Congress highlights - ASCO GU 2023

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.

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

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.