Shifting Therapies to Earlier Settings Could Bolster Treatment Options in mHSPC and Oligometastatic Prostate Cancer

Neeraj Agarwal, MD, FASCO

As ongoing research and clinical trials aim to improve outcomes for patients with metastatic castration-resistant prostate cancer (mCRPC), investigations evaluating established therapies in earlier settings, such as in patients with metastatic hormone-sensitive prostate cancer (mHSPC) or oligometastatic prostate cancer, could serve as another avenue for improving outcomes for the broader patient population, according to Neeraj Agarwal, MD, FASCO.

“Moving these drugs [to earlier settings] and having more targeted therapy early on will hopefully improve survival outcomes with a higher magnitude down the line,” Agarwal said in an interview with OncLive® during the US Prostate Cancer Conference (USPCC).

In the interview, Agarwal touched on unmet needs across the prostate cancer spectrum, ongoing investigations examining various agents and combinations in novel settings, and the utility of prostate–specific membrane antigen (PSMA) PET imaging. Agarwal is a professor of medicine, the Presidential Endowed Chair of Cancer Research, and director of the Genitourinary Oncology Program at the Center of Investigational Therapeutics of the University of Utah Huntsman Cancer Institute in Salt Lake City.

OncLive: Could you provide an overview of some of the key areas of contention within the field of prostate cancer, where consensus in clinical practice is lacking?

Agarwal: There cannot be a clinical trial to address every single clinical question, or at least, there may not be level 1 evidence for many of those questions we discussed during the [USPCC] meeting. For example, when we diagnose a patient with mHSPC and you look at disease volume, how should it be defined? CT scans and bone scans have been standard modalities to assess the volume status of the disease. Now we have PSMA PET scans. If the disease is low volume on the conventional scans and high volume on the PSMA PET scan, how do you categorize that patient’s [disease]?

Similarly, in the biochemical recurrence setting, when you do a PSMA PET scan and a patient is found to have metastatic disease, do they have high-volume disease or low-volume disease? Would you treat these patients—like you would treat somebody with high-volume, mHSPC—with triplet therapy, when these data are based on conventional scans? [Perhaps] these patients have biochemical recurrence, or they could have [recently] been treated with intermittent androgen deprivation therapy [ADT], for example.

There are multiple questions which are lingering [across the prostate cancer realm]. We are increasingly upgrading comprehensive genomic profiling. What if a patient has low-volume disease on a PSMA PET scan and has tumor suppressor gene loss, such as an RB1 mutation, RB1 loss, or p53 loss? Would you use chemotherapy for those patients, knowing that they may not respond very well to traditional androgen receptor [AR] pathway inhibitors?

Could you expand on the potential PARP inhibitor–based combinations in prostate cancer?

Moving on to mCRPC setting, we have seen multiple large phase 3 trials of PARP inhibitor and AR pathway inhibitor combinations. Now, the field is grappling with earlier use vs later use of these PARP inhibitors. We saw the data from the [phase 2] BRCAaway trial [NCT03012321] from Maha HA Hussain, MBChB, [of Northwestern Feinberg School of Medicine,] and colleagues, showing that if we combine AR pathway inhibition with a PARP inhibitor, it seems like there is synergy between these 2 drugs.

[Findings from BRCAaway presented at the 2024 Genitourinary Cancers Symposium showed that] patients with BRCA1/2 or ATM mutations [experienced a median progression-free survival] of 39 months [95% CI, 22–not reached] when treated with abiraterone acetate [Zytiga] plus olaparib [Lynparza] and prednisone vs 8.4 months [95% CI, 2.9-17.0] with abiraterone acetate plus prednisone alone [and 14 months (95% CI, 8.4-20.0) for olaparib alone]. Even if you take into account the complete treatment from day one [of the study] to the end of crossover, [the median PFS for the 2 control arms] was 16 months.¹

Furthermore, we discussed other genes beyond BRCA1/2, such as CDK12 mutations, PALB2 mutations, and RAD51 mutations. We have seen compelling data with the PARP inhibitor/AR pathway inhibitor combination therapies in these subsets of patients—especially those with CDK12 mutations—which we have not seen with PARP inhibitor monotherapy.

What potential do radiopharmaceuticals have to further alter the prostate cancer treatment paradigm?

Moving on to the radioligand therapy lutetium Lu 177 vipivotide tetraxetan [Pluvicto; formerly 177Lu-PSMA-617], what is the role of dosimetry? What is the role of doing molecular imaging as patients are receiving treatment? For example, if patients have a PSMA-negative scan after two doses of vipivotide tetraxetan, are they going to benefit from further dosing? Should we stop treatment after 2 doses and leave those extra 3 to 4 doses for the time when they have relapse, recurrence, or re-expression of PSMA, or rising prostate-specific antigen, for example? [Regarding] some kind of deintensification strategy in patients receiving vipivotide tetraxetan, the answer is not clear.

