Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Methods
TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing.
Findings
Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9–30·2) for the talazoparib group and 24·6 months (14·4–30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months–not reached) for talazoparib plus enzalutamide and 21·9 months (16·6–25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51–0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3–4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group.
Interpretation
Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations.
Funding
Preclinical studies suggest that a co-inhibition of the androgen receptor and PARP might extend the benefit of PARPi in metastatic castration resistant prostate cancer (mCRPC), even in tumours without HRR gene alterations. Based on this rational, three phase III trials have been conducted to evaluate the efficacy and safety of the combination of a PARP inhibitor and an androgen-receptor pathway inhibitor (ARPI) as first line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of the homologous recombination repair (HRR) status:
TALAPRO-2 has been recently published in The Lancet journal. It is a double-blind, randomised, placebo-controlled trial that compared enzalutamide + talazoparib or placebo in patients with mCRPC. To be enrolled, patients needed to be naïve of life-prolonging systemic therapy for mCRPC but previous treatment by docetaxel or abiraterone in metastatic hormone-sensitive setting were allowed. Enrolment began without any selection on HRR status (cohort 1, all-comers population). Once enrolment was completed in cohort 1, enrolment continued but was restricted to patients with HRR gene alterations (cohort 2). The HRR status was conducted prospectively on blood-samples or tumour tissue using FondationMedicine tests (BRCA1, BRCA2, PALB2, ATM, ATR, CHEK2, FANCA, RAD51C, NBN, MLH1, MRE11A, CDK12). The primary endpoint was radiological progression-free survival (rPFS) assessed by a blinded independent central review.
A total of 805 patients were included in cohort 1. The median PSA at baseline was 18 ng/ml (talazoparib arm) and 16 (placebo arm). Only 21% of the patients had a HRR gene alteration. The vast majority of the patients (93%) had not been treated previously with ARPI at an earlier stage. After a median follow-up of 2 years, the rPFS was significantly improved in enzalutamide + talazoparib arm compared to enzalutamide + placebo group (not reached vs 21.9 months, HR 0.63; 95% CI 0.51–0.78; p<0.0001).
The benefit was more significant in HRR+ patients (27.9 vs 16.4 months, HR 0.46 95% CI 0.30-0.70) and BRCA 1/2 patients (HR 0.23 95%CI 0.10-0.53) but was also observed in HRR- population (not reached vs 22.5 months, HR 0.70 95%CI 0.54-0.89). The other secondary endpoints were also in favour of talazoparib + enzalutamide arm (including time to initiation of cytotoxic chemotherapy, objective response rate, time to PSA progression). The overall survival data were not mature. Regarding the toxicity profile, the most common adverse events (AE) in talazoparib + enzalutamide were: anaemia (66%, including 46% grade 3/4), neutropenia (36%, including 18% grade 3/4), and fatigue (34%, including 4% grade 3/4). More than half of the patients (56%) had a dose reduction of talazoparib/placebo due to AE in talazoparib arm vs 7% in placebo arm.
The TALAPRO-2 trial shows very similar results to the PROpel trial, with a clear rPFS benefit in patients with mCRPC, especially in BRCA 1/2 mutated patients, but not only. It contrasts with the MAGNITUDE trial, in which patients with HRR- status had no benefit. Regarding safety profile, adding a PARPi is also associated with more adverse events leading to a dose reduction of talazoparib in half of the patients. However, it’s important to keep in mind that the AE related to PARPi occur during the first three months, and then decrease over time.
To summarise, these three trials (MAGNITUDE, PROpel, TALAPRO-2) have shown a clear benefit of adding a PARPi to ARPI in BRCA 1/2 patients with a mCRPC. Even though a statistical difference was observed also in HRR- patients in PROpel and TALAPRO-2 trials, the benefit was less significant and must be balanced with the AE associated with PARPi. Based on these results, the FDA approved abi + olaparib and abi + niraparib for use in BRCA 1/2 patients and enza + talazoparib for use in HRR+ patients, whereas EMA gave a broad authorisation for abi + olaparib (regardless of BRCA and HRR status). The European decision is still pending for enza + talazoparib.
However, it’s important to keep in mind that the majority of the patients enrolled in these trials were treated with only androgen deprivation therapy (ADT) at metastatic hormone-sensitive setting, whereas the standard of care is currently ADT + ARPI +/- docetaxel in mHSPC patients. The benefit of the combination ARPI + PARPi in patients previously treated with ARPI at mHSPC setting is unclear.