Research round-ups
Article summaries
Arun Azad (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia) provides insights from the PETRANHA trial, a phase 1/2 study of hormonal agents with saruparib in patients with metastatic prostate cancer. View transcript.
Chapters
0:05 PETRANHA trial rationale and unmet needs
00:36 Saruparib vs non-selective PARP inhibitors
01:09 Interim findings of the PETRANHA trial
02:47 Next steps for clinical research
03:59 Patient considerations and individualized care
“The bottom line is that, hopefully, our patients and their family members can really know about all of their options, so they can make the best decision for them.” Neal Shore stresses the importance of the multidisciplinary team in the oncology space, noting the benefits of collaborative care for both patients and healthcare professionals. View transcript.
Neal Shore discusses final overall survival in the EMBARK trial, testing enzalutamide compared against or combined with leuprolide, highlighting “one of the best” overall survival results for patients with metastatic castration-resistant prostate cancer in a phase 3 trial. View transcript.
By Litha Mfiki
The phase 3 CAPItello-281 trial results show that adding capivasertib to abiraterone and androgen deprivation therapy (ADT) improves radiographic progression-free survival (rPFS) in PTEN-deficient patients with metastatic hormone-sensitive prostate cancer (mHSPC).
Karim Fizazi (Université Paris-Saclay, Villejuif, France) presented the final data at the European Society for Medical Oncology (ESMO) Congress 2025 in Berlin, Germany. The study evaluated the efficacy and safety of capivasertib, a pan-AKT inhibitor, in combination with abiraterone acetate and prednisone plus ADT in patients with de novo mHSPC characterized by PTEN deficiency.
The trial met its primary endpoint, demonstrating a statistically significant improvement in rPFS for the 507 patients given capivasertib plus abiraterone versus the 505 given placebo plus abiraterone. Median rPFS was 33.2 months in the capivasertib arm compared with 25.7 months in the control arm.
These findings reinforce the association between PTEN loss and a more aggressive prostate cancer phenotype, said Fizazi.
Exploratory subgroup analyses revealed a gradient of increasing treatment benefit with higher PTEN deficiency thresholds. Hazard ratios for rPFS ranged from 0.84 in patients with ≥10% PTEN loss to 0.65 in those with complete PTEN loss.
Interim overall survival (OS) analysis at 26.4% maturity showed a numerical trend favoring the capivasertib arm, with formal OS testing planned at a later data cutoff. Additionally, the combination therapy was associated with a 5.2-month improvement in time to castration resistance, defined by radiographic progression or symptomatic skeletal events.
Safety findings were consistent with the known profiles of the study drugs. Grade ≥3 adverse events occurred in 67% of patients receiving capivasertib plus abiraterone, compared with 40% in the control arm. Diarrhea was the most frequently reported adverse event in the combination arm (52%). Treatment discontinuation due to adverse events was reported in 18.3% of patients in the capivasertib group versus 4.8% in the placebo group.
ESMO 2025 takeaways: Alicia Morgans
Alicia Morgans (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) shares key takeaways from the European Society for Medical Oncology (ESMO) Congress 2025, including promising data on radiopharmaceuticals, molecular biomarkers, and survivorship care in prostate cancer. View transcript.
Chapters
00:05 Key highlights in prostate cancer at ESMO 2025
02:15 Practice-changing data from ESMO 2025
03:31 Emerging trends in prostate cancer treatment
By Litha Mfiki
Radioligand therapy may enter the metastatic hormone-sensitive prostate cancer (mHSPC) treatment landscape, with promising results from the phase 3 PSMAddition trial presented at the European Society of Medical Oncology (ESMO) Congress 2025.
The researchers randomized 1,144 treatment-naive or minimally treated patients (≤45 days of prior therapy) with PSMA-positive mHSPC to receive either lutetium-177 prostate-specific membrane antigen (177Lu-PSMA)-617, at a dose of 7.4 GBq every 6 weeks for six cycles, plus androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI), or ADT plus ARPI alone.
Stratification was based on disease volume, age, and primary tumor treatment. Baseline characteristics were well balanced, with most patients presenting with bone metastases and high Gleason scores.
The primary endpoint was met at the second interim analysis (median follow-up, 23.6 months), reported Scott Tagawa (Weill Cornell Medicine, New York, USA).
At this point, the 177Lu-PSMA-617 arm showed a 28% improvement in radiographic progression-free survival (rPFS); 24.3% of patients in this arm had a primary endpoint event, compared with 30.1% of those given ADT plus ARPI. This benefit was consistent across key subgroups.
Objective response rate also favored the radioligand arm, and there was a positive trend in overall survival.
Invited discussant Arun Azad (Peter MacCallum Cancer Centre, Melbourne, Australia) acknowledged the trial’s significance but raised key considerations. “While rPFS benefit is clear, further data are needed to determine the impact on overall survival and long-term toxicity,” he said.
Azad noted that 87% of screened patients were eligible, suggesting a broad recruitment strategy. He emphasized the need for biomarker-driven selection, referencing PSMA mean standardized uptake value and dosimetry data to identify patients most likely to benefit.
Safety data showed increased rates of grade ≥3 cytopenias (14.4% vs 5.0%) and dry mouth (grade 1, 41.0% vs 3.4%) in the radioligand arm versus the ADT plus ARPI arm. Quality of life, assessed via FACT-P and EQ-5D, remained comparable between arms.
TALAPRO-2: PROs light path for PARP inhibitor decisions
Patient-reported outcomes (PROs) from TALAPRO-2 may offer some insight into the optimal use of poly (ADP-ribose) polymerase (PARP) inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC).
As previously reported, the addition of talazoparib to enzalutamide significantly improves radiographic progression-free survival (PFS), irrespective of whether or not participants had homologous recombination repair (HRR) gene alterations.
The latest analyses, reported in two papers in The Lancet Oncology, reveal a similar story for PROs. However, the author of an accompanying commentary, Matthew Cooperberg (University of California, San Francisco, USA), highlights distinctions between the findings in men with HRR mutations and in the all-comers cohort that he believes may help guide treatment selection.
Among 394 participants with HRR mutations, those given talazoparib and enzalutamide had a median time of 27.1 months before definitive deterioration of global health status/quality of life (GHS/QoL), measured with the EORTC Core QoL Questionnaire (QLQ-C30) and prostate cancer-specific urinary symptoms per EORTC QoL Questionnaire-Prostate (QLQ-PR25).
The corresponding time for those given placebo with enzalutamide was just 19.3 months, giving a significant HR of 0.69 (P=0.032), report Andre Fay (Hospital Nora Teixeira, Porto Alegre, Brazil) and team. Likewise, the median times to deterioration for urinary symptoms were non-estimable versus 30.2 months, giving an HR of 0.56 (P=0.022).
Cooperberg notes that talazoparib has a similar magnitude of effect on QoL as on PFS and overall survival, and points out that this should be expected given that “mortality from prostate cancer is nearly universally preceded by functional decline and worsening pain.”
In the 793 participants in the all-comers cohort, reported by Nobuaki Matsubara (National Cancer Center Hospital East, Chiba, Japan) and colleagues, the median time to definitive deterioration in GHS/QoL was also longer for those given talazoparib rather than placebo, at 38.0 months versus 25.0 months, with an HR of 0.78.
However, Cooperberg stresses that this “barely cleared statistical significance,” with a CI of 0.62–0.99 and P=0.038 without adjustment for multiple comparisons. In line with this, the difference in time to deterioration of urinary symptoms was not significantly different between the two groups.
The commentator also highlights that “differences in change from baseline between the treatment groups did not meet the threshold for clinical meaningfulness.”
He says: “Crucially, because outcomes for the HRR wild-type subgroup were not presented, the all-comers benefit appears likely to be driven almost entirely by patients with HRR alterations.”
Cooperberg stresses the “clear evidence” from TALAPRO-2 of the oncological and QoL benefits of PARP inhibition in patients with HRR alterations.
But he concludes: “For patients without such molecular indicators of anticipated benefit, treatment intensification can likely be personalised more productively with other alternatives.”
Preserving quality of life in mCRPC
Want expert tips on supporting wellbeing in people with mCRPC? Hear Stephen Freedland and Axel Merseburger on a whole-patient approach to care.
Barriers to equitable testing
Evidence for the benefits of HRR testing is stacking up, so why aren’t all patients tested in practice? Read about the barriers to optimal care.
TOPARP-B analysis ties reversion mutations to PARPi resistance in mCRPC
Serial circulating tumor DNA (ctDNA) analyses in patients with metastatic castration-resistant prostate cancer (mCRPC) from the TOPARP-B trial support a role for reversion mutations in acquired poly (ADP-ribose) polymerase inhibitor (PARPi) resistance.
Both the TOPARP-B trial and the PROfound trial showed that patients with BRCA2 homozygous deletion had the most durable responses to PARPi treatment. A possible mechanism underlying PARPi resistance may be reversion mutations in genes such as BRCA2 and PALB2, which could restore some homologous recombination repair functionality.
This latest research was conducted by George Seed (The Institute of Cancer Research, London, UK) and colleagues and reported in Cancer Cell. It focused on 19 patients from TOPARP-B who had a confirmed response to PARPi and at least three samples available for analysis, and whose tumors had mutations in BRCA2 or PALB2.
By the end of treatment, 79% of tumors had reversion mutations with the potential to restore function protein, comprising 114 frameshift reversions that restored the native reading frame and 34 stop-gain reversions that removed a stop codon, again restoring the functional reading frame.
There were a median of six reversion mutations per patient, and eight patients concluded treatment with multiple co-existing reversions.
Even an apparent complete homozygous deletion did not always remain that way. When the researchers looked in detail at patients with homozygous BRCA2 deletions, they found that one had rare subclonal wild-type tumor cells present prior to the start of treatment “providing a pool of DNA-repair competent cells selected for by subsequent treatment.”
Notably, the emergence of reversion mutations was linked to early tumor progression, with a significant correlation between the detection rate of reversion mutations and poorer radiographic progression-free survival (rPFS) and overall survival (OS).
Median rPFS was 5.59 months for patients with at least one reversion mutation versus 8.81 months for those with none. The corresponding OS durations were 13.9 versus 21.4 months.
However, some patients had disease progression despite few or no detectable reversions, leading the researchers to suggest that “either very small reverted subclones are vitally important in disease progression, or that alternative mechanisms of olaparib resistance other than reversions play an important clinical role.”
The researchers acknowledge several limitations of their study, including the small number of participants and samples and use of a targeted sequencing panel, which restricted the scope of the analysis.
Understanding resistance mechanisms is crucial for developing next-generation therapeutic strategies and improving patient outcomes.
This research underscores the complexity of PARPi resistance in mCRPC and the potential of ctDNA for real-time monitoring of patients. Continuous research and development of new therapeutic approaches are essential to overcome resistance and enhance patient care.
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