What’s the Rationale for Adding PARP Inhibitors to Androgen Pathway Inhibitors for Patients with Prostate Cancer?

Over the last few years, the evidence has been mounting for the role of DNA repair in prostate cancer. What started with the Stand Up 2 Cancer (SU2C) International Dream Team discovery of 23% homologous recombination repair gene alteration rate in metastatic castration-resistant prostate cancer (mCRPC), followed by the identification of an 11.8% germline alteration rate in metastatic prostate cancer, has now led to broad sweeping successes with the introduction of PARP inhibitors to our clinics.1,2 

The TRITON2 trial demonstrated a 43.5% objective response rate with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious BRCA1 or BRCA2 alteration.3 This trial led to the United States Food and Drug Administration (FDA) granting accelerated approval to rucaparib for the treatment of men with 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.4

Meanwhile, the PROfound trial was a randomized phase 3 trial for patients with mCRPC and who previously progressed on abiraterone and/or enzalutamide.5 Superior median progression-free survival (PFS) was observed for the patients in the olaparib (7.4 months) vs. abiraterone or enzalutamide (3.6 months) arms in the BRCA1, BRCA2, or ATM altered cohort. The analysis of this cohort was pre-designated as the primary endpoint; however, even when adding the other cohort with alterations in any of 12 other prespecified homologous recombination repair genes, a significant PFS benefit was sustained. This resulted in a 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.6 Since that approval, we have just seen the release of the overall survival data from PROfound as positive, with a 19.1 versus 14.7 month (p=0.02) median overall survival of olaparib versus control therapy, respectively, in the BRCA1, BRCA2, or ATM altered cohort.7

Recognizing that patients with these specific homologous recombination repair gene alterations are the minority of patients, there are many efforts underway to study combination therapies with PARP inhibitors.  Previously, in this column, I’ve discussed the biologic rationale and early clinical data of combination therapy PARP inhibition with a PD-1/PD-L1 checkpoint inhibition antibody.8  A currently widespread approach is to combine PARP inhibition with androgen pathway inhibition.  There is preclinical rationale to suggest synergism and even potential for synthetic lethality.

For example, PARP-1 seems to have dual functions in DNA damage repair and transcription factor regulation. Specifically, PARP-1 is recruited to sites of androgen receptor (AR) function, promoting occupancy, and AR transcriptional function.9 In multiple models, PARP-1 is required for AR function, tumor cell growth, and generation and maintenance of castration-resistance. Not surprisingly, PARP-1 targeting potently suppresses tumor cell proliferation.

Alternatively, AR also helps maintain homologous recombination gene expression and activity in prostate cancer. Specifically, PARP-mediated repair pathways are upregulated following androgen deprivation therapy, and this increased PARP activity is essential for prostate cancer cell survival.10 This lends credence to the concept that co-inhibition of AR and PARP pathways may enhance anti-neoplastic activity against prostate cancer.

There is some early clinical evidence of activity for this combination therapy approach. The most mature data is from a 171 patient phase 2 trial of patients who previously received docetaxel for mCRPC and who were randomized to abiraterone with prednisone with or without olaparib.11 The primary endpoint of radiographic PFS (rPFS) was positive in favor of the olaparib/abiraterone arm with a median rPFS of 13.8 months vs. 8.2 months in the placebo/abiraterone arm (p = 0.034). Slightly under 15% of patients were proven to be homologous recombination repair mutated, which is lower than other trials have shown, but there was no clear imbalance between the arms. As a result, the phase 3 PROpel trial (NCT03732820) randomized approximately 720 chemotherapy and new hormonal agent naïve mCRPC patients 1:1 to abiraterone with olaparib vs. abiraterone with placebo with rPFS as the primary endpoint. The PROpel trial has been fully accrued, and we await results.

Other efforts of combination PARP inhibition with androgen pathway inhibitors have reported less mature data.  For example, the TALAPRO-2 trial has reported on an initial 19 patients with mCRPC enrolled in two dosing cohorts of 13 patients receiving talazoparib 1 mg po qd and 6 patients receiving talazoparib 0.5 mg po qd, both in combination with standard dose enzalutamide.12  Both dosing cohorts saw rather uniform PSA declines in all patients with acceptable safety profiles. The second part of the TALAPRO-2 trial is currently randomizing 1,018 patients to enzalutamide with or without talazoparib 0.5 mg po qd with the primary endpoint of rPFS (see below).

