ASCO GU 2025: HRR in mCRPC

A new treatment option for HRR-deficient mCRPC

There are limited therapy options for people with metastatic castration-resistant prostate cancer (mCRPC); with a real-world median overall survival of only 13 months,¹ new and effective treatments are dearly needed. Here we summarize the final overall survival (OS) results for the selected population with homologous recombination repair (HRR) gene alterations in the TALAPRO-2 trial, presented at the 2025 American Society of Clinical Oncology (ASCO) Genitourinary (GU) Cancers Symposium, with Karim Fizazi (Institut Gustave Roussy, University of Paris-Saclay, Orsay, France) sharing his opinion on the implications of these findings for patients. We also present a poster round-up, with a focus on unmet needs around HRR testing, as well as emerging treatments for HRR mutation-positive mCRPC.

TALAPRO-2: Radiographic progression-free survival

TALAPRO-2 is a phase 3 trial aiming to evaluate the efficacy of adding talazoparib to enzalutamide as first-line treatment in patients with mCRPC, unselected for or with HRR alterations (cohort 1 and 2, respectively). The results, which have already been published, demonstrated that talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in radiographic progression-free survival (rPFS), compared with the standard-of-care enzalutamide monotherapy. 

Similar results were seen in the HRR-deficient patient subgroup, with a median rPFS not reached (NR) versus 13.8 months with enzalutamide alone (HR, 0.45; 95% CI, 0.33–0.61; P<0.0001).

TALAPRO-2: Updated results for rPFS and final OS

Neeraj Agarwal (Huntsman Cancer Institute at the University of Utah, Salt Lake City, USA) presented an update from this study for cohort 1 showing that the rPFS benefit was maintained after 2 years of additional follow-up, with a 13.6-month improvement seen with the addition of talazoparib to enzalutamide.

The final OS results for the unselected cohort also favored talazoparib plus talazoparib versus enzalutamide alone (45.8 vs 37.0 months respectively), with a 20.4% reduction in risk of death and an 8.8-month improvement in OS.

There were no new safety signals with the longer follow-up of TALAPRO-2.

TALAPRO-2: Talazoparib improves OS in HRR-deficient patients

In a very encouraging development, a similar survival benefit was seen in patients with HRR-deficient mCRPC (cohort 2). Results presented by Fizazi showed that median OS with talazoparib plus enzalutamide was 45.1 months (35.4–NR), which was 14 months longer than with enzalutamide alone (31.1 months, 27.3–35.4). Furthermore, a 38% reduced risk of death at a median follow-up of 44.2 months was seen in the combination treatment arm. To the authors’ knowledge, this is the longest median OS reported in men with HRR-deficient mCRPC.

Looking at subgroups, patients with BRCA1/2 alterations had a 50% reduction in risk of death with the combination treatment, and those with non-BRCA1/2 gene alterations had a 27% lower risk of death. Fizazi noted that treatment with talazoparib plus enzalutamide benefited HRR-deficient patients regardless of age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), Gleason score, stage at diagnosis, baseline prostate-specific antigen (PSA), site of metastases, or prior abiraterone or docetaxel (for metastatic castration-sensitive PC).

These results indicate that combination talazoparib plus enzalutamide has the potential to become a standard of care for the first-line treatment of mCRPC with HRR gene mutations, including and beyond BRCA1/2.

Karim Fizazi discusses the results of TALAPRO-2 and their implications for first-line treatment of mCRPC, particularly for patients with HRR gene alterations. View transcript.

During discussions about the TALAPRO-2 trial results, Tanya Dorff (City of Hope Comprehensive Cancer Center, Duarte, California, USA) noted that “AR pathway inhibitors and PARP (poly-ADP ribose polymerase) inhibitors have clearly demonstrated synergy that will extend their utility to a broader population.” She reminded the audience of the importance of molecular selection to inform the magnitude of benefit, emphasizing germline and somatic testing as crucial procedures.

We can expect next-generation sequencing results to support genetic counseling with patients and aid in discussions about potential benefits and the risks.

Posters round-up

HRR mutation testing and directed management: An unmet need

Despite the findings of TALAPRO-2 and the growing recognition that genetic factors are important for management and treatment decisions in metastatic prostate cancer, a vote held during the first case from the general session “Case-Based Session: Evolving Landscape of the Management of Oligometastatic Disease” revealed that around 10% of the participants did not think that genetic testing was necessary for the patient case being presented. Testing and use of test-guided treatment remains a widespread unmet need in real-world clinical practice, as shown by Neil Shore (Carolina Urologic Research Center, Myrtle Beach, USA), Pedro Barata (University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA), and Micah Ostrowski (Huntsman Cancer Institute at the University of Utah, Salt Lake City, USA), who all presented posters with US data.

Notably, results from the analysis led by Shore revealed that less than a quarter of patients received HRR mutation testing at the time of mCRPC diagnosis; nearly half were not tested at all. Furthermore, PARP inhibitor (PARPi) treatment was delayed in more than half of patients, with only a third receiving PARPi prior to third line of treatment.

Similarly, in their research Barata and team found that around half of patients did not receive HRR mutation testing; patients were less likely to be tested if they had metastatic disease or a Gleason score <8 at diagnosis, or no known family history of an HRR-mutation-related cancer.

In their poster, Ostrowski and team showed that despite the survival benefit of PARPis in patients with BRCA1/2 mutations, around half of patients in their analysis did not receive them.

Continuing education and raising awareness about the importance of HRR mutation testing, standardizing testing practices, and improved access to therapies are needed to improve patient outcomes in mCRPC.

Olaparib with abiraterone for HRR mutation-positive mCRPC

Fred Saad (Centre Hospitalier de l’Université de Montréal/CRCHUM, Quebec, Canada) presented a post-hoc analysis of the phase 3 PROpel trial, which looked at the efficacy of adding olaparib to abiraterone in patients carrying germline or somatic BRCA1 or BRCA2 mutations.

First-line use of olaparib plus abiraterone resulted in 87% reduction in risk of disease progression or death and a 77% reduction in risk of death in patients with a germline mutation; in patients with a somatic mutation, this regimen resulted in an 81% reduction in risk of disease progression or death and 74% reduction in risk of death. These results highlight the importance of both tumor and circulating tumor DNA testing to inform treatment options.

Combination olaparib with abiraterone may be more effective than sequential monotherapy

Finally, a gene expression analysis from the phase 2 BRCAAway trial of abiraterone, olaparib, or abiraterone plus olaparib in mCRPC was presented by Zachary Reichert (University of Michigan, Ann Arbor, USA). In their research, Reichert and his team found that the AR pathway appears to be consistently altered in patients with mCRPC, regardless of HRR gene mutation status.

High androgen receptor gene expression was associated with poor response to either abiraterone or olaparib monotherapy in patients with BRCA2-related HRR mutations; this was not the case in the abiraterone plus olaparib treatment arm, suggesting that the combination of abiraterone plus olaparib may be more effective for patients with HRR mutations with AR-addicted tumors.

Reference

1. Aly, 2020. Survival in patients diagnosed with castration-resistant prostate cancer: a population-based observational study in Sweden. https://www.doi.org/10.1080/21681805.2020.1739139.