Congress highlights

mCRPC at ASCO 2024: Trials and treatments

Catch up on key data on metastatic castration-resistant prostate cancer (mCRPC) presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, from radioligands to artificial intelligence (AI).

CHAARTED-2: Adding cabazitaxel to abiraterone brings benefits in mCRPC

“[T]here were two cooperative-group studies that stood out to me at ASCO this year: CHAARTED-2 and A-DREAM.” Dr Alexander Chehrazi-Raffle (City of Hope Comprehensive Cancer Center, Duarte, California, USA). View transcript.

Christos Kyriakopoulos (University of Wisconsin Carbone Cancer Center, Madison, USA) presented EA8153 (CHAARTED2), a prospective randomised phase 2 open-label trial following on from the results of E3805 (CHAARTED).

In CHAARTED, adding docetaxel to androgen-deprivation therapy resulted in a significant survival benefit in patients with high-volume metastatic hormone-sensitive prostate cancer

Given that most patients will nevertheless progress to become castration resistant, the hypothesis of CHAARTED2 is that combining a second-generation androgen receptor (AR) inhibitor (abiraterone) with a second-line chemotherapy (cabazitaxel) could improve outcomes by eradicating resistant clones with chemotherapy, prolonging patient response to the AR inhibitor.

Eligible patients had mCRPC as defined by PCWG3 criteria despite androgen-deprivation therapy (ADT) and had undergone at least three cycles of treatment with docetaxel for metastatic castration-sensitive prostate cancer. Exclusion criteria included any prior treatment for CRPC (excluding radium-223 or sipuleucel), ECOG performance status of >2 and grade ≥2 peripheral neuropathy at baseline.

The 233 study participants were stratified by ECOG performance status (0 vs 1–2), time from initiation of ADT to development of CRPC (≤12 months vs >12 months) and the presence/absence of visceral metastasis.

All patients continued ADT as per standard of care and were randomised 1:1 across two arms:

• Cabazitaxel 25 mg/m² every 21 days up to six cycles, abiraterone acetate 1,000 mg daily, prednisone 5 mg twice daily
• Abiraterone acetate 1,000 mg daily, prednisone 5 mg twice daily

The primary endpoint of progression-free survival was significantly improved with cabazitaxel plus abiraterone versus abiraterone alone, at a median of 14.9 months versus 9.9 months (HR, 0.73; 80% CI, 0.59–0.90; P=0.049). There was no effect on overall survival, but the presenter noted that the study was underpowered for this endpoint.

Combination treatment did not produce any new safety concerns. The most common adverse events of grade 3 or higher were hypertension, at 10.1% with combination therapy versus 11.1% with abiraterone alone; neutropenia, at 10.1% versus 0%; and leukopenia, at 8.3% versus 0%.

Kyriakopoulos concluded by cautioning that changes in the treatment landscape with the introduction of doublet and triplet therapies for metastatic castration-sensitive prostate cancer limit the applicability of these results.

Dr Chehrazi-Raffle reveals the subgroup of patients who achieved better treatment outcomes in CYCLONE-2. View transcript.

PSMAfore: ¹⁷⁷Lu-PSMA-617 delays HRQoL decline in mCRPC

Hear why Dr Chehrazi-Raffle thinks the quality-of-life data from PSMAfore was “one of the most informative… on prostate cancer” at ASCO 2024. View transcript.

Karim Fizazi (Gustave Roussy Institute, Paris-Saclay University, Villejuif, France) presented health-related quality of life (HRQoL) and pain outcomes from PSMAfore, the second phase 3 trial of ¹¹⁷Lu-PSMA-617.

The trial’s clinical outcomes showed that, among the 468 participants with confirmed progressive mCRPC, those randomised to the ¹⁷⁷Lu-PSMA-617 arm had a significantly reduced risk of adverse event or death compared with those assigned to change to a different AR pathway inhibitor (ARPI, 49.1% vs 71.8%).

This prespecified HRQoL analysis, conducted at the trial’s second interim analysis, shows that the improved clinical outcomes are accompanied by improved HRQoL, in line with results from the VISION trial.

Crossover was allowed to the ¹⁷⁷Lu-PSMA-617 arm upon radiographic progression; this occurred in 80% of eligible participants.

The median time to worsening of cancer-specific HRQoL, measured with the Functional Assessment of Cancer Therapy–Prostate, was 7.46 months in the ¹⁷⁷Lu-PSMA-617 arm compared with 4.27 months in the ARPI change arm (HR, 0.59; 95% CI, 0.47–0.72).

There was also a significant delay to worsening of general HRQoL, measured with the EuroQoL 5-Dimension 5-Level instrument, at a median of 6.14 months versus 3.88 months (HR, 0.61; 95% CI, 0.50–0.76).

Consistent with this, there was a significant delay to worsening of pain intensity on the Brief Pain Inventory–Short Form, at a median of 5.03 months versus 3.71 months (HR, 0.69; 95% CI, 0.56–0.85), with similar results seen for pain interference and disease-related pain.

Of note, the HRQoL benefits of ¹⁷⁷Lu-PSMA-617 treatment persisted after exclusion of disease progression and death events from the analysis.

Fizazi concluded that the findings support ¹⁷⁷Lu-PSMA-617 as a treatment option for patients who have progressed on a second-generation ARPI.

“Practitioners should obtain somatic testing via tissue or liquid-based assays, as these tests can open the door to more personalised treatments.” Dr Chehrazi-Raffle. View transcript.

“This first human study reported at ASCO… is the first to investigate actinium-225, which is a highly active alpha-emitting radioligand.” Dr Chehrazi-Raffle. View transcript.

Artificial intelligence for managing prostate cancer?

PC global incidence is expected to rise from 1.4 million in 2020 to 2.9 million by 2040, and Liang Cheng (Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA) noted in his presentation that this calls for early diagnosis systems to integrate AI for evaluation of biopsy specimens. Increased diagnostic workload in the USA and Canada, reflecting 17.5% fewer working pathologists but 16.6% more physicians in the workforce between 2007 and 2017, lend urgency to these calls.

Rising workloads can prolong selecting systemic treatments for localised PC. In his presentation, Irbaz Bin Riaz (Mayo Clinic, Rochester, Minnesota, USA) highlighted several clinical barriers:

• “There is too much information to digest”
• Evidence is rapidly changing in guidelines
• ‘Real biomarkers’ have not been identified to aid prognostication
• Data from clinical trials does not apply to individual patients

Cheng highlighted several areas in which AI is showing clear promise in assisting with PC diagnosis and prognosis, as follows:

PC detection and diagnosis

Accumulating evidence shows that advances in AI technology can improve PC histology identification and grading to “almost perfect”, according to Cheng. AI shows diagnostic specificity and sensitivity across pathological subspecialties, including uropathology; however, its use is limited by patient selection and risk of data bias.

