Congress highlights - ASCO 2023

Health-related quality of life in men with metastatic prostate cancer

By Dawn O’Shea

Quality of life (QoL) is an important outcome for patients with metastatic prostate cancer (PC). An estimated 70% of men with advanced disease develop bone metastases and associated pain. The rates of fatigue and urinary and sexual dysfunction are substantial¹.

In previous studies, men with metastatic PC generally rated their QoL and physical functioning poorly, compared with clinically important threshold values, indicating a need for clinical attention².

While some QoL issues arise as a result of the disease pathology, the life-extending treatments we have at our disposal are also associated with negative effects on QoL.

Although there is a large volume of evidence showing the oncological benefits of treatments, health-related quality of life (HRQoL) data have been scarce in comparison. Data from two phase 3 trials presented at this year’s ASCO meeting may go some way towards addressing this dearth of evidence on the effect of treatment on QoL.

Phase 3 trial data on prostate cancer therapies are now shedding light on the QoL effects on patients

The TALAPRO-2 trial compared talazoparib plus enzalutamide with enzalutamide alone as first-line treatment for metastatic castration resistant prostate cancer (mCRPC)³. Previously published results from the trial showed statistically significant improvement in radiographic progression free survival (rPFS) with the combination treatment (HR [hazard ratio] = 0.63).

At the 2023 ASCO Annual Conference, Professor Neeraj Agarwal (Cancer Research at the Huntsman Cancer Institute, University of Utah, USA) presented findings on the secondary endpoint of patient-reported outcomes (PROs). These were assessed at baseline and every 4 or 8 weeks until radiographic progression using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25.

The data showed that, although the treatment effect on global health status (GHS)/QoL significantly favoured enzalutamide alone, the predefined threshold of clinical meaningfulness was not met. There were no significant differences between the arms in any functioning scales.

A significantly longer time to definitive deterioration (TTD) was observed for talazoparib plus enzalutamide (HR = 0.78; median: 30.8 vs 25.0 months), and there was a numerically greater delay in TTD in urinary symptoms with combination treatment (HR = 0.76; P=0.105; median not reached vs 35.9 months).

Commenting on the results, Agarwal said: “The impact of treatment on patients’ QoL is important to consider alongside efficacy and safety results. Maintaining or improving QoL is a major goal of treatment for patients with mCRCP.”

“In this all-comer population, compared with placebo plus enzalutamide, treatment with tala plus enzalutamide significantly prolonged time to deterioration in GHS/QoL. This may reflect improved and sustained disease control.”

He added: “There were no clinically meaningful differences in deterioration in any of the functional scales between arms.”

In this brief video clip, Professor Agarwal summarises outcome data from the TALAPRO-2 study, which he states is “compelling, and will change clinical practice in the near future”. He also outlines practical implications from the phase 3 ALLIANCE trial, which investigated a novel first-line hormonal therapy for mCRPC.

Efficacy, safety and quality of life should all be considered in managing patients with prostate cancer

Professor Andrew Armstrong from the Duke Cancer Institute at Duke University in North Carolina presented similar results from the PROpel trial⁴.

PROpel met its primary endpoint and showed significantly prolonged investigator-assessed rPFS with abiraterone plus olaparib versus abiraterone alone as of the primary analysis cut-off date of July 2021. Armstrong presented data up to December 2022.

At baseline, most patients had a BSI-SF item 3 (worst pain, pain severity and pain interference) pain score <4 and were not taking opiates for cancer pain.

Mean change from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score was similar in both treatment arms, as was the number of FACT-P total deterioration events. Even in the BRCA mutation (BRCAm) positive group, the difference between the two treatment arms was only 3.64 on FACT-P.

Similarly, mean changes in Brief Pain Inventory - Short Form (BPI-SF) scores showed no overall difference between arms over the study period, and there was no difference in the time to pain progression.

In terms of symptomatic skeletal-related events, there was a trend favouring the combination, with an HR of 0.82. The risk reduction was much greater in BRCAm patients, at 0.31.

Approximately 13% to 17% of patients required the use of opiates, with no significant difference between the treatment groups. In BRCAm patients there was a trend favouring olaparib, with an HR of 0.39, although the finding is not clinically significant at this time.

