The Role of Oncology Nurses and Advanced Practice Providers in the Treatment of Patients With HRR-Deficient mCRPC

00:00:00: You are listening to an ADIS Journal podcast.

00:00:05: Hello and welcome to this podcast hosted by the Journal Oncology and Therapy.

00:00:10: My name is Jennifer Lloyd and I'm an Advanced Practice Provider, or APP, at the Intermountain Medical Center Oncology Clinic in Murray, Utah.

00:00:18: I'm pleased to be joined today by Julia Batten, who is also an APP.

00:00:22: Julia

00:00:22: works at the Huntsman Cancer Institute in Salt Lake City, Utah.

00:00:26: Thank you and hello everyone.

00:00:29: In this podcast, Julia and I will share with you how we as APPs can help support our patients who have metastatic castrate-resistant prostate cancer, or MCRPC, with alterations in homologous recombination repair, or HRR genes.

00:00:44: We will focus on those patients who receive treatment with the poly-ADP ribose polymerase, or PARP inhibitor, Talzoperib, plus the Androgen Receptor Pathway Inhibitor, or ARPI, and Zalutamide.

00:00:58: This combination treatment was approved by the U.S.

00:01:00: Food and Drug Administration or FDA in twenty twenty three for use in patients with MCRPC and HRR gene alterations.

00:01:08: So to put this podcast into context, let's start with some background information on HRR genes and prostate cancer.

00:01:17: HRR is a multi-gene DNA repair pathway which plays a critical role in maintaining genomic stability.

00:01:23: About one-quarter of patients with MCRPC have tumors with alterations in genes that are directly or indirectly involved in this pathway.

00:01:31: The presence of these alterations often indicates a more aggressive prostate cancer and poorer prognosis for our patients.

00:01:38: But the presence of these alterations also makes cancer cells more susceptible to treatment with PARP inhibitors.

00:01:44: So now that we know patients with HR or prostate cancer often have a poor prognosis and may be candidates for some targeted treatment options, let's explore how we best identify these patients.

00:01:56: Julia, what are your thoughts on this topic?

00:01:59: Thanks, Jennifer.

00:02:00: And as you mentioned, identifying patients whose tumors had HRR gene alterations is key to treating them with the most appropriate therapy.

00:02:10: We do this by performing genetic testing on samples from the patient.

00:02:14: The type of sample needed for testing depends on whether we are looking for somatic or germline alterations.

00:02:21: Somatic gene alterations are those that are acquired over a patient's lifetime and are only present in the patient's tumor cells.

00:02:28: So testing for somatic gene alterations requires a sample that includes tumor DNA.

00:02:35: This can be obtained from either the tumor itself or from circulating tumor DNA found in a patient's blood.

00:02:42: In contrast, germline gene alterations are inherited and present in all cells.

00:02:48: Samples typically used for testing for germline alterations are a cheek swab, sputum, or blood draw.

00:02:55: It is important to note that patients whose samples are negative for germline HRR gene alteration can still have an acquired somatic HRR gene alteration.

00:03:06: Similarly, somatic testing should not replace germline testing, as this may lead to missed germline alterations and up to one-fifth of patients.

00:03:16: It is also important to note that germline testing can have consequences for family members, as we will explain later.

00:03:24: As many different HRR genes can be altered, both somatic and germline testing involves the use of multi-gene panels so that many genes can be tested at the same time.

00:03:35: Jennifer, perhaps you can build on this and give our listeners an overview of the current guidelines that provide recommendations for the genetic and biomarker testing of patients with prostate cancer.

00:03:48: Yes, absolutely.

00:03:50: The American Neurological Association, or AUA, and NCCN, guidelines help clarify who should be tested and when germline and somatic testing are appropriate.

00:04:01: In twenty twenty three, the AUA updated their guidelines for patients diagnosed with advanced prostate cancer.