Gleason grading

Combining AI and pathologist review for assessing grade prostate biopsies can improve tumour detection, review time, and inter-pathologist agreement (from 69.7% to 75.3%). AI-based Cribriform Area Index can benefit PC risk stratification (HR, 1.65; 95% CI, 1.13–2.40; P=0.025).

PC molecular classification and outcome prediction

AI can be trained to detect specific molecular changes in PC pathology, such as PTEN loss and TMPRSS2:ERG fusion status. Combining radiomic and pathomic features in an AI tool can better predict post-surgical outcomes (rising prostate-specific antigen and extraprostatic-extension) than these features alone.

How AI can aid treatment selection for PC

“Precision medicine has arrived for mCRPC, which is a big win for patients, as there are more personalised therapies, and they can offer superior efficacy in many cases.” Dr Chehrazi-Raffle. View transcript.

Riaz recommends the use of an “ecosystem” of AI agents for gathering and summarising information on a patient with PC from multiple sources, including lab, radiology, pathology and guideline data, to derive and order a treatment plan, which the clinician can accept or reject in the patient’s electronic health record (EHR). He proposes:

Ideally, the wealth of patient information documented in EHR can be quickly integrated by AI (‘multi-modal integration’) to make individualised treatment selection, predict response, and assess 5-year survival probability.

Challenges facing AI in the oncology setting

• Lack of high-quality open-source datasets
• Difficulty in generalising AI results
• Difficulty in tracking rare cancer conditions and ethnic variability
• Clinical workflow integration
• Regulatory barriers and reimbursement

Hear why Dr Chehrazi-Raffle was impressed by long-term follow-up data from a phase 1/2 study of mevrometostat plus enzalutamide in CRPC. View transcript.

Dr Alexander Chehrazi-Raffle

Dr Chehrazi-Raffle is Assistant Professor, Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA. He specialises in genitourinary cancer and aims to provide a patient-centred experience where people play an active role in developing a treatment plan tailored to their needs.

Disclosures: Personal fees from ASCO Direct, Aveo, Exelixis, Medical Oncology Association of Southern California, OncLive/MJH Life Sciences, and Tempus Labs.

mCRPC in focus at ASCO GU 2024

BRCAAway: Abiraterone, olaparib or both in mCRPC with HRR mutations

Maha Hussain (Robert H Lurie Comprehensive Cancer Center, Chicago, Illinois, USA) presented on the BRCAAway trial, which evaluates the efficacy of an androgen receptor inhibitor (ARi) versus a poly adenosine diphosphate-ribose polymerase inhibitor (PARPi) versus the combination of the two in people with mCRPC and mutations in the BRCA1/2 or ATM genes.

Deleterious germline or somatic HRR mutations are evident in ~20% of people with mCRPC

Promising synergism between PARPi and ARi has been shown preclinically.

BRCAAway procedure and endpoints

Eligible patients (mCRPC with no prior exposure to PARPi, ARi, or chemotherapy) received tumour next generation sequencing and germline testing. Patients shown to have inactivating BRCA1/2 and/or ATM alterations were randomised and received abiraterone + prednisone, olaparib monotherapy, or olaparib + abiraterone/prednisone.

• Primary endpoints: Radiographic progression free survival (rPFS), clinical assessment or death
• Secondary endpoints: Measurable disease response rate, prostate-specific antigen (PSA) response rate and adverse events

BRCAAway efficacy and safety findings

Hussain observed that the trial participants given abiraterone/prednisone + olaparib showed a longer median rPFS (39 months) than those given abiraterone + prednisone (8.4 months) or olaparib monotherapy (14 months). The rates of grade 3 events were 21%, 14% and 19%, respectively.

Neal Shore (Carolina Urologic Research Center, Myrtle Beach, USA) analyses the BRCAAway trial.

CONTACT-02: Cabozantinib + atezolizumab vs second novel hormonal therapy for mCRPC

Neeraj Agarwal (Huntsman Cancer Institute, University of Utah, Salt Lake City, USA) presented the findings of the phase 3 CONTACT-02 study.

People with mCRPC who have progressed on NHT have a poor prognosis (median overall survival <2 years), especially those with visceral or extra-pelvic nodal metastasis

Following novel hormonal therapy (NHT) failure, a second NHT or chemotherapy are the only available non-targeted treatments for these patients; chemotherapy use is limited by frailty, toxicity or patient preference.

What is cabozantinib?

Cabozantinib is a multitargeted tyrosine kinase inhibitor that can improve rPFS and overall survival (OS) in refractory mCRPC and a subgroup of men with visceral metastases⁵.

The COSMIC-021 trial showed that cabozantinib + atezolizumab is efficacious and tolerable in post-NHT mCRPC.

CONTACT-02 evaluated cabozantinib + atezolizumab versus a second NHT in people with mCRPC and extra-pelvic soft tissue metastasis after progression on a first NHT. Eligible patients were randomised and received cabozantinib + atezolizumab, or a second NHT (abiraterone + prednisone, or enzalutamide).

Dual primary endpoints

rPFS and OS in all randomised patients.

CONTACT-02 summary findings

• Cabozantinib + atezolizumab significantly improved rPFS compared with a second NHT in mCRPC patients with extrapelvic nodal or visceral disease
• Median rPFS was significantly longer for patients receiving cabozantinib + atezolizumab than those receiving a second NHT (6.3 vs 4.2 months; HR 0.65, 95% CI, 0.50–0.84; P=0.0007), including those with liver metastasis (6.0 vs 2.1 months; HR 0.47, 95% CI, 0.30–0.74) or prior docetaxel treatment for metastatic castration-sensitive prostate cancer (8.8 vs 4.1 months; HR 0.55, 95% CI, 0.32–0.96)
• OS analysis is incomplete
• Rates of grade 3–4 treatment-related adverse events were 33% with cabozantinib + atezolizumab versus 8% with a second NHT

The ACE study: Cognitive function with abiraterone acetate + prednisolone vs enzalutamide

Amit Bahl (University Hospitals Bristol, UK) presented the ACE study, a multicentre prospective evaluation of cognitive function in patients with mCRPC treated with abiraterone acetate + prednisolone or enzalutamide. Abiraterone acetate + prednisolone, and enzalutamide, are approved for mCRPC.

