Congress highlights
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
- 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.
As homologous recombination repair (HRR) testing becomes more commonly practiced among clinicians, when and how should it be integrated into prognostic and treatment strategies for metastatic castration-resistant prostate cancer (mCRPC)? Here, we summarize the latest research on the use of HRR testing in the assessment and treatment of mCRPC, as presented at the 40th Annual European Association of Urology (EAU) Congress.
Check back here soon to hear the thoughts of Pedro Barata (University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA) on the key messages to emerge from this year’s congress.
Elevating HRR testing in mCRPC through liquid biopsy and NGS
While next-generation sequencing (NGS) of tumor tissue is the current gold standard for identifying HRR mutations, it has its shortcomings. Combining liquid biopsy with NGS has been proposed as an effective strategy to overcome informational gaps; two posters presented at the congress demonstrated the potential benefits of this approach.
In the first, Xiaoxiao Guo (Beijing Friendship Hospital, China) reported that 47 patients with mCRPC received HRR testing via liquid biopsy after failure of either abiraterone acetate plus prednisolone or of enzalutamide, revealing that 89.66% had at least one somatic mutation.
These patients were more likely to receive multi-line therapy than 45 propensity-matched patients who did not undergo liquid biopsy. For example, approximately 50% versus 10% received a third-line treatment. Moreover, tested patients had a higher overall survival compared with untested patients, at a median of 31 months versus 20 months (P=0.004).
Presenting the second poster, Fabrizio Di Costanzo (Università di Napoli Federico II, Naples, Italy) advocated for the use of liquid biopsy in patients whose blood samples exhibit a circulating tumor DNA (ctDNA) fraction value greater than 10%, noting that it lacks “the downsides of tissue aging and wasting” that can occur with solid tumor biopsy.
In a cohort of 72 patients from the TARGET trial, ctDNA sequencing identified alterations including gene loss, exon rearrangement, frameshift mutations, and point mutations. Di Costanzo reported that these findings informed treatment approaches, including three patients being enrolled onto early-phase trials.
Breakthroughs in HRR testing and treatment for metastatic prostate cancer
A poster session on advanced therapeutic approaches in metastatic prostate cancer included two presentations involving HRR testing – one in mCRPC and one in metastatic hormone-sensitive prostate cancer (mHSPC).
In a presentation underlining the place of HRR testing in mCRPC, Diwei Zhao (Sun Yat-sen University Cancer Center, Guangzhou, China) and team demonstrated a positive response to pamiparib among 42 patients, including 11 with deleterious BRCA1/2 alterations and 40 with a homologous recombination deficiency (HRD) score greater than 9, who progressed after receiving at least one line of treatment with an androgen receptor signaling inhibitor.
Patients with BRCA1/2 alterations had better responses than the overall patient group, with higher radiologic progression-free survival (rPFS; 7 vs 4 months), objective response rate (ORR; 33.3 vs 17.6%), and prostate-specific antigen (PSA) response rate (27.3 vs 21.4%).
The researchers say their findings highlight the “promising activity” of pamiparib monotherapy in this patient group but stress that further investigations are needed to verify the results.
Extending the focus beyond mCRPC, the updated efficacy results from the PROact trial, presented by Junlong Zhuang (Nanjing Drum Tower Hospital, Nanjing University, China), introduced a potential novel treatment combination for HRR-mutated mHSPC.
This trial, conducted in patients with mHSPC who had at least one HRR gene mutation, showed “encouraging efficacy” of olaparib combined with abiraterone and prednisone. During a median follow-up of 14 months, all 30 patients achieved a PSA50 response, and all but one achieved PSA90. The ORR in 13 assessed patients was 84.6%, including one complete response and 10 partial responses.
The researchers noted that the primary endpoint of rPFS will be reported “in due course.”
Enhancing existing tools in metastatic prostate cancer
While developing new prognostic and treatment techniques for metastatic prostate cancer is essential, it is also important to optimize use of existing methods and information.