However, time to cytotoxic chemotherapy was prolonged with olaparib plus abiraterone versus placebo plus abiraterone. In the BCRAm population, the median time to cytotoxic chemotherapy was not reached in the combination arm compared to 14.9 months in those receiving abiraterone plus placebo.

Commenting on the findings during a discussion session, Dr Ravi Madan from the National Cancer Institute in Bethesda, USA, pointed out that QoL has important implications, not just for the patient on a daily basis, but has also been shown to have an association with improved survival⁵.

He highlighted the findings from the CHAARTER trial of docetaxel plus androgen deprivation therapy (ADT) compared with ADT alone in metastatic hormone-sensitive prostate cancer⁶.

“They found something really interesting. Patients in the highest quartile for QoL had about a 70-month survival, regardless of ADT or intensification with chemotherapy. The worst quartile actually has a survival closer to 29 months,” he said.

Madan said these new data from PROpel and TALAPRO-2 will help clinicians achieve the ultimate goal, which is finding the balance between treatment and QoL for patients.

HRR mutations in mCRPC prognosis and treatment

By Dawn O’Shea

Watch Professor Agarwal describe testing innovations in the TALAPRO-2 clinical trial, focusing on the agreement level between tumour testing and circulating tumour (ctDNA) testing. He elaborates on study outcomes related to the testing data and clinical implications for testing in the mCRPC setting.

Be diligent about performing genetic testing on all prostate cancer patients. That was the message from two large phase 3 trials presented at the 2023 ASCO Annual Meeting.

The most up-to-date results from the CAPTURE⁷ and TALAPRO-2⁸ trials show that mutations in homologous recombination repair (HRR) genes are crucially important in predicting response to treatment.

Men with BRCA have a worse prognosis than those without, but a better response to combination therapy than men with other HRR mutations

Lead investigator Dr David Olmos, from Hospital Universitario 12 de Octubre in Madrid, presented data from the CAPTURE study, which investigated the prevalence of somatic/germline HRR mutations in men with metastatic castration-resistant prostate cancer (mCRPC) receiving first‑line treatment stratified by BRCA status.

Of 729 patients included, 13.2% had a BRCA1/2m, 17.4% had a non-BRCA HRR mutation and the remaining 69.4% did not have an HRR mutation. BRCA2 and ATM mutations were the most common. About 5.5% of the patients had alterations in more than one gene.

Over 60% of participants were treated with novel hormonal therapy or taxane, and 80.7% received at least second-line treatment. Median age at baseline was 72.2 years, 63.5% had a Gleason score >7, and 13.3% presented with visceral metastases.

The data revealed that BRCA-mutated (BRCAm) patients had a 70% higher risk of radiographic progression compared with non-BRCAm patients. Radiographic progression-free survival (rPFS) was 7.1 months in men with BRCAm compared with 10.3 months in those without.

BRCAm patients had significantly worse median overall survival (OS) than those without BRCAm, at 19.4 months and 27.9 months, respectively, equating to an 8-month difference. BRCAm patients had an almost twofold increased risk of death over time.

An exploratory analysis of the BRCA1/2m group found no significant differences in rPFS or OS between bi-allelic and mono-allelic alterations, germline and somatic mutations, or BRCA1 versus BRCA2m.

“These result support the importance of screening for germline and somatic BRCA alterations to deliver more precise care to our patients, especially in light of the evidence of poorer outcomes for BRCA patients,” Dr Olmos said.

“It is crucial to screen early for HRR mutations, particularly in BRCA1/2, to begin timely, targeted mCRPC treatment and improve prognosis,” he said.

Also presented at this year’s annual meeting were new findings from the phase 3 TALAPRO-2 trial of talazoparib plus enzalutamide as first-line therapy for unselected (cohort 1; previously reported) or selected (cohort 2) patients with mCRPC and HRR gene alterations.

Talazoparib and enzalutamide significantly increased rPFS, with a 55% reduction in the risk of progression or death. Median rPFS was 18.8 months for patients in the enzalutamide only arm compared with not reached in the talazoparib and enzalutamide arm.

In the data presented by Dr Karim Fizazi, University of Paris-Saclay, Villejuif, patients with BRCA alterations derived a large benefit from combination treatment with talazoparib plus enzalutamide, with an 80% reduction in the risk of progression or death. Patients with HRR non-BRCA alterations demonstrated a more modest benefit, with a hazard ratio (HR) of 0.68.