00:04:07: These guidelines recommended that patients with MCRPC should be offered germline testing, if not performed already, as well as somatic testing to identify DNA repair deficiencies such as HRR gene alterations.

00:04:22: They also point out that other genetic changes may be identified, such as microsatellite instability status, which can inform a patient's prognosis.

00:04:31: As you have heard, germline testing may also identify other mutations with potential familial risk of associated malignancies.

00:04:39: For patients with metastatic hormone-sensitive prostate cancer, the AUA guidelines say that clinicians should offer germline testing and should consider somatic testing and genetic counseling.

00:04:51: The NCCN guidelines on prostate cancer and the NCCN guidelines on genetic or familial high risk assessment for breast, ovarian, pancreatic, and prostate cancer are applicable for patients with MCRPC.

00:05:04: These guidelines recommend germline testing for prostate cancer susceptibility genes, such as those involved in HRR, in patients with prostate cancer at any age with any of the following.

00:05:17: One, metastatic or node-positive prostate cancer.

00:05:21: Two, high-risk or very high-risk disease.

00:05:24: Three, Ashkenazi Jewish ancestry.

00:05:26: Or four, a family history of breast, ovarian, pancreatic or prostate cancer.

00:05:32: These guidelines also say that germline testing may be considered for, one, any patient aged fifty-five years or younger who have prostate cancer.

00:05:42: or, two, patients of any age with intermediate-risk prostate cancer with intradectal or cribiform histology.

00:05:50: Limited data suggests that both of these histological patterns have increased genomic instability.

00:05:56: These guidelines also recommend somatic testing for HRR gene alterations in patients with metastatic prostate cancer and say that it can be considered for patients with regional prostate cancer.

00:06:07: Thanks, Jennifer, for describing these recommendations.

00:06:10: For more details, the AUA guidelines can be found on the AUA website in the guidelines and quality section.

00:06:18: And the NCC guidelines can be found on the NCCN website in the guidelines.

00:06:23: Treatment by Cancer Section.

00:06:26: So, genetic and biomarker testing are clearly recommended for patients with MCRPC.

00:06:32: We therefore need to ensure that patients are tested and referred to genetic counselors who can guide them through the process and the possible implication of the results.

00:06:42: Jennifer, do the guidelines give any recommendations for genetic counseling?

00:06:47: Yes, they do.

00:06:48: The NCCN guidelines on prostate cancer strongly recommend genetic counseling if a patient has a positive germline test for a pathogenic or likely pathogenic variant.

00:06:59: Following on from this would be cascade testing of relatives to assess family members who may be at risk for developing related cancers.

00:07:07: Genetic counseling is also recommended if no pathogenic variant is found but there is a positive family history or when only variants of uncertain significance are identified to help guide patients about decisions pertaining to surveillance and future testing.

00:07:23: However, despite these recommendations, it looks as though over half of patients with metastatic prostate cancer do not undergo genetic or biomarker testing.

00:07:32: With understanding of the available guidelines, nurses and APPs can help educate patients and ensure that they get the appropriate tests and counseling to inform risk, prognosis, and treatment decisions.

00:07:44: I totally agree, and a potential targeted treatment option is the combination of a PARP inhibitor with an ARPI, as we mentioned at the start of this podcast.

00:07:54: The combination of Talazaprib plus Enzalutamide has been approved by the US FDA for the treatment of adult patients with HRRG mutated metastatic CRPC.

00:08:06: Other PARP inhibitor and ARPI combinations approved by the US FDA are Alaparib, or neuroparib, plus abiraterone acetate and prednisone for adult patients with BRCA, G-mutated MCRPC.

00:08:22: But we will not be discussing these here.

00:08:25: Jennifer, I think we should first introduce the design of the TALOPRO II trial, which was the basis of the approval for TALOSAPRIB plus enzolutamide in the U.S

00:08:35: Good idea, Julia.

00:08:37: The combination of talizoperib plus enzalutamide was investigated in the TALIPRO-II trial by comparing its efficacy and safety versus enzalutamide alone as a first-line treatment in patients with MCRPC.