The Phase 1b BEDIVERE trial evaluated niraparib in combination with either apalutamide or abiraterone acetate/placebo.13 Results of the pharmacokinetics and toxicity assessment of the combination with apalutamide demonstrated that the niraparib 200 mg po qd dose led to low plasma drug levels, while niraparib 300 mg po qd dosing led to 2 of 3 patients experiencing dose-limiting toxicity. As a result, further investigation of this combination was halted. With abiraterone, 3 of 8 patients experienced dose-limiting toxicity with niraparib 300 mg po qd; however, 0 of 4 experienced dose-limiting toxicity with niraprib 200 mg po qd. Therefore, the niraparib 200 mg po qd dose is the recommended phase 2 dose for combination with abiraterone and is being evaluated in the phase 3 MAGNITUDE trial (NCT03748641).

Ultimately, the future use of PARP inhibitors in combination with androgen pathway inhibitors in prostate cancer will depend upon trial results from randomized patient populations. Although the above provides some preclinical and early clinical rationale, further investigation is warranted. Below, I list some ongoing trials that combine a PARP inhibitor with an androgen pathway inhibitor for patients predominantly with mCRPC, although earlier efforts into the metastatic castration-sensitive prostate cancer (mCSPC) setting are now also underway. The primary results of these trials will be additionally charged to convincingly prove that the therapeutic combination of PARP inhibition with androgen pathway inhibition is synergistic or at least additive for an unselected patient population of prostate cancer patients. That important endeavor will require a deep interrogation of the molecular features of the patients enrolled in the below trials.

Relevant trials currently open for accrual

  1. AMPLITUDE – Phase 3: Abiraterone +/- Niraparib in homologous recombination repair gene mutated metastatic castration-sensitive prostate cancer (NCT04497844)
  2. CASPAR – Phase 3: Enzalutamide +/- Rucaparib in mCRPC (NCT04455750)
  3. ZZ-First – Phase 2: Enzalutamide with Talazoparib in high volume mCSPC (NCT04332744)
  4. ASCLEPluS – Phase 1/2: Prostate SBRT, abiraterone/prednisone, leuprolide and niraparib for high risk and node positive prostate cancer (NCT04194554)
  5. RAMP – Phase 1: Enzalutamide with rucaparib cohort and abiraterone with rucaparib cohort for mCRPC (NCT04179396)
  6. MAGNITUDE – Phase 3: Abiraterone/prednisone +/- niraparib (NCT03748641)
  7. QUEST – Phase 1/2: Niraparib combinations for mCRPC (one arm with abiraterone) (NCT03431350)
  8. TALAPRO-2 – Phase 3: Enzalutamide +/- Talazoparib in mCRPC (NCT03395197)
  9. BRCAAway: Phase 2: Abiraterone vs. Olaparib vs. abiraterone + Olaparib for mCRPC patients with DNA repair defects (NCT03012321)
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

References

  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. Abida W, Patnaik A, Campbell D, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol 2020; Epub August 14, 2020.
  4. "FDA Grants Accelerated Approval To Rucaparib For BRCA-Mutated Metastat". 2020. U.S. Food And Drug Administration.
  5. De Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 2020; 382(22):2091-102.
  6. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer.
  7. Hussain M, Mateo J, Fizazi K, et al. Survival with Olaparib in metastatic castration-resistant prostate cancer. N Engl J Med 2020; Epub September 20, 2020.
  8. Yu, Evan. 2020. "PARP With PD-1/PD-L1 Inhibition: Is There Any Magic To The Combination In A Molecularly Unselected Patient Population?". Urotoday.Com.
  9. 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.
  10. 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.
  11. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomized, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018; 19:975-86.
  12. Agarwal N, Shore ND, Dunshee C, et al. Clinical and safety outcomes of TALAPRO-2: A two-part phase III study of talazoparib in combination with enzalutamide in metastatic castration-resistant prostate cancer. J Clin Oncol 37, 2019 (suppl; abstr 5076).
  13. Saad F, Chi KN, Shore ND, et al. Phase Ib study of niraparib plus androgen receptor-targeted therapy in patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2020; 38:6_suppl, 122-122.
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