EAU 2023: State-of-the-Art Lecture: PARP Inhibitors: For Which Mutations and When?

(UroToday.com) The 2023 European Association of Urology (EAU) annual congress held in Milan, Italy between March 10^th and 13^th, 2023 was host to a session addressing precision medicine in patients with metastatic castrate-resistant prostate cancer (mCRPC). Dr. Bertrand Tombal delivered a state-of-the-art lecture discussing the appropriate timing and patient selection for PARP inhibitor use.

Dr. Tombal began by summarizing the current treatment paradigm for advanced prostate cancer in 2023.

Specifically pertaining to PARP inhibitors, the following drugs have been evaluated in the 3^rd line setting as summarized below:

Currently, the European Medical Agency (EMA) has approved Olaparib (Lynparza®) as:

• Monotherapy for the treatment of adult patients with mCRPC and BRCA1/2 mutations (germline and/or somatic) who have progressed following prior therapy that included a new hormonal agent.
• In combination with abiraterone and prednisone/prednisolone for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated

Niraparib (Akeega®) is also EMA approved as:

• Fixed-dose combination niraparib 50 mg with 500 mg abiraterone acetate or 100 mg niraparib with 500 mg abiraterone acetate
• For the treatment of adult patients with mCRPC and BRCA1/2 mutations (germline and/or somatic) in whom chemotherapy is not clinically indicated

Talazoparib (Talzenna®) and rucaprib (Rucabra®) have yet to be approved by the EMA.

As first-line treatment regimens for metastatic castrate sensitive prostate cancer have evolved since 2015, so has our cohort of patients with mCRPC. Dr. Tombal distinguished between two cohorts of mCRPC patients:

1. Historical mCRPC: Patients progressing on ADT alone
2. Intensified mCRPC: Patients progressing on ADT + an androgen receptor pathway inhibitor or docetaxel

Most patients nowadays are “historical” mCRPC patients. However, with time, we will see more patients with “intensified” mCRPC, which will have important treatment implications when considering the sequencing of agents in this setting.

Starting with the “intensified” mCRPC cohort, how/when do we use PARP inhibitors? PROfound was a randomized, open-label, phase III trial evaluating efficacy and safety of olaparib versus enzalutamide or abiraterone in patients with mCRPC with alterations in any of 15 predefined genes with a direct or indirect role in homologous recombination repair whose disease had progressed on prior new hormonal agent therapy.¹ Cohort A included patients with alterations in BRCA1, BRCA2 or ATM, while Cohort B patients included any one of 12 other homologous recombination repair alterations (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D or RAD54L). Patients were randomized 2:1 to olaparib (300 mg BID) or the physician’s choice of enzalutamide (160 mg/day) or abiraterone (1000 mg/day + prednisone 5 mg BID). The primary endpoint was radiographic progression-free survival (rPFS) in Cohort A, assessed by blinded independent central review and analyzed via a stratified log-rank test. Crossover to olaparib was allowed after blinded independent central review progression. 

Among patients in Cohort A (BRCA1/2, ATM), image-based PFS was significantly improved with the use of olaparib (median PFS: 7.4 versus 3.6 months, HR: 0.34, p<0.001).

OS benefits were observed in the BRCA1/2 and ATM altered cohort with median OS improved from 14.7 to 19.1 months (HR: 0.69, 95% CI: 0.50 – 0.97, p=0.02). Significantly, no OS survival benefit was observed in cohort B (HR: 0.96, 95% CI: 063 – 1.49).

Toxicity with olaparib is not insignificant with grade 3 or worse adverse events observed in 51% of patients in the olaparib arm (38% in control arm). Furthermore, anemia, nausea, and fatigue were observed in a non-insignificant proportion of patient.

Taking the results of PROfound into consideration, when should we use PARP inhibitors in patients who had developed mCRPC following ADT + ARPi use? Dr. Tombal believes that patients progressing on one of the ARPis should be tested for DNA repair mutations, with Olaparib 300 mg BID offered to patients with BRCA1/2 mutations.