We also talked about mCRPC. What is the role of docetaxel and cabazitaxel? In the [phase 2] Thera-P trial [NCT03392428], cabazitaxel seemed to have a good efficacy compared with vipivotide tetraxetan after failure of docetaxel.²

There are so many questions which can be answered in future clinical trials, but we do not have those answers right now. These types of consensus meetings have been conducted so that we can have some answers for our colleagues and for all of us. We hear from experts and renowned investigators in the field about what they think, and an esteemed panel will decide, at least as a consensus answer, for these questions that remain unanswered by clinical trials. I look forward to the final outcome of this meeting. Hopefully, we'll get these consensus statements out in the community, and I’m hoping that this will help me in my clinic and my colleagues elsewhere.

What are some unmet needs in prostate cancer that future research might address beyond what you have already mentioned?

mCRPC remains a lethal disease. After the failure of novel hormonal therapy or AR pathway inhibitors, the survival is about 2 years, or [potentially] less. All these medications or new agents we have seen recently have incrementally improved survival. However, there is a huge unmet need, given metastatic prostate cancer remains the second most common cause of cancer-related death in men.

How can we improve outcomes? Personalizing medicine by increasing the use of more targeted therapies [could help]. We have seen PARP inhibitors and radioligand therapies, and this is just a start. We will be seeing more data on actinium, which is alpha radiation therapy. We will also see multiple phase 3 trials in the mHSPC setting, such as the TALAPRO-3 trial [NCT04821622] using the PARP inhibitor talazoparib [Talzenna] early on [during treatment] in combination with enzalutamide [Xtandi]. We will see the [phase 3] CAPItello-281 trial [NCT04493853] with capivasertib [(Truqap) in combination with abiraterone acetate] in patients who are PTEN deficient. We also have [the phase 3] PSMAddition trial [NCT04720157], which is using vipivotide tetraxetan early on.

Could you elaborate on the utility and limitations of PSMA PET imaging? Specifically, could you discuss its current areas of use and any shortcomings you perceive?

PSMA PET scans are a very welcome addition to the imaging armamentarium [for patients with] prostate cancer, and it is already changing the way we look at prostate cancer [and how] we treat prostate cancer. [For example,] when patients are planning to have surgery and a PSMA PET scan shows metastatic disease outside of the pelvis, does this change treatment? Should it change treatment? I believe it should. These patients may be better candidates for other therapy, or if you are using surgery and radiation for these patients, there could be a role of systemic therapy for these patients.

Similarly, in patients who have mHSPC, if they are found to have high-volume disease on the PSMA PET scan and low-volume disease or oligometastatic disease on the CT and bone scans, is there any role for oligometastatic radiation therapy in those patients who already have been shown to have high-volume [disease with] multiple other lesions on the PSMA PET scan? Probably not. Therefore, oligometastatic radiation therapy may not be the right approach for those patients who are found to have 3 or 4 lesions on the conventional scans, but 15 lesions, for example, on the PSMA PET scan.

Of course, moving to vipivotide tetraxetan therapy, [PSMA PET scans] are definitely used for patient selection, and hopefully, we'll be using other molecular imaging scans in patients who are receiving radioligand therapy and to tailor radioligand therapy for these patients. PSMA PET scans are going to help us with treatment planning in the localized setting, planning regarding oligometastatic radiation in the metastatic setting, and hopefully, tailoring the dose of vipivotide tetraxetan in patients who are planning to get the radioligand therapy.

Could you provide your insights on the incorporation of quality-of-life (QOL) data in prostate cancer trials? How could future trials improve in recording patient-reported outcomes?

QOL assessments are currently done by a standardized questionnaire, which has been used in multiple trials. However, like any other tool, [nothing] is perfect, and we can always continue to make them better. The QOL questionnaires—the traditional way we do them right now—are done when patients come to the clinic. What happens to those adverse effects [AEs] that happen 7 days after the clinic visit and go away 7 days before the [next] visit? Those AEs are likely not going to be captured by QOL questionnaires obtained during the visits. This can be improved by wearables that patients go home with, which will allow them to monitor and enter their QOL perception [away from the clinic]. [This could better capture] how they perceive their QOL on a daily basis. Patients could also use electronic questionnaires when they are at home, which will allow them to again enter their own QOL data on a more regular basis.

Additionally, QOL questionnaires, in my view, can be simplified. They are too long, in my view, for many of my patients, and they may not have the patience [to complete them consistently]. They don't have the time to do those long questionnaires. There is room for improvement with those questionnaires, just as we have room for improvement with everything in our lives.

References

1. Hussain M, Kocherginsky M, Agarwal N, et al. BRCAAway: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) bearing homologous recombination-repair mutations (HRRm). J Clin Oncol. 2024;42(suppl):19. doi:10.1200/JCO.2024.42.4_suppl.19
2. Hofman MS, Emmett L, Sandhu S, et al. Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. 2024;25(1):99-107. doi:10.1016/S1470-2045(23)00529-6