There is a limited understanding of the impact of abiraterone acetate + prednisolone or enzalutamide on cognition, fatigue and depression. The ACE study aims to help close this gap.

Assessment of cognitive function in ACE

The cognition of eligible patients (≥18 years, mCRPC diagnosis, able to provide informed consent) was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessment tool prior to initiating study treatments. CANTAB assessment was repeated at 3, 4 and 6 months. Cognitive function and fatigue were measured with the Functional Assessment of Cancer Therapy tool and depression with the Patient Health Questionnaire 9.

ACE key findings

Bahl concluded that overall cognitive outcomes were comparable in patients receiving either treatment at 3 and 6 months, as were outcomes for the spatial working memory, rapid information processing and spatial information processing domains. However, participants taking enzalutamide had significantly poorer results than those taking abiraterone acetate + prednisolone for the reaction time task at both timepoints.

Patients taking enzalutamide also had more fatigue and depression than those taking abiraterone acetate + prednisolone at both assessment points.

“I think these are really important studies as they continue to help us in our conversations that we have with patients.” Neal Shore assesses the ACE trial.

Learn more about how unmet needs in mCRPC are being addressed

Combination therapies: Use in mCRPC and high-risk localised disease

Why combine PARPi and ARPi for prostate cancer?

Ravindran Kanesvaran (National Cancer Centre Singapore) explained the rationale for combining poly adenosine diphosphate-ribose polymerase inhibition (PARPi) and androgen receptor pathway inhibition (ARPi) in patients with homologous recombination repair (HRR) deficient or non-deficient tumours.

• ARPi upregulates PARP activity and downregulates HRR gene expression, inducing a phenotype similar to HRR deficiency
• PARPi disrupts single strand break repair, leading to double strand breaks
• PARPi supresses AR transcriptional activity and may attenuate resistance to ARPi

Preclinical data suggest that co-inhibition of AR and PARP can benefit tumours with or without mutations, noted Kanesvaran.

ARPi and PARPi metanalysis of mCRPC clinical trials

Supporting this, in a metanalysis of PROpel, TALAPRO-2 and MAGNITUDE, PARPi combined with ARPi increased overall survival and progression free survival (PFS)⁶ relative to placebo plus ARPi in mixed cohorts with metastatic castration resistant prostate cancer (mCRPC).

When stratified by HRR status, there was a significant PFS benefit with the combination versus placebo plus ARPi for all subgroups, but with the largest effect seen in participants whose tumours were HRR deficient or BRCA mutated, rather than HRR non-deficient⁶.

ARPi and PARPi enter clinical practice for mCRPC

Kanesvaran noted that the FDA and EMA have approved ARPi + PARPi for specific subpopulations. Olaparib + abiraterone (PROpel) and niraparib + abiraterone acetate + prednisone (MAGNITUDE) are approved for men with BRCA-mutated mCRPC, and talazoparib + enzalutamide (TALAPRO-2) has been approved by the FDA for those with HRR-mutated mCRPC (decision pending from EMA as of January 2024).

Darolutamide + androgen deprivation therapy for high-risk/very-high risk localised prostate cancer

Junlong Zhuang (Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, China) presented data from a phase 2 trial on darolutamide + androgen deprivation therapy (ADT) for localised, high/very-high risk prostate cancer.

Who were the eligible patients?

Eligible patients had high-risk/very high-risk localised prostate cancer, with an Eastern Cooperative Oncology Group performance status ≤1 and at least one of:

• Primary tumour stage ≥T3
• Serum prostate-specific antigen (PSA) ≥20 ng/mL
• Gleason score ≥8
• Regional lymph node involvement

Enrolled participants received 6 months of darolutamide + ADT prior to radical prostatectomy.

• Primary endpoint: pathological response rate; the proportion of patients with pathologic complete response (pCR) or minimal residual disease (MRD)
• Secondary endpoints included PSA progression-free survival, positive surgical margins rate, downstaging rate

What were the results?

Thirty patients received radical prostatectomy. The median age of patients was 71.0 years. Baseline median PSA level was 37.8 ng/mL. Most patients had very high risk, localised prostate cancer (93.3%).

Of the 30 men involved in the trial, 27 (90%) achieved undetectable PSA levels (<0.01 ng/mL). The pCR rate was 6.7% and the MRD rate was 33.3%, resulting in a pathological response rate of 40.0%.

Twenty patients (66.7%) achieved downstaging; four patients (13.3%) had positive surgical margins.

The researchers therefore concluded that darolutamide + ADT for 6 months prior to radical prostatectomy is effective for patients with localised, high/very-high risk prostate cancer.

Neal Shore (Carolina Urologic Research Center, Myrtle Beach, USA) provides an overview of real-world research data presented at ASCO GU.

References

1. Shore ND, Moul JW, Pienta KJ, Czernin J, King MT, Freedland SJ. Biochemical recurrence in patients with prostate cancer after primary definitive therapy: treatment based on risk stratification. Prost Cancer Prost Dis. 2023. doi.10.1038/s41391-023-00712-z.
2. Roach III M, Hanks G, Thames Jr H, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006;65(4):965–974.
3. Schaeffer EM, Srinivas S, Adra N, An Y, Barocas D, Bitting R, et al. Prostate Cancer, Version 4.2023, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21(10):1067–1096.
4. Shore ND, de Almeida Luz M, De Giorgi U, Gleave M, Gotto GT, Haas GP, et al. LBA02-09 EMBARK: A Phase 3 Randomized Study of Enzalutamide or Placebo Plus Leuprolide Acetate and Enzalutamide Monotherapy in High-risk Biochemically Recurrent Prostate Cancer. J Urol. 2023;209(Suppl 4):e1190.
5. Smith M, De Bono J, Sternberg C, Le Moulec S, Oudard S, De Giorgi U, et al. Phase III Study of Cabozantinib in Previously Treated Metastatic Castration-Resistant Prostate Cancer: COMET-1. J Clin Oncol. 2016;34(25):3005–3013.
6. Messina C, Giunta EF, Signori A, Rebuzzi SE, Banna GL, Maniam A, al. e. Combining PARP Inhibitors and Androgen Receptor Signalling Inhibitors in Metastatic Prostate Cancer: A Quantitative Synthesis and Meta-analysis. Eur Urol Oncol. 2023. Doi.10.1016/j.euo.2023.07.013.