A key late-breaking presentation from an international research group highlighted that while randomized controlled trials (RCTs) provide the highest level of evidence, their strict exclusion criteria limit their applicability in real-world situations.
By comparing the characteristics of 177,347 patients with metastatic prostate cancer identified in the MarketScan database with the inclusion/exclusion criteria for RCTs in newly diagnosed patients, the team found that only 38% were eligible for all RCTs, while 8% were ineligible for any RCT.
“When we choose some kind of treatment for a specific patient, based on the results of these trials, we should remember that those patients were cherry-picked,” said the presenter.
The researchers called for future RCTs to adopt less restrictive criteria to include a more representative patient population.
In the same session, Lotte Zuur (Netherlands Cancer Institute, Amsterdam) emphasized the need for a more potent treatment regimen for treatment-naive N1 prostate cancer and presented results from the PROQURE-I study, which aimed to address this issue.
External beam radiotherapy (EBRT) combined with long-term androgen deprivation therapy (ADT) is the current standard of care for this patient group, but these early trial findings demonstrate the potential of adding 177Lu-PSMA-617 to EBRT plus ADT.
The researchers initially treated six patients with one cycle of 9 GBq and, following a protocol amendment, treated an additional six with two cycles of 7.4 GBq. None of these patients experienced a grade 3 or higher adverse event.
Furthermore, Zuur reported that the combined treatment approach increased the dose delivered to the primary tumor and affected lymph nodes. She said that they now intend to assess the approach in a phase 2 trial.
Pedro Barata (University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA) reflects on the latest research on homologous recombination repair (HRR) testing in the evaluation and treatment of metastatic castration-resistant prostate cancer (mCRPC) presented at the 40th Annual European Association of Urology (EAU) Congress (EAU25). View transcript.
Chapters
0.00 Pamiparib in mCRPC with HRR alterations
3:19 CAPTURE study: Prognostic value of non-BRCA HRR
5:50 Abiraterone plus SBRT: Impact of BRCA status
10.02 ctDNA as a management tool for mCRPC
13:20 PARP inhibitors in HRR+ mHSPC: PROact update
ASCO 2025 catch-up: HRR in treatment selection
How can homologous recombination repair (HRR) shape treatment strategies in metastatic prostate cancer (mPC)? Here, we summarize the latest research highlighting the transformative role of HRR testing in guiding precision therapies and improving patient outcomes, as presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.
We also report on a potential new standard of care for metastatic castration-sensitive prostate cancer (mCSPC) in the AMPLITUDE trial. Check back here soon to watch an interview with the lead investigator.
Predictive power of HRR in treatment selection
Personalized treatment approaches in metastatic castration-resistant prostate cancer (mCRPC) are gaining increasing attention among clinicians. One area of particular interest is HRR testing, which has emerged as a valuable predictive tool for guiding therapeutic decisions.
Stefanie Zschäbitz (National Center for Tumor Disease, Heidelberg, Germany) presented exploratory biomarker analyses of the TALAPRO-2 study, providing insights into which HRR alterations are most responsive to the “dual targeting of PARP and androgen receptor.”
As previously reported, the combination of talazoparib plus enzalutamide showed higher overall response rates (ORR) than enzalutamide plus placebo (69.4% vs 39.1%), as well as longer radiographic progression-free survival (rPFS; 30.7 vs 12.3 months), and improved overall survival (OS; 45.1 vs 30.8 months).
The latest data show that the greatest benefit occurred in patients with BRCA2-mutated tumors, with an ORR of 86.4% and both rPFS and OS not reached. Similar trends were observed in BRCA1, PALB2, CDK12, and ATM subgroups. CHEK2 showed modest benefit, while other HRR genes could not be assessed due to low prevalence.
On a similar theme, Steven Blinka (Fred Hutchinson Cancer Center, Seattle, Washington, USA) presented findings on the role of HRR alterations in predicting response to radium-223 in mCRPC with bone metastases.
