Are There Any Other PARP Inhibitor Combinations in Prostate Cancer We Should Be Exploring?

I’ve now written many articles about PARP inhibitor use in prostate cancer.  We currently have United States Food and Drug Administration (FDA) approval, on an accelerated pathway, for rucaparib for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who harbor a deleterious BRCA1 or BRCA2 germline or somatic alteration and who have been treated with androgen receptor (AR)-directed therapy and taxane-based chemotherapy.1  We also have full FDA approval for olaparib for the treatment of patients with pathogenic germline or somatic homologous recombination repair gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone.2  Recognizing that response rates still approximate the 40-50% range, even with DNA repair gene alteration biomarker selection, there have been many proposals for rationale combination therapies with PARP inhibitors.


Previously, I highlighted the combination of PARP inhibition with PD-1/PD-L1 inhibition.Although this offered hope, a recent randomized phase 3 trial, the KEYLYNK 010 trial, was terminated for futility.4  Results should be presented soon from this trial, and hopefully, there will be many lessons learned in the field.

On the contrary, there have been some recent signs of success with combination therapy.  I have discussed the rationale for adding PARP inhibitors to androgen pathway inhibitors in another article.5  At the 2022 ASCO Genitourinary Cancers Symposium, the PROpel trial presented positive radiographic progression-free survival (rPFS) results (median 24.8 vs. 16.6 months; HR 0.66, 95% CI 0.54-0.81; p<0.0001) in an unselected patient receiving first-line mCRPC Olaparib with abiraterone acetate when compared to placebo plus abiraterone acetate.6  However, overall survival data is not yet mature.  Interestingly, the MAGNITUDE trial confirmed the benefit of niraparib with abiraterone acetate in a BRCA1/2 alteration mandated cohort with rPFS of 16.6 vs. 10.9 months.7  However, there was no benefit to niraparib with abiraterone acetate compared with abiraterone acetate alone in a prespecified composite endpoint for biomarker negative patients (rPFS HR 1.09; 95% CI 0.75-1.57).  Overall survival in this trial is also not yet mature.

The results from the PROpel trial are quite intriguing in that they imply some sort of additive or synergistic properties between Olaparib and abiraterone acetate.  There is data to point towards PARP-1 promotion of androgen receptor (AR) occupancy and androgen receptor (AR) transcriptional function.8  Not surprisingly, PARP-1 targeting potently suppresses tumor cell proliferation, although one could also theorize that a PARP inhibitor at high enough doses could also have off-target effects that could lead to inhibition of cell proliferation as well.  Alternatively, PARP-mediated repair pathways are upregulated following androgen deprivation therapy, and this increased PARP activity is essential for prostate cancer cell survival.9  This lends support for co-inhibition of AR and PARP pathways.  Although intriguing, fine dissection of patient subgroups with and without specific gene mutations will need to be performed in future analyses for a more complete understanding of the data.

The PROpel trial results likely provide additional promise for ongoing PARP inhibitor combination trials with androgen pathway inhibitors in the metastatic castration-sensitive disease state.  I also recently discussed this topic and presented ongoing clinical trials relevant to this patient population.10

With previous coverage in this monthly article of PARP inhibitor use for patients with homologous recombination deficiency and other discussions of combination therapy with immuno-oncology agents and androgen pathway inhibitors, this month we will look to cover PARP inhibitor combinations with other therapies.  There is logic to combining PARP inhibitors with PI3kinase inhibitors, as these agents may just operate on downstream signal transduction pathways affected similarly by androgen pathway inhibitors.  Similarly, bromodomain inhibitors, EZH2 inhibitors, and histone deacetylase inhibitors also may have functions that intersect with the androgen signaling pathways.  Another set of agents to consider in combination with PARP inhibitors are agents that directly cause DNA damage.  This may include radiopharmaceuticals and cytotoxic chemotherapy agents that induce breaks in DNA.  Since both PARP inhibitors can cause myelosuppression, combinations with other potentially myelosuppressive agents will need to be closely monitored for toxicity.

Below, I list some ongoing trials that combine a PARP inhibitor with the novel approaches mentioned above.  We now have a role for single agent PARP inhibition for biomarker-selected patients with mCRPC and a potential future role in combination with abiraterone acetate for first-line mCRPC treatment.  However, we should remain aggressive in testing the provocative novel combinations below.

Relevant novel PARP inhibitor combination trials currently open for accrual

  • Phase 1/2 trial of NUV-868 (BD2-selective bromodomain inhibitor) in combination with Olaparib in solid tumors, including prostate cancer (NCT05252390)
  • Phase 1a/1b trial of Talazoparib + Tazemetostat (EZH2 inhibitor) in mCRPC (NCT04846478)
  • Phase 2 trial of Telaglenastat (glutaminase inhibitor) + Talazoparib in prostate cancer (NCT04824937)
  • Phase 1 trial of Talazoparib in combination with Belinostat (histone deacetylase inhibitor) for mCRPC, breast and ovarian cancer (NCT04703920)
  • Phase 1 trial of CYH33 (PI3Kα–selective inhibitor) in combination with Olaparib in patients with advanced solid tumors, including prostate cancer (NCT04586335)
  • Phase 1/2 trial of Copanlisib (pan-PI3K inhibitor) with Rucaparib in mCPRC (NCT04253262)
  • Phase 1/2 trial of Talazoparib and Temozolomide in prostate cancer (NCT04019327)
  • LuPARP - Phase 1 trial of 177Lu-PSMA-617 and Olaparib in mCRPC (NCT03874884)
  • COMRADE - Phase 1/2 trial of Olaparib with Radium-223 in bone mCRPC (NCT03317392)
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. https://www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate.
  2. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer.
  3. Yu EY. Urotoday Clinical Trials Portal.PARP with PD-1/PD-L1 inhibition: Is There Any Magic to the Combination in a Molecularly Unselected Patient Population? On-line: February 15, 2019.
  4. https://www.merck.com/news/merck-announces-keylynk-010-trial-evaluating-keytruda-pembrolizumab-in-combination-with-lynparza-olaparib-in-patients-with-metastatic-castration-resistant-prostate-cancer-to-stop-for-f/
  5. Yu EY. Urotoday Clinical Trials Portal. What’s the Rationale for Adding PARP Inhibitors to Androgen Pathway Inhibitors for Patients with Prostate Cancer? On-line: October 1, 2020.
  6. Saad F, et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2022; 40:6_suppl, 11-11.
  7. Chi KN, et al. J Clin Oncol 2022; 40:6_suppl, 12-12.
  8. Schiewer MJ, Goodwin JF, Han S, et al. Dual roles of PARP-1 promote cancer growth and progression. Cancer Discov 2012; 2(12):1134-49.
  9. Asim M, Tarish F, Zecchini HI, et al. Synthetic lethality between androgen receptor signalling and the PARP pathway in prostate cancer. Nat Commun 2017; 8(1): 374.
  10. Yu EY. Urotoday Clinical Trials Portal. Can PARP Inhibitors Make It into the Metastatic Castration-Sensitive Prostate Cancer Disease State? On-line: February 1, 2022.