PARP inhibitors: where do we go from here?

By Dawn O’Shea

With PARP inhibitors (PARPIs) now firmly established in the treatment of metastatic castration-resistant prostate cancer (mCRPC), questions remain to be answered as to how PARPIs should fit into the treatment paradigm and which patients should receive them.

New data from the Phase 3 TALAPRO-2 trial, presented at the 2023 ASCO Genitourinary Symposium, shows that talazoparib plus enzalutamide achieved the longest progression-free survival (PFS) seen to date in any randomised clinical trial of PARPIs as first-line treatment for mCRPC¹. The benefit was seen in patients with or without homologous recombination repair (HRR) gene mutations.

Talazoparib plus enzalutamide reduced the risk of progression or death by 34% compared to enzalutamide plus placebo in all participants with mCRPC, regardless of HRR mutations. More significantly, the risk was reduced by 57% in patients with HRR mutations. At 25 months, median imaging-based PFS was not yet reached in the talazoparib arm compared to 21.9 months in the control arm.

When analysed according to HRR mutation status, benefit was seen in both HRR mutated and unmutated (or unknown) patients, but the effect was greater in patients with known alteration in HRR-mediating genes.

There was a high rate of cytopenias in the talazoparib arm. The most common treatment emergent adverse events (TEAEs) resulting in dose reductions were anaemia (43.2%), neutropenia (15.1%), and thrombocytopenia (5.5%). The onset of grade 3-4 anaemia occurred at a median time of 3.3 months.

Despite this, patients receiving talazoparib reported statistically significant improvements in time to clinically-meaningful deterioration of quality of life.

PARPI talazoparib added to enzalutamide effectively increased PFS regardless of HRR status and delayed deterioration in global health status and quality of life

Presenting the findings, Neeraj Agarwal from the Huntsman Cancer Institute at the University of Utah, said the results from this primary analysis of the trial support the use of talazoparib plus enzalutamide as first-line treatment for mCRPC, regardless of HRR alteration status.

However, Elena Castro, from the Instituto de Investigación Biomédica de Málaga, questioned the conclusion. She said it might be too soon to recommend the treatment for patients without HRR mutated tumours.

“I think HRR status does matter,” she said. “We need to better understand the benefit of combining androgen receptor pathway inhibitors and PARPIs because the balance between the potential benefit and side effects depends on HRR status and may also depend on other factors.”

Watch Professor Karim Fizazi (University of Paris Saclay in Villejuif, France) analyse combination androgen receptor pathway inhibitor and PARPI data for mCRPC, presented at this year’s ASCO.

The latest results from the Phase 3 TRITON3 trial go some way towards addressing this issue.

In TRITON3, chemotherapy-naive patients with BRCA1/2 or ATM gene alterations who had received at least one second-generation androgen pathway inhibitor in any setting were randomised to receive rucaparib or physician’s choice of docetaxel or either enzalutamide or abiraterone acetate². The comparator arm was purposefully designed to allow docetaxel as opposed to a second androgen pathway inhibitor, making this the first study to compare a PARPI to docetaxel.

The trial had an ordered stepdown analysis in which the BRCA1/2 subgroup was analysed first for the primary endpoint of radiographic PFS (rPFS). If there was a significant response, analysis progressed to the intention to treat (ITT) population, combining BRCA and ATM subgroups.

As of August 2022, median rPFS in the BRCA1/2 population was 11.2 months (95% confidence interval [CI] 9.2–13.8) in those treated with rucaparib. This compared to a median of 6.4 months (95% CI 5.4–8.3) in the physician’s choice group collectively, 8.3 months (95% CI 6.1–9.9) in those receiving docetaxel and 4.5 months (95% CI 3.3–5.8) in those treated with abiraterone or enzalutamide.

In the ATM group, however, rPFS was 8.1 months in the rucaparib arm and 6.8 months in those receiving physician’s choice of therapy, showing no significant difference between rucaparib and the control treatment. This is consistent with the findings of previous randomised controlled trials.

The primary toxicity associated with rucaparib was anaemia, with 29% of rucaparib patients receiving at least one blood transfusion versus 2% in the control arm.

Another PARPI, rucaparib, improved rPFS in patients with mCRPC by 2.9 months or more when compared to either docetaxel or a choice between abiraterone or enzalutamide

Lead author, Alan H. Bryce from Mayo Clinic presented the interim overall survival (OS) data from the BRCA subgroup. The data are immature at present but show a positive trend in favour of rucaparib compared with the treating physician’s choice of treatment (24.3 vs 20.8 months). Interim OS was 18.9 months with docetaxel and 22.1 months with abiraterone or enzalutamide.

Elena Castro, from the Instituto de Investigación Biomédica de Málaga, Spain, said the results of TALAPRO-2 and TRITON3 go some way towards addressing the gaps left by the Phase 3 PROFOUND trial of a third PARPI, olaparib. However, she advised caution in interpreting the results.

“We need to keep in mind that benefit in rPFS does not always translate to a benefit in OS. We know that from other trials in mCRPC but we also know it from trials conducted on PARPI use in ovarian cancer,” she said.

Given that patients with HRR mutations have a median survival half that of patients with non-mutated tumours, there is a significant unmet need for new therapeutic approaches for these patients. The evidence presented at ASCO GU 2023 suggests that both monotherapy and combining a PARPI and a second-generation androgen pathway inhibitor may deliver long sought-after improvements for this population.

Watch the video below for Professor Karim Fizazi’s (University of Paris Saclay in Villejuif, France) summary of combination treatment data for mCRPC, presented at ASCO 2023.

Recommendations on sequencing mCRPC therapies

By Dawn O’Shea

As the therapeutic armamentarium for metastatic castration-resistant prostate cancer (mCRPC) continues to grow, the burning question is, what is the optimal sequence for first-, second- and third-line settings to deliver the maximum benefit to patients?

That was the dilemma addressed by Dr Silke Gillessen, from the Oncology Institute of Southern Switzerland, at this year’s ASCO Genitourinary Symposium³.

“The most important factor in the choice of first-line treatment for mCRPC is what treatment the patient received in the hormone sensitive setting,” she said.

For patients who received androgen-deprivation therapy (ADT) alone or ADT with docetaxel, abiraterone and enzalutamide are the preferred first-line options.

“The important questions at the moment relate to whether PARP inhibitors (PARPIs) be added to this [option] and should they be used only in selected patients or in all comers,” Dr Gillessen said.

