21P - Cross-resistance between platinum-based chemotherapy (PlCh) and PARP inhibitors (PARPi) in castration-resistant prostate cancer (CRPC)

Background

CRPC patients (pts) with loss-of-function alterations in genes associated with homologous recombination (HR) can derive benefit from both PARPi and PlCh. Cross-resistance between these agents is well recognized in other tumour types and evidence of ‘reversion’ mutations in HR genes is emerging. Yet, optimal treatment sequence and data on cross-resistance in CRPC is lacking.

Methods

In this retrospective pre-planned single-centre study we describe intra-patient responses to PlCh and PARPi, assessed by the order of these HR-deficiency-targeting-agents (HRDtA; PARPi→PlCh or PlCh→PARPi). All pts were treated with both PlCh and PARPi, but agents were not necessarily given directly sequential.

Results

All 28 CRPC pts were metastatic and HR deficient, mostly due to BRCA2 inactivation (79%). Sixteen pts received PARPi→PlCh and 12 PlCh→PARPi. Pts with PlCh→PARPi had a significant shorter time to CRPC (median 10 vs. 18 months, P=0.040) and were significantly more often synchronous metastatic (92% vs. 44%, P=0.016). Progression-free survival (PFS) on the initial HRDtA was longer than the PFS on the subsequent HRDtA (median 5.3 versus 3.4 months, P=0.016). The median PFS on PARPi, given as subsequent HRDtA, was 0.9 months shorter than when administered first. For PlCh the PFS was 3.6 months shorter as subsequent HRDtA than as initial. Of the PARPi→PlCh pts, 6/16 (38%) had a >50% PSA decline to PlCh and 2/8 (25%) evaluable pts had a radiographic response to PlCh. In the PlCh→PARPi group, 6/10 (60%) evaluable pts had a >50% PSA decline to PARPi and 5/9 (56%) a radiographic response to PARPi. In total, 12/26 (46%) had a >50% PSA decline and 7/17 (41%) a radiographic response to a subsequent HRDtA. Overall survival from CRPC did not significantly differ depending on the order of HRDtA (PARPi→PlCh 45 months vs. PlCh→PARPi 33 months, hazard ratio 1.42, P=0.401).

Conclusions

This study suggests cross-resistance between PARPi and PlCh in HR deficient CRPC pts. PlCh appears to induce less cross-resistance to PARPi than vice versa. Still, >40% of the cohort is sensitive to a subsequent HRDtA. Serial assessment of (liquid) biopsies is warranted to unravel the mechanisms defining cross-resistance.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Radboud University Medical Center, Nijmegen, The Netherlands.

Funding

Has not received any funding.

Disclosure

I.M. Van Oort: Financial Interests, Personal and Institutional, Advisory Role: Bayer, Astellas, Janssen, MSD/AstraZeneca; Financial Interests, Institutional, Research Grant: Astellas, Janssen, Bayer. J. Schalken: Financial Interests, Personal, Invited Speaker: Astellas, Bayer. N. Mehra: Financial Interests, Personal, Advisory Board: Pfizer, Roche, MSD, AstraZeneca, Astellas, JNJ; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Astellas, Pfizer; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Institutional, Invited Speaker: BMS, Janssen; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Personal, Leadership Role, Head of the Prostate Cancer Working Group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Personal, Principal Investigator, co-PI: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Personal, Leadership Role: Castration-resistant Prostate Cancer Registry. All other authors have declared no conflicts of interest.