00:08:50: The trial is an ongoing, double-blind, randomized phase three study, so some patients are still taking part in the study, but no new patients will be enrolled.

00:09:00: Patients received either Talazoprib, zero point five milligrams daily, reduced to zero point three five milligrams daily if they had moderate renal impairment or matching placebo.

00:09:11: And all patients received Encelutamide, a hundred and sixty milligrams daily.

00:09:16: Before randomization, all patients prospectively provided solid tumor tissue and or blood-based samples which were assessed for the presence of HRR gene alterations.

00:09:26: But not all patients in the trial had HRR gene alterations.

00:09:30: The first patients were enrolled into an unselected cohort regardless of HRR gene alteration status.

00:09:37: This unselected cohort included a hundred and sixty-nine patients with tumor HRR gene alterations known as HRR deficient.

00:09:44: and six hundred and thirty six patients without tumor HRR gene alterations.

00:09:50: An additional two hundred and thirty patients who were selected for tumor HRR gene alterations were then recruited.

00:09:56: These two hundred and thirty additional patients were combined with the one hundred and sixty nine previously enrolled patients to complete a combined HRR deficient cohort of three hundred and ninety nine patients.

00:10:09: This HRR-deficient cohort had tumors with one or more alterations in at least one of twelve HRR genes.

00:10:17: The HRR genes assessed were ATM, ATR, ERCA-I, ERCA-II, CDK-II, CHEC-II, FANCA, MLH-I, MRE-XI-A, NBN, LB-II, and RAD-XI-C.

00:10:40: In line with the approval of TALA's operative plus enzalutamide for HRR gene mutated MCRPC in the

00:10:46: U.S.,

00:10:46: the HRR-deficient cohort will be the focus of our discussion.

00:10:51: Thanks, Jennifer.

00:10:52: This sets the scene nicely for us to look at the main efficacy results in the HRR-deficient cohort.

00:10:59: We should look first at the primary endpoint of the trial.

00:11:02: This was radiographic progression-free survival by Blinded Independent Central Review.

00:11:08: For this podcast, we will refer to this as PFS.

00:11:13: The primary analysis of this endpoint was conducted after a medium follow-up of approximately seventeen months at a cutoff date of October third, twenty-twenty-two.

00:11:24: In this cohort, treatment with Talosaprib plus Enzalutamide significantly improved PFS versus placebo plus Enzalutamide.

00:11:35: with a hazard ratio of zero point four five indicating a fifty-five percent reduction in the risk of disease progression or death.

00:11:44: For further specific values, we refer you to the original twenty twenty-four publication by Fizzazzi et al.

00:11:51: in the journal Nature Medicine.

00:11:54: At this data cutoff, the median PFS was thirteen point eight months for the placebo plus enzalutamide group and had not been reached for the telosaprib.

00:12:04: plus enzalutamide group.

00:12:06: PFS was analyzed again at the time of the final analysis of overall survival, after a median follow-up of approximately forty-four months at a cutoff date of September third, twenty-twenty-four.

00:12:20: At this later time, the median PFS was thirty point seven months for talozaprid plus enzalutamide versus twelve point three months for placebo plus enzalutamide.

00:12:32: and the corresponding hazard ratio was zero point four seven.

00:12:37: If we look at the PFS results for particular HRR genes, patients with MCRPC harboring BRCA-I and or BRCA-II alterations experience the most benefit from treatment with Talosaprid plus Enzalutamide.

00:12:54: Post hoc analysis at the time of the primary PFS analysis demonstrated that patients with MCRPC harboring BRCA-I and two alterations had a lower risk of radiographic progression or death, with a hazard ratio of zero point two indicating an eighty percent reduction in risk.

00:13:15: For patients with MCRPC harboring non-BRCA-I or two HRR alterations, the hazard ratio at the time of the primary analysis was zero point six eight.