She highlighted new clinical trial data presented at the symposium, including the latest results from the PROpel (abiraterone plus olaparib vs abiraterone alone), TALAPRO-2 (enzalutamide plus talazoparib vs enzalutamide plus placebo), TRITON3 (rucaparib versus physician's choice of therapy in patients with homologous recombination repair [HRR] gene deficiency), and MAGNITUDE (niraparib with abiraterone and prednisone vs abiraterone acetate and prednisone) Phase 3 trials. All of these trials found that the addition of a PARPI improved radiographic progression-free survival (rPFS), with a particularly significant benefit in patients with HRR mutations. 

For patients who received ADT alone in the hormone sensitive stage, Dr Gillessen recommended the combination of a PARPI and androgen receptor pathway inhibitor (ARPI) as first-line treatment for patients with HRR mutation-positive mCRPC. However, she said she is much more sceptical of this approach for patients without mutations. Regarding second-line treatment she recommended docetaxel for chemotherapy-naïve patients or radium-223 for selected patients, with and without mutations. Cabazitaxel, ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA) and radium-223 are recommended for both groups in the third-line setting.

Her recommendations are similar for patients who received ADT and docetaxel in the hormone sensitive stage, except for the omission of docetaxel.

Selection of appropriate treatments following ADT, initial chemotherapy or androgen receptor pathway inhibitor is increasingly important and should take into account HRR mutation status

“A more frequent situation, at least in my practice, is patients who received ADT and an ARPI for metastatic hormone-sensitive prostate cancer (mHSPC). In this situation, the main question is, in the majority of patients with a BRCA mutation, would you recommend docetaxel or a PARPI in the first-line treatment of mCRPC?” she asked.

“We asked that exact question to more than 100 experts at the Advanced Prostate Cancer Consensus Conference (APCCC) in April 2022. More than 75% recommended a PARPI. Only 13% recommended docetaxel.”

For non-mutated patients, Dr Gillessen recommended the same approach. She remarked, however, that the sequence of docetaxel may soon change as new data suggest ¹⁷⁷Lu-PSMA after an ARPI, but before chemotherapy, improves rPFS.

She recommended olaparib or rucaparib as first-line treatment for mutation-positive patients, but in mutation-negative patients, she recommended cabazitaxel, ¹⁷⁷Lu-PSMA and radium-22 for selected patients.

“We need to address patient selection for PARPIs in the mCRPC setting,” she said. “We need to know who are the mutation-negative patients that profit from PARPIs.”

She concluded her talk by reminding colleagues that bone modifying agents (BMAs) are important and should not be forgotten in the management of mCRPC.

Professor Karim Fizazi (University of Paris Saclay in Villejuif, France) considers key clinical issues related to improved rPFS in non-BRCA mCRPC.

A presentation by Dr Aaron Mitchell from Memorial Sloan Kettering Cancer Center, New York, showed that this area of mCRPC treatment requires increased awareness⁴.

Physician awareness of secondary prostate cancer management issues, particularly related to bone modifying agents, shows room for improvement in light of recent physician surveys

Dr Mitchell and his team interviewed 15 physicians who treated prostate cancer at an academic cancer centre and an affiliated network of community-based practices. They found incomplete awareness of guideline recommendations for the screening and treatment of low bone mineral density.

Current guidelines recommend the use of BMAs to reduce the incidence of skeletal-related events in patients with mCRPC and bone metastases, but not for those with metastatic hormone-sensitive prostate cancer (mHSPC).

Prior studies have demonstrated the underuse of BMAs for patients with mCRPC and overuse for those with mHSPC.

In this study, participants were asked about their experiences and perceptions around the current recommendations, guideline adherence, and barriers to such adherence. They were also asked about their views on potential interventions to improve guideline-adherent BMA use, and the three interventions that would be most helpful in reducing BMA underuse and overuse.

All respondents indicated that they were aware of the recommendation for use of BMAs in mCRPC patients with bone metastases. However, 14% were unaware of the recommendation against BMA use in patients with mHSPC. Almost 30% believed BMAs could be appropriate for mHSPC patients, depending on the burden of metastatic disease. Over a third were unaware of the recommendations for baseline DEXA scan.

The most commonly identified barriers to BMA use for mCRPC patients were obtaining dental clearance and having insufficient clinic time.

The findings show that among the myriad of new therapeutic options available, physicians who treat patients with prostate cancer must be continually mindful of the importance of BMAs in the treatment paradigm.

Increasing physician awareness of treatment options and other aspects of patient management should be a priority

New therapeutic targets and concepts for mCRPC

By Dawn O’Shea

Intratumour myeloid cells, T cell exhaustion and metabolic dependencies are just some of a myriad of the new therapeutic targets that are being explored for the treatment of prostate cancer, presentations at the 2023 ASCO Genitourinary Symposium showed. The data suggest a wave of new therapies may be on the horizon.

With such an array of novel therapies under investigation, Johann Sebastian de Bono from University College London Cancer Institute, gave an overview of new targets and new concepts for the treatment of prostate cancer⁵.

“Selective tumour cell death remains the ‘Holy Grail’ and this is a rapidly burgeoning research space,” he said.

Targets that are currently being explored include androgen receptor (AR) gene splicing, apoptosis inhibition, novel synthetic lethal strategies, metabolic dependencies, epigenetic remodelling, and novel immunotherapy strategies.

Dr de Bono and his team have been looking at B7-H3 (CD276), which is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule for therapeutic targeting alone or in combination with programmed cell death-1 (PD-1)-targeted therapies⁶.

“There is very impressive antitumor activity with a B7-H3 immunoconjugate with a cytotoxic payload, for this disease. There's now early clinical evidence with a B7-H3 targeting conjugate. There [are] at least two of these in Phase 1/2 trials, with very early data at multiple dose levels,” he told the meeting. “I think this is going to be an important target.”

In this video, Professor Karim Fizazi (University of Paris Saclay in Villejuif, France) reviews some of the emerging molecular targets and concepts for mCRPC management presented at ASCO 2023.

The androgen receptor also remains a key target, Dr de Bono said. During the symposium, Michael Philip Sun and colleagues published Phase 1 results of a Phase 1/2 study of pembrolizumab and an AR pathway inhibitor (ARPI) in combination with ²²⁵Ac-J591, a potent alpha-prostate-specific membrane antigen-targeted radionuclide therapy which leads to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, thereby increasing the level and duration of response to pembrolizumab plus an ARPI⁷.