Among 49 patients treated with radium-223, 53.1% experienced a decline in prostate-specific antigen (PSA) levels. Among the 10 patients who underwent DNA sequencing, four had HRR alterations, specifically mutations in BRCA2, CHEK2, MRE11A, and SPOP.
Based on these findings, the researchers have launched a prospective trial to determine whether HRR alternatives influence the efficacy of treatment with radium-223 in patients with bone metastasis.
This trial is ongoing and had enrolled 22 of a target 60 patients at the time of the presentation.
Addressing racial disparities in HRR-driven metastatic prostate cancer
Improving outcomes for patients with mPC, especially among underserved racial and ethnic groups, remains a critical need.
Qian Qin (University of Texas Southwestern, Dallas, USA) presented two studies that emphasized the importance of inclusive HRR testing by examining both real-world genetic prevalence and treatment efficacy.
In the first study, Qin and team used real-world data from the GuardantINFORM database to analyze patients with mPC according to their ethnicity.
Among those assessed with the laboratory-developed test gene panel (BRCA1/2, ATM, CDK12, CHEK2, FANCA, MLH1, PALB2, RAD51D), the prevalence of HRR alteration rates was significantly higher in non-Hispanic White patients (22.8%) compared with non-Hispanic Black patients (18.1%) and Hispanic patients (19.6%).
This trend was also observed among those assessed with the companion diagnostic panel (BRCA1/2, ATM, CDK12, MLH1), where HRR alteration rates were 16.7% in non-Hispanic White patients versus 15.0% in non-Hispanic Black patients and 15.3% in Hispanic patients. However, BRCA1/2 mutations were found at similar rates across all groups, and use of poly ADP ribose polymerase (PARP) inhibitors was similar for all ethnicities.
Qin also introduced HARMONY, a phase 2, open-label clinical trial evaluating the efficacy of combining niraparib, abiraterone acetate, and prednisone in Hispanic/Latino and non-Hispanic Black men with HRR gene-altered, metastatic hormone-sensitive prostate cancer. Qin noted that the trial “may reveal differences in clinical outcomes with greater precision,” potentially informing personalized treatment strategies by deepening our understanding of genomic alterations.
AMPLITUDE: A promising new standard for HRR-altered mCSPC
The use of PARP inhibitors has become the standard of care for HRR-altered mCRPC. The AMPLITUDE trial, presented by Gerhardt Attard (Cancer Institute, University College London, UK), is testing the extension of this approach to patients with HRR-altered mCSPC.
A total of 696 patients were randomized to receive either niraparib plus abiraterone acetate and prednisone (AAP) or AAP alone.
The primary endpoint, rPFS, was significantly improved in the niraparib plus AAP group, with the median not reached compared with 29.5 months in the control group (HR, 0.63). This benefit was even more pronounced in patients with BRCA1/2 mutations (HR, 0.52).
The effect was consistent across predefined subgroups, and there was also a significant improvement in the time to symptomatic progression and a nonsignificant improvement in survival with the combination treatment.
Grade 3/4 adverse events were more common with niraparib plus AAP than with AAP alone (75.2% vs 58.9%), including higher rates of anemia and hypertension, but the presenter noted that this amounted to only a small increase in the rate of people discontinuing treatment, of less than 5%.
Attard said that the results of AMPLITUDE support niraparib plus AAP “as a new treatment option for patients with mCSPC with HRR alterations.”
“The main finding definitely is that it is not only BRCA1 and BRCA2 patients who have a benefit, although the benefit is smaller in patients with non BRCA HRR alterations.” Stefanie Zschäbitz (National Center for Tumor Diseases, Heidelberg, Germany) discusses the TALAPRO-2 trial, focusing on the latest subgroup analyses presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. View transcript.
“Upfront testing will probably be logistically easier for healthcare providers, identify more patients, and be associated with greater efficacy and greater benefit for patients.” Gerhardt Attard (University College London Cancer Institute, UK) discusses the findings of the AMPLITUDE trial presented at the 2025 ASCO Annual Meeting. View transcript.
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