00:13:27: correlating with a thirty-two percent reduction of disease progression or death.

00:13:32: Now, Jennifer, I understand that although patients in the Talopro II trial could have received prior treatment with an ARPI, not many did.

00:13:42: Yes, that's right.

00:13:43: A limitation of the Telepr-II trial is that, when it was carried out, ARPIs were not commonly used to treat castration-sensitive prostate cancer, and their use has since become more commonplace.

00:13:55: Among the HRR-deficient cohorts, thirty-four patients had received a prior ARPI, either abiraterone or or terenol.

00:14:04: In these patients, the hazard ratio for PFS was zero point five three, which is similar to that in the whole cohort.

00:14:11: although the confidence interval was wide at zero point two to one point four two.

00:14:17: So the benefit of TALA's operative plus enzolutamide in patients who have received a prior ARPI requires confirmation.

00:14:25: Thanks Jennifer.

00:14:26: So we've discussed the results for the primary analysis of PFS.

00:14:30: At that time, the results for overall survival, which was a key secondary endpoint of TALA Pro II, were immature.

00:14:38: The final overall survival analysis has now been carried out.

00:14:42: Perhaps you can explain what this showed.

00:14:45: Yes, the results at the final analysis in the HRR Deficient Cohort showed that treatment with Talazoprid plus enzalutamide significantly improved overall survival versus placebo plus enzalutamide, with a hazard ratio of zero point six two, indicating a thirty eight percent reduction in the risk of death.

00:15:04: The median overall survival was forty-five point one months versus thirty-one point one months respectively.

00:15:10: Again, patients with MCRPC harboring BRCA one and two alterations seem to experience the most benefit from treatment with telzopper plus enzalutamide with a hazard ratio of zero point five indicating a fifty percent reduction in the risk of death.

00:15:27: By comparison, patients with MCRPC harboring non-BRCA one and two alterations had a hazard ratio of zero point seven three, indicating a twenty-seven percent reduction in risk of death.

00:15:40: So, telzoperative plus enzalutamide improved both PFS and overall survival.

00:15:46: Julia, we know that quality of life is a huge importance for patients with MCRPC.

00:15:51: So, what happened to the patient's quality of life with this combination?

00:15:55: Together with the observed efficacy benefits, definitive deterioration in the global health status quality of life measure was delayed by treatment with Talazaparit plus Enzalutamide compared with placebo plus Enzalutamide in patients with MCRPC harboring HRR gene alterations at the primary analysis.

00:16:16: Patient reported quality of life was then maintained with extended follow-up.

00:16:22: Thanks, Julia.

00:16:23: Now, in addition to considering the potential benefits for a patient starting talizoperib plus enzalutamide, we need to consider how the likely adverse events will affect the patient and how these can be managed to minimize their impact.

00:16:36: What information about the talizoperib plus enzalutamide combination do you think would be crucial for nurses and APPs to know?

00:16:44: Indeed.

00:16:45: It's important for nurses and APPs to be familiar with the safety profile of talizoperib.

00:16:50: plus enzolutamide.

00:16:52: This will help them to monitor patients for potential adverse events and appropriately educate patients who are about to start treatment.

00:17:00: Let us look at the common adverse events in patients in the HRR deficient cohort treated with Talazaprid plus enzolutamide from the primary analysis of the TALAPRO-II trial at the data cutoff of October, twenty-twenty-two.

00:17:14: Common grade three or higher, which are severe, Hematologic adverse events in at least five percent of patients were anemia, forty-one percent, utropenia in nineteen percent, thrombocytopenia in seven percent, and leukopenia in six percent of patients.

00:17:31: Common non-hematologic adverse events of any grade in at least twenty percent of patients were fatigue, defined as both fatigue and esthenia, in forty-nine percent, nausea in twenty-one percent, and decreased appetite in twenty percent.