Twelve patients with progressive metastatic castration-resistant prostate cancer (mCRPC) received an ARPI of physician’s choice, pembrolizumab, and a single infusion of ²²⁵Ac-J591 at two different doses. Four patients remained progression free and on study after six months of follow-up. However, seven patients developed an unexpected cytokine release syndrome 7–14 days following treatment. After pausing the ARPI, this reaction improved within one week.

Trials are also exploring chimeric antigen receptor (CAR)-T cell immunotherapies. In an abstract, a team led by Mark N. Stein from the Herbert Irving Comprehensive Cancer Center in New York, presented the findings of a Phase 1, multicentre trial of prostate stem cell antigen (PSCA)-specific GoCAR T cells (BPX-601) in patients with mCRPC⁸.

Of seven evaluable patients, PSA50 response was observed in three patients at Day 28. Preliminary results demonstrated partial response in one patient, stable disease in three, and progressive disease in one. One patient continued on study with stable disease after more than nine months, with persistent evidence of rimiducid responsiveness.

All patients developed cytokine release syndrome. Immune-effector cell associated neurotoxicity syndrome occurred and resolved in two patients and one patient experienced dose-limiting neutropenic sepsis with possible haemophagocytic lymphohistiocytosis.

As with many other malignancies, the gut microbiome is emerging as an area of interest. Nobuaki Matsubara and colleagues conducted a comprehensive analysis of the relationship between the gut microbiome and treatment outcome of androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive (mCSPC) and mCRPC. They found that faecal samples from mCRPC patients had more Klebsiella and Enterobacteriaceae than those with mCSPC, whereas mCSPC had more Akkermansia and Bifidobacterium. The researchers say these differences and diversity might influence the outcomes of ADT-based treatment in prostate cancer⁹.

Professor Karim Fizazi (University of Paris Saclay in Villejuif, France) is optimistic about the future management of mCRPC. Watch the video below to learn why.

“This is a time of unprecedented opportunity and promise for improving the care of our patients suffering from advanced prostate cancer. It's also a time of unprecedented responsibility for us to really be careful as to how we develop these trials and to make sure that we're doing our utmost to move things forward as quickly as possible,” Dr de Bono said.

“The background biology of prostate cancer is now increasingly clear, although there is still a lot to understand. Interpatient heterogeneity is now incontrovertible. Prostate cancer is not one disease, and I think we have to be very thoughtful about whether our future Phase 3 trials should still treat advanced prostate cancer as one disease.”

“There are many promising precision medicine strategies that could make it [into practice] in the future. I think things are looking good for our patients suffering from prostate cancer, but holistic consideration of the patient and their disease, and the stroma, microbiota, etc., really need to be considered to change patient care,” Dr de Bono concluded.

References

1. Agarwal N, Azad A, Carles J, Fay AP, Matsubara N, Heinrich D, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Presented at the ASCO Genitourinary Symposium 2023, 16-18 February. San Francisco. LBA17.
2. Bryce AH, Piulats JM, Reaume MN, Ostler PJ, McDermott RS, Gingerich JR, et al. Rucaparib for metastatic castration-resistant prostate cancer (mCRPC): TRITON3 interim overall survival and efficacy of rucaparib vs docetaxel or second-generation androgen pathway inhibitor therapy. Presented at the ASCO Genitourinary Symposium 2023, 16-18 February. San Francisco. 18.
3. Gillessen S. How to Best Use Current Drugs: Treatment Sequencing and Combinations for Metastatic Castration-Resistant Prostate Cancer. Presented at the ASCO Genitourinary Symposium 2023, 16-18 February. San Francisco.
4. Mitchell AP, Persaud S, Chimonas S, Salner AL, Palyca P, Farooki A, et al. Barriers to guideline-concordant use of bone modifying agents for prostate cancer. Journal of Clinical Oncology. 2023;41(6_suppl):68-68.
5. De Bono JS. New targets, new concepts for metastatic castration-resistant prostate cancer. Presented at the ASCO Genitourinary Symposium 2023, 16-18 February. San Francisco.
6. Guo C, Figueiredo I, Gurel B, Neeb A, Seed G, Crespo M, et al. B7-H3 as a Therapeutic Target in Advanced Prostate Cancer. Eur Urol. 2023;83(3):224-238.
7. Sun MP, Nauseef JT, Palmer J, Thomas JE, Stangl-Kremser J, Bissassar M, et al. Phase I results of a phase I/II study of pembrolizumab and AR signaling inhibitor (ARSI) with 225Ac-J591. Journal of Clinical Oncology. 2023;41(6_suppl):181-181.
8. Stein MN, Teply BA, Gergis U, Strickland D, Senesac J, Bayle H, et al. Early results from a phase 1, multicenter trial of PSCA-specific GoCAR T cells (BPX-601) in patients with metastatic castration-resistant prostate cancer (mCRPC). Journal of Clinical Oncology. 2023;41(6_suppl):140-140.
9. Matsubara N, Sakai S, Yamashita R, Misumi T, Shiota M, Eto M, et al. The comprehensive analysis of relationship between gut microbiome and treatment outcome of androgen deprivation therapy (ADT)-based treatment in patients with metastatic castration-sensitive and -resistant prostate cancer. Journal of Clinical Oncology. 2023;41(6_suppl):213-213.