Why opt for genetic testing in this situation with potential PARPi treatment as opposed to docetaxel. Dr. Tombal argues that a post-hoc analysis of PROfound by Dr. Maha Hussain demonstrated that overall survival in the BRCA1/2 patients who had no prior taxane exposure was superior to those with a prior taxane. As such, Dr. Tombal argues that we should attempt to treat those patients in the pre-docetaxel setting to maximize the benefit with these PARPi agents.

It is important to note that only about 10% of patients have BRCA1/2 mutations, as such, it will be only a minority of such mCRPC patients who will be eligible for the PARPi olaparib. There does not appear to be a benefit in patients with other HRR gene mutations

What about patients with “historical” mCRPC with progression on ADT alone (i.e. not previously exposed to ARPis)? PROpel is a global, randomized, double-blind phase III trial in men with mCRPC. Eligible participants had received no prior abiraterone and had stopped an alternative ARPi more than 12 months prior to enrollment. Docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) was allowed. Patients were randomized to receive full-dose abiraterone 1000 mg daily with either placebo or full-dose olaparib 300 mg BID. The primary endpoint was investigator-assessed rPFS. OS was the key secondary endpoint.²

PROpel met its primary endpoint with the addition of olaparib to abiraterone resulting in a 34% reduction in progression or death in (rPFS HR = 0.66, 95% CI 0.54 - 0.81; P < 0.0001). The addition of olaparib improved median rPFS by 8.2 months (24.8 versus 16.6).

In the final OS update presented at ASCO GU 2023, combination olaparib + abiraterone was associated with clinically meaningful, if not statistically significant, OS benefits (42.1 versus 34.7 months; HR: 0.81, 95% CI: 0.67 – 1.00, p=0.054).

Using a similar study design and patient cohort eligibility criteria (biomarker unselected), with some differences in other eligibility criteria, TALAPRO-2 similarly assessed the combination of a PARPi (talazoparib) and an ARPi (enzalutamide).

TALAPRO-2 met its primary endpoint of blinded independent central review rPFS (not reached versus 21.9 months; HR: 0.63, 95% CI: 0.51 – 0.78, p<0.001).

One of the important study design characteristics of both PROpel and TALAPRO-2 is that they enrolled biomarker-unselected mCRPC patients in the first line setting. These populations were HRR status ‘agnostic’. As such, should we offer this combination therapy to all patients presenting with mCRPC in the first line setting? Dr. Tombal explains that technically you could, with the combination of olaparib/abiraterone currently EMA approved with talazoparib/enzalutamide likely to follow suit soon. However, side-effects, mainly grade 3 or worse anemia, are quite substantial, requiring intense monitoring. As such, he would recommend reserving this combination approach for patients with BRCA1/2 mutations.

In summary, Dr. Tombal proposed the following schema:

• For patients progressing on ADT + ARPi (intensified mCRPC)
  • Patients progressing on one of the ARPis should be tested for DNA repair mutations
  • Patients with BRCA1/2 mutations should be offered Olaparib 300 mg BID
  • For the other patients
    • The level of evidence for switch to abiraterone/olaparib or enzalutamide/talazoparib is weak
    • There are other options with more robust benefit (chemo, PSMA-Lu, Ra-223) to be discussed
• For patients progressing on ADT alone (historical mCRPC)
  • There is scientific rationale to recommend abiraterone/olaparib (or talazoparib/enzalutamide) as standard of care 1^st line treatment in an HRR status agnostic population instead of abiraterone or enzalutamide monotherapy
  • But doing so will result in exposing a large group (the non-BRCA1/2) to an insignificant increase in toxicity with a disputable benefit
    • Offer combination PARPi/ARPi to patients with BRCA1/2 mutations
    • Discuss case by case for the others: the relatively small incremental benefit in rPFS is neutralized by the increased toxicity

Presented by: Bertrand Tombal, MD, PhD, Chairman of the Department of Surgery and Full Professor of Urology at the Université Catholique de Louvain, Ottignies-Louvain-la-Neuve, Belgium

1. De Bono, Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2020. 382:2091-2102.
2. Clarke, Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med Evidence. 2022. DOI:https://doi.org/10.1056/EVIDoa2200043