Presenting the results, Dr Fizazi said: “I am happy to show that patients with BRCA1 and of course those with BRCA2 derived an important benefit from the combination treatment, with HRs of 0.17 and 0.19, respectively.”

“I think this is important because I hear colleagues sometimes wondering whether they should or not treat all patients with a BRCA1m with a PARP inhibitor. [Based on this data] this appears to be yes.”

Adding talazoparib to enzalutamide improves survival in men with BRCAm mCRPC

As expected from previous studies, men with ATM or CHEK2 alterations did not receive benefit from the combination. When a cluster approach was used, only patients from the BRCA and CDK12 clusters showed statistically significant benefit.

“I believe that talazoparib in combination with enzalutamide, if approved, has the potential to become a standard of care first-line treatment option for patients with mCRPC and HRR alterations,” said Dr Fizazi.

Discussing the findings, Dr David James VanderWeele, from Northwestern University, said CAPTURE and TALAPRO-2 clearly show that molecular testing is important for all men with metastatic prostate cancer, but he said questions remain as to whether how these tests are managed and which genes should be tested⁹.

“Should we test for all HRR genes, which affect about 25–30% of patients, or should we just test patients for BRCA1/2 alterations, which affect 10–12%? Should we only test for germline mutations in BRCA1/2, which affect 5–6%, or should we skip testing altogether because we’re going to be giving everyone a PARP-inhibitor as part of some combination therapy?” he asked.

In addition, research is needed to determine if a PARP inhibitor and an androgen receptor inhibitor are best given sequentially or in combination.

BRCAAWAY is a small trial that is examining this uncertainty. Participants are randomised to abiraterone followed by olaparib (arm 1), olaparib followed by abiraterone (arm 2), or abiraterone and olaparib in combination (arm 3). Although the data are not yet mature, they show 12-month PFS rates of 40%, 49% and 95%, respectively, at this time¹⁰.

“The take-home message from these studies is that HRR mutations carry a worse prognosis. Alterations in BRCA1/2 – whether somatic or germline – carry an even worse prognosis,” said Dr WanderWeele. “The bottom line is do the molecular testing because the results of these tests are very important.”

He added: “Because of my research interests and institutional obligations, I have many reasons to do this consistently but in the last couple of months I’ve taken a closer look at my patients, and I have identified a couple of dozen who needed to undergo somatic and germline testing, so I encourage everyone to do the same.”

Biomarkers to guide treatment decisions in mCRPC

By Dawn O’Shea

With an ever-growing armament of therapies available to treat metastatic castration-resistant prostate cancer (mCRPC), the challenge now is to determine which therapies are most efficacious for individual patients. Identifying biomarkers of efficacy and resistance to different treatment modalities is essential to optimise outcomes.

To that end, several presentations at the 2023 ASCO Annual Meeting provided evidence of biomarkers for a number of treatment approaches, including radiotherapy, androgen deprivation therapy (ADT) and PARP inhibitors.

A team from the Erasmus MC Cancer Institute in the Netherlands found that an affordable and robust genome-wide aneuploidy (GWA) test – the modified Fast Aneuploidy Screening Test-Sequencing System (mFAST-SeqS) – can predict response to androgen receptor signalling inhibitors (ARSIs)¹¹.

Blood samples were collected from prospectively enrolled mCRPC patients at baseline (n = 134) and at an early time point (n = 20) during treatment with abiraterone or enzalutamide. GWA scores were categorised as high or low based on a cutoff of 5.

Treatment duration was significantly shorter in men with a high GWA score at baseline versus those with a low GWA score (median 221 and 82 days, respectively). A similar association was seen in patients with a high GWA score early in treatment (123 and 42 days).

The data suggest a GWA score, based on mFAST-SeqS of circulating free DNA, is a useful tool to predict response to ARSI in patients with mCRPC.

A readily available test for aneuploidy may predict response to androgen receptor signalling inhibitor treatment in mCRPC

The current dataset is being extended to include 199 baseline and 78 early treatment samples and will also include mCRPC patients treated with taxanes.