00:17:47: Importantly, there were no new safety signals identified when the safety data were analyzed at the time of final analysis after an extended follow-up of nearly two years.

00:17:58: Thank

00:17:59: you for telling us about this frequently occurring adverse events.

00:18:03: How were dose modification strategies used to manage these adverse events, especially the hematologic events, and did patients end up stopping treatment because of adverse events?

00:18:14: In total, Ten percent of patients permanently discontinued talizoperative due to adverse events.

00:18:20: Most commonly, anemia in four percent of patients.

00:18:24: But for most patients, dose interruptions or reductions were used to manage adverse events.

00:18:29: Dose interruption of talizoperative due to adverse events occurred in fifty-eight percent of patients and was also most commonly due to anemia in forty-two percent and also to neutropenia in fifteen percent and thrombocytopenia and nine percent.

00:18:46: Similarly, dose reduction of Talazaprid due to adverse events occurred in fifty-two percent of patients and was also most commonly due to anemia in forty-three percent, neutropenia in fifteen percent, and thrombocytopenia in six percent.

00:19:04: So it's clear that dose modifications are widely used to manage hematologic adverse events associated with Talazaprid plus Enzalutamide.

00:19:13: This really raises the question of what nurses and APPs can do to help with the monitoring and management of adverse events.

00:19:21: Jennifer, what are your thoughts?

00:19:23: There are many ways that we as nurses and APPs can help these aspects of treatment.

00:19:28: Regarding the frequency of monitoring, we need to ensure that all patients being treated with talizoprib have complete blood counts monitored monthly and as clinically indicated.

00:19:39: And for patients who have grade three or four events of anemia, neutropenia, or thrombocytopenia, the dosing of talizoprib should be put on hold and blood counts monitored weekly.

00:19:51: In addition, we should encourage the early detection of adverse events by educating patients and their caregivers on the early signs of common adverse events.

00:20:00: For anemia, these can include fatigue, dizziness, and shortness of breath, since early intervention can help limit treatment interruptions.

00:20:09: Nurses and APP should screen patients for dose limiting effects such as nausea and fatigue and treat with anti-imetics and fatigue management as soon as possible.

00:20:18: Nurses and APPs can also ensure that patients with persistent hematologic toxicities are referred to a hematologist for further evaluation and can work within their established protocols to manage dysmodifications.

00:20:31: Julia, do you have anything to add based on your clinical experience?

00:20:36: Yes, I think it's worth noting that for older or frail patients, I would consider seeing them two weeks after starting therapy to evaluate how they are tolerating therapy.

00:20:46: If it's not possible to evaluate them in clinic, I would schedule a check-in telephone call or a virtual visit at two weeks.

00:20:53: Thanks, Julia.

00:20:55: So we've talked about dose reduction interruptions, making this a good point for us to discuss the recommended dosing of Talazoprib for patients with MCRPC and dose modifications after adverse events occur.

00:21:08: Yes, I agree.

00:21:09: So for patients with HRR gene-alterated MCRPC, The recommended starting dose of Talosaprib is zero point five milligrams taken orally once daily in combination with Enzalutamide.

00:21:24: And this should be modified to a starting dose of zero point three five milligrams once daily for patients with moderate renal impairment and zero point two five milligrams for patients with severe renal impairment.

00:21:38: The Talosaprib capsules are taken whole with or without food.

00:21:42: at roughly the same time each day.

00:21:45: And if the patient vomits or misses a dose of talizaprib, they should take their next dose at the usual time and should not take an extra dose.

00:21:54: Jennifer, it would be great to get your insights on how dosing of talizaprib can be modified to manage adverse events.

00:22:02: Certainly.

00:22:03: An interruption or reduction in dosing of talizaprib may be needed depending on the type of adverse event and its severity.

00:22:10: If a dose reduction is needed, the first dose reduction is to zero point three five milligrams.

00:22:16: The second is to zero point two five milligrams and the third to zero point one milligram each.

00:22:23: once daily.