ASCO 2023 – Developments in metastatic castration-resistant prostate cancer

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

1. Holm M, Doveson S, Lindqvist O, Wennman-Larsen A, Fransson P. Quality of life in men with metastatic prostate cancer in their final years before death - a retrospective analysis of prospective data. BMC Palliat Care. 2018;17(1):126.
2. Giesinger JM, Loth FLC, Aaronson NK, Arraras JI, Caocci G, Efficace F, et al. Thresholds for clinical importance were established to improve interpretation of the EORTC QLQ-C30 in clinical practice and research. Journal of Clinical Epidemiology. 2020;118:1-8.
3. Agarwal N, Azad A, Matsubara N, Saad F, Giorgi UD, Joung JY, et al. Patient-reported outcomes (PROs) among men receiving talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA as first-line (1L) treatment for metastatic castration-resistant prostate cancer (mCRPC): Results from a phase 3 study (TALAPRO-2). Journal of Clinical Oncology. 2023;41(16_suppl):5013-5013.
4. Thiery-Vuillemin A, Saad F, Oya M, Vianna K, Özgüroğlu M, Gedye C, et al. Health-related quality of life (HRQoL) and pain outcomes for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who received abiraterone (abi) and olaparib (ola) versus (vs) abi and placebo (pbo) in the phase III PROpel trial. Journal of Clinical Oncology. 2023;41(16_suppl):5012-5012.
5. Madan R. Quality in the Context of Quantity: Evaluating Treatment Intensification. Presented at the ASCO 2023, 2-6 June. Chicago.
6. Lledo DS, Chu X, Jarrard DF, Carducci MA, DiPaola RS, Wagner LI, et al. Patient reported quality of life (QOL) and survival outcomes: Analysis of ECOG-ACRIN E3805 chemohormonal androgen ablation randomized trial (CHAARTED) in prostate cancer (PCa). Journal of Clinical Oncology. 2023;41(16_suppl):5014-5014.
7. Lorente D, Alameda D, Cattrini C, Romero-Laorden N, Lozano R, Lopez-Casas PP, et al. Presence of somatic/germline homologous recombination repair (HRR) mutations and outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) receiving first-line (1L) treatment stratified by BRCA status. Journal of Clinical Oncology. 2023;41(16_suppl):5003-5003.
8. Azad A, Matsubara N, Carles J, Fay AP, Giorgi UD, Joung JY, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. Journal of Clinical Oncology. 2023;41(16_suppl):5004-5004.
9. VanderWeele DJ. DDR and PARP inhibitors: What’s the damage? Presented at the American Society of Clinical Oncology 2023, 2-6 June. Chicago, Illinois. Genitourinary Cancer - Prostate, Testicular, and Penile.
10. Hussain MHA, Kocherginsky M, Agarwal N, Zhang J, Adra N, Paller CJ, et al. BRCAAWAY: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects. Journal of Clinical Oncology. 2022;40(16_suppl):5018-5018.
11. Jong Ad, Weerd Vd, Beaufort C, Hamberg P, Lolkema MP, Wilting SM, et al. mFAST-SeqS based aneuploidy score in circulating cell-free DNA and role as early response marker in patients with metastatic prostate cancer treated with androgen receptor signaling inhibitor. Journal of Clinical Oncology. 2023;41(16_suppl):5058-5058.
12. Gupta S, Keerthikumar S, Pasam A, Crumbaker M, Joshua AM, Lam E, et al. Circulating tumor cells (CTCs) in patients with metastatic castration resistant prostate cancer (mCRPC) treated with olaparib plus 177lutetium-prostate specific membrane antigen-617 (177Lu-PSMA-617) in the LuPARP trial. Journal of Clinical Oncology. 2023;41(16_suppl):5064-5064.

13. Tann M, Sims J, Auxier A, Althouse SK, King J, Adra N. Real-world data for predictors of PSA response to Lu177-PSMA-617 in metastatic castration resistant prostate cancer. Journal of Clinical Oncology. 2023;41(16_suppl):e17044-e17044.

ESMO Congress 2023: Highlights on metastatic castration-resistant prostate cancer

Emerging immunotherapy for mCRPC

By Simon van Rysewyk

What is STEAP1?

The tumour-associated antigen six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is expressed in many prostate tumours, and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). A STEAP1-targeted monoclonal antibody (mAb) 2+1 T-cell engager (TCE) molecule, AMG 509 (xaluritamig), has been developed to redirect T cells to eliminate prostate cancer cells that express STEAP1¹.

At the European Society for Medical Oncology (ESMO) Congress 2023, William K Kelly (Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA) presented the first clinical report of xaluritamig, and described the monotherapy dose exploration from the first-in-human open-label, multicentre phase 1 study in patients with mCRPC from North America, Europe, Asia and Australia².

Study methods

Eligible men aged ≥18 years had mCRPC resistant to prior hormonal therapy and 1–2 taxane regimens, satisfactory organ function and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–1. Xaluritamig was given intravenously (IV) weekly or every other week at various dose levels (DL). The primary endpoint was to assess efficacy and safety².

Was xaluritamig efficacious?

• At higher DLs (DL8–15), prostate-specific antigen (PSA) responses were more frequent than in lower DLs (DL1–7)²
• PSA50 (≥50% PSA decline) responses occurred in 42patients (47.2%); PSA90, in 24 patients (27.0%)²
• Response Evaluation Criteria in Solid Tumours (RECIST) responses included 15 (22.7%) confirmed partial response (PR) and 30 (45.5%) stable disease (SD)²
• At higher DLs, 14patients (38.9%) had confirmed PR and 12 (33.3%) SD²

What were the safety results?

Treatment-emergent adverse events were reported for all patients. The most common adverse events (AEs) were cytokine release syndrome (CRS; 72.2%), fatigue (52.6%), anaemia (45.4%), pyrexia (40.2%) and myalgia (39.2%). CRS occurred mainly in cycle 1 and improved with premedication and step dosing².

Conclusion

In this first-in-human dose exploration, xaluritamig showed encouraging efficacy (PSA, RECIST), low-grade CRS, and mostly grade 1 or 2 AEs that were clinically manageable.

This study offers proof of concept for STEAP1 as a target for TCEs and support for further investigation of xaluritamig as a potential treatment for mCRPC

Combination treatment synergies for mCRPC: New clinical trial data

By Simon van Rysewyk

Pembrolizumab plus enzalutamide for mCRPC

Current treatments for mCRPC are not curative, and median survival following progression to mCRPC is approximately 3 years. Accumulating evidence indicates synergism with enzalutamide and the PD-1 inhibitor pembrolizumab for mCRPC^3,4.

Julie N Graff (Portland VA Research Foundation, Oregon, USA) presented outcome data from the phase 3 randomised KEYNOTE-641 clinical trial, which investigated the efficacy and safety of pembrolizumab plus enzalutamide for men with mCRPC who had not received chemotherapy, were abiraterone-naive, or intolerant to, or had progressed on, abiraterone acetate.

What were the study procedures and endpoints?

Eligible patients aged ≥18 years with confirmed mCRPC and no prior chemotherapy except docetaxel were randomised 1:1 to pembrolizumab 200 mg or intravenous placebo every 3 weeks for ≤35 cycles plus enzalutamide 160 mg orally daily.

Primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).

Did the trial support the study hypotheses?

The trial endpoints were not met:

• OS (median, 24.7months [pembrolizumab + enzalutamide] vs 27.3 months [placebo + enzalutamide]; HR, 1.04; 95% CI, 0.88−1.22; P=0.66)
• rPFS (median, 10.4months [pembrolizumab + enzalutamide] vs 9.0 months [placebo + enzalutamide]; HR, 0.98; 95% CI, 0.84−1.14; P=0.41)

The boundary for futility for OS was crossed and the trial was discontinued.

