yet in metastatic castration-resistant prostate cancer (mCRPC) for unselected populations, hope remains that earlier use may offer benefit to our patients.


I have also discussed PARP inhibitors in ongoing trials previously for patients with mCRPC, both in combination with novel hormonal agents and with PD-1/PD-L1 inhibitors.3, 4  We currently have FDA approval for single agent use of rucaparib5 and olaparib6 for biomarker selected patients with homologous recombination deficiency and mCRPC.  Interestingly, the randomized phase 3 PROPEL trial was recently press released and is reported to show that Olaparib in combination with abiraterone acetate significantly delayed disease progression in an unselected population receiving first-line therapy for mCRPC.7  We also should see the specifics of this data very soon, and we should have many questions relevant to this trial.  Specifically, what does the distinct data looks like for homologous recombination proficient and deficient populations when displayed separately?  This gets to the heart of the question as to whether PARP inhibition has significant activity in a patient population that does not harbor homologous recombination deficiency.  Additionally, will progression-free survival be sufficient or will overall survival be necessary to change the standard of care for this patient population?

While we ponder these issues, this further illuminates the efforts that are ongoing with PARP inhibitors in the mCSPC disease state.  There is both ongoing biomarker selected and unselected efforts for mCSPC patients.  The PARP inhibitor trials that probably have the greatest chance of success for patients with mCSPC are those with strong biomarker enrichment strategies.  However, the upcoming results from the PROPEL trial certainly provides promise to broaden our considerations of PARP inhibitor use for unselected prostate cancer patients with earlier stages of disease.  As previously discussed, there may be the rationale for this approach even in patients who are homologous recombination proficient.3 

As a result, we should place aggressive efforts to accrue to the below trials, which are a mix of biomarker-selected and -unselected patients for eligibility.  In the near future, the ability to accrue to these trials could be further challenged with the adoption of the PEACE-1 and ARASENS trial results, as combination chemohormonal therapy strategies with ADT plus docetaxel plus either abiraterone acetate or darolutamide could ultimately become the dominant treatment strategy for patients with mCSPC.  That only strengthens the rationale to focus rapid accrual for patients with mCSPC to the below PARP inhibitor trial efforts. 

Highlighted PARP inhibitor Trials for patients with mCSPC

  • Randomized phase 3 trial of enzalutamide with talazoparib vs. enzalutamide with placebo in patients with DNA repair deficiency (NCT04821622)
  • Phase 2 study of ADT, abiraterone and talazoparib in an unselected population (NCT04734730)
  • AMPLITUDE – randomized phase 3 trial of abiraterone/prednisone with or without niraparib in homologous recombination repair gene mutated patients (NCT04497844)
  • ZZ-First – Randomized phase 2 study of ADT with enzalutamide +/- talazoparib in an unselected population (NCT04126070)
  • TRIUMPH – Phase 2 trial of rucaparib as an alternative for those who decline or are ineligible to ADT (NCT03413995)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References:

  1. Yu EY. "Metastatic Castration-Sensitive Prostate Cancer, The Advances Keep Coming With Chemohormonal Therapy." Urotoday Clinical Trials Portal. On-line: November 2021.
  2. Yu EY. "Combination Strategies with PD-1/PD-L1 Inhibition for Patients with Metastatic Castration-Sensitive Prostate Cancer."Urotoday Clinical Trials Portal. On-line: January 2022.
  3. Yu EY. "What’s the Rationale for Adding PARP Inhibitors to Androgen Pathway Inhibitors for Patients with Prostate Cancer?"Urotoday Clinical Trials Portal. On-line: October 2020.
  4. Yu EY. "PARP with PD-1/PD-L1 inhibition: Is There Any Magic to the Combination in a Molecularly Unselected Patient Population?"Urotoday Clinical Trials Portal. On-line: February 2019.
  5. "FDA Grants Accelerated Approval To Rucaparib For BRCA-Mutated Metastat". 2022. U.S. Food And Drug Administration. 
  6. "FDA Approves Olaparib For HRR Gene-Mutated Metastatic Castration-Resis". 2022. U.S. Food And Drug Administration.
  7. Lynparza. 2022. "Lynparza In Combination With Abiraterone Significantly Delayed Disease Progression In All-Comers In Propel Phase III Trial In 1St-Line Metastatic Castration-Resistant Prostate Cancer". Astrazeneca.Com.