Meanwhile, the LuPARP trial is investigating the safety and efficacy of olaparib in combination with the targeted radioligand therapy ¹⁷⁷Lu-PSMA [prostate-specific membrane antigen]-617 in mCRPC patients who have progressed on an ARSI and docetaxel. New trial data presented at the conference by researchers from the Peter MacCallum Cancer Centre in Melbourne, Australia, suggest circulating tumour cell (CTC) profiling could be valuable in tracking response to ¹⁷⁷Lu-PSMA-617 therapy¹².

Twenty-six patients with high PSMA expression on PSMA positron emission tomography (PET) received 7.4 GBq of ¹⁷⁷Lu-PSMA-617 every 6 weeks with escalating doses of olaparib for up to six cycles. Blood was collected for CTC analysis at baseline, 12-weekly for 48 weeks, thereafter every 24 weeks, and finally at disease progression.

The data revealed high rates of total and PSMA-positive CTCs in PSMA-expressing mCRPC. At baseline, 23 of 26 patients (88%) had detectable CTCs. Of these, 17 (74%) had detectable PSMA+ CTCs, indicating heterogeneity of PSMA expression in CTCs.

The CTC positivity rates (% of cases ≥1 CTC) at week 12, 24, 36, 48 and at disease progression were 57%, 58%, 75%, 36% and 100%. PSMA+ CTC positivity rates were 38%, 36%, 22%, 50% and 56%, respectively.

Fifteen of 20 evaluable patients with paired baseline and week 12 CTCs had at least a 50% decline in total CTC count. Nine of these 15 patients achieved at least a 50% reduction in PSA levels (PSA50 response). Of these, five had 100% CTC clearance at week 12. Fourteen of 15 evaluable patients had at least a 50% PSMA+ CTC decline, with 13 achieving complete CTC clearance by week 12.

Genomic heterogeneity was evident in baseline and on-treatment CTCs, including recurrent loss of PTEN, TP53, BRCA2, ATM and RB1, and gain of AR and MYC.

The data suggest serial CTC profiling may assist in tracking response to ¹⁷⁷Lu-PSMA-617 therapy.

Circulating tumour cells and HRR mutations may offer means to track response to targeted radioligand therapy with ¹⁷⁷Lu-PSMA-617

Rebecca Hassoun and colleagues from the Indiana University Simon Comprehensive Cancer Center, found that prior taxane exposure and homologous recombination repair mutations (HRR) were also predictive of PSA response to ¹⁷⁷Lu-PSMA-617¹³.

In this study, men with mCRPC who progressed after an ARSI and taxane chemotherapy (or who refused chemotherapy) were treated with ¹⁷⁷Lu-PSMA-617. Patients with at least 6 weeks of follow-up (n = 45) were included in the analysis.

At baseline PSMA PET, 37 patients had PSMA with disease in bone, 28 with lymph node involvement, five with lung metastasis, four with liver metastasis and one with brain metastasis. Fourteen patients had one prior ARSI and 31 had more than two prior ARSI. Five patients had not received prior taxane chemotherapy, 18 had received one prior taxane regimen, 14 had received two and eight had received at least three taxane regimens. Ten had previously received a PARP inhibitor.

At a median follow-up of 2.8 months, 21 (46.7%) patients achieved a PSA30 response and 18 (40.0%) achieved a PSA50 response.

Men with homologous recombination repair (HRR) mutations were almost twice as likely to achieve a PSA30 and PSA50 response, albeit this was not statistically significant. Only three of 14 patients who received one prior ARPI achieved PSA responses. Of the five patients who did not receive prior taxane chemotherapy, three achieved PSA30 and PSA50.

The authors concluded that there is a trend of higher PSA30 and PSA50 response rates to ¹⁷⁷Lu-PSMA-617 in patients with higher PSMA expression, less prior taxane exposure, and in patients with HRR mutations.

These studies, and a number of others presented at the conference, offer promise for identifying biomarkers of efficacy and resistance to specific therapies, facilitating precision medicine and optimising the benefits for patients.

In this video, watch Professor Agarwal review some of the real-world evidence (RWE) on mCRPC presented at the June 2023 ASCO Annual Meeting. He highlights RWE on the clinical use of ¹⁷⁷Lu-PSMA-617, radium-223 and immunotherapy combinations for mCRPC.

References

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