Any-grade and grade ≥3 treatment-related adverse events were reported in 77.9% and 31.2%, respectively, of 615 patients with ≥1 dose pembrolizumab and enzalutamide, and in 61.6% and 10.8% of 620 patients with ≥1 dose placebo and enzalutamide.

Conclusion

In KEYNOTE-641, pembrolizumab and enzalutamide did not benefit efficacy outcomes in men with mCRPC who had not received chemotherapy or abiraterone. The combination was associated with more treatment-related adverse events than placebo. Graff concluded:

A randomised, phase 2 trial of enzalutamide plus
¹⁷⁷Lutetium-PSMA-617 for mCRPC (ENZA-p)

Enzalutamide and lutetium-177-prostate-specific membrane antigen-617 (¹⁷⁷Lu-PSMA-617) improve OS in mCRPC^5,6. ENZA-p is an open-label, randomised phase 2 clinical trial that evaluates combining enzalutamide with adaptive dosing of ¹⁷⁷Lu-PSMA-617 versus enzalutamide alone as first-line treatment for mCRPC. Louise Emmett (University of New South Wales, Sydney, Australia), primary investigator of ENZA-p, presented the results at ESMO 2023.

Endpoints of ENZA-p and trial procedure

• Primary: Prostate-specific antigen progression-free survival (PSA–PFS)
• Secondary: rPFS; PSA50% (≥50% PSA decline) and PSA90% response rates (PSA50RR, PSA90RR); adverse events (AEs); OS

Patients were randomised 1:1 to enzalutamide 160 mg daily or enzalutamide 160 mg daily plus adaptive dosing with 7.5 GBq ¹⁷⁷Lu-PSMA-617 on days 15 and 57; two additional doses of ¹⁷⁷Lu-PSMA-617 were given if persistent PSMA-positive disease was evident on interim ⁶⁸Ga-PSMA positron emission tomography (PET; day 92).

Primary endpoint results

• PSA–PFS was longer with enzalutamide + ¹⁷⁷Lu-PSMA-617 versus enzalutamide alone (median 13 months vs 7.8 months; HR, 0.43; 95% CI, 0.29−63; P<0.001)
• PSA50RR and PSA90RR were higher with enzalutamide + ¹⁷⁷Lu-PSMA-617 versus enzalutamide alone: 93% (77/83) versus 68% (54/79) (P<0.001) and 78% (65/83) versus 37% (29/79)
  (P<0.001)

Conclusion

Adaptive dosing with ¹⁷⁷Lu-PSMA-617 in addition to enzalutamide can benefit efficacy outcomes in the mCRPC setting. This trial therefore supports this combination as a potential first-line treatment for mCRPC. Emmett made this closing prediction:

MAGNITUDE update: Niraparib with abiraterone acetate plus prednisone for mCRPC

In the phase 3 MAGNITUDE trial, niraparib and abiraterone acetate plus prednisone (NIRA + AAP) significantly improved rPFS in people with BRCA+ mCRPC⁷.

Primary investigator Kim Nguyen N Chi (Vancouver Prostate Cancer, Canada) presented the final analysis of MAGNITUDE.

What the final analysis incudes

• Secondary endpoints of OS and time to cytotoxic chemotherapy (TCC)
• Time to symptomatic progression (TSP) and patient-reported outcomes

Final analysis results

In the final analysis, 113 patients received NIRA + AAP. The results showed:

• OS benefit favouring NIRA + AAP over placebo + AAP (HR, 0.79; 95% CI, 0.55–12; P=0.18)
• Improvement in TSP (HR, 0.56; 95% CI, 0.37–85; P=0.01)
• Clinically meaningful improvement in TCC (HR, 0.60; 95% CI, 0.39–92; P=0.02)
• Time to worst pain progression and time to pain interference progression favoured NIRA + AAP

Conclusions

NIRA + AAP could emerge as a standard of care for this subgroup of patients with mCRPC.

Pain and analgesic use in men with mCRPC initiating first-line treatment

By Simon van Rysewyk

What is this presentation about?

Oncology nurse Ulrika Rönningås (Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden) presented data from the prospective study PROCEED (N=143), which evaluated three dimensions of pain (frequency, severity, distress) measured using the Memorial System Assessment Scale (MSAS). Analgesic use was collected from medical records. Seventy-two men starting first-line treatment for mCRPC were included.

What did the study find for men with mCRPC on analgesics?

• 9% (n=46) used analgesics
• 8 % had pain ‘frequently’ or ‘almost constantly’
• 51% reported ‘quite a bit’ or ‘very much’ distress
• 5% reported ‘severe’ or ‘very severe’ pain

What did the study find for men with mCRPC not on analgesics?

• 1% (n=26) did not use analgesics
• 44% had pain ‘frequently’ or ‘almost constantly’
• 19% had ‘severe’ pain; no participant not using analgesics reported ‘very severe’ pain
• 38% reported ‘quite a bit’ or ‘very much’ distress

What do the study data mean?

According to Rönningås, pain experience in men with mCRPC differs between those using analgesics from those who do not. Pain management was not effective for more than half of the participants with mCRPC, even for those using analgesics.

Rönningås recommends that “men with mCRPC starting life-prolonging treatment may benefit from a structured multidimensional assessment. When the disease has progressed to an mCRPC phase, an early integrated palliative approach with thorough symptom management may be essential in order to obtain the best possible quality of life”.

References

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2. Kelly WK, Danila DC, Lin CC, Lee JL, Matsubara N, Ward PJ, et al. Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study. Cancer Discov. 2023:OF1–OF14.
3. Graff JN, Liang LW, Kim J, Stenzl A. KEYNOTE-641: A Phase III study of pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer. Future Oncol. 2021;17(23):3017–3026.
4. Graff JN, Tagawa ST, Hoimes CJ, Gerritsen WR, Vaishampayan UN, Elliott T, et al. Pembrolizumab plus enzalutamide for enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC): Updated analyses after one additional year of follow-up from cohorts 4 and 5 of the KEYNOTE-199 study. J Clin Oncol. 2021;39:5042.
5. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. New Eng J Med. 2014;371(5):424–433.
6. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahba RK, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. New Eng J Med. 2021;385(12):1091–1103.
7. Chi KN, Rathkopf DE, Smith MR, Efstathiou E, Attard G, Olmos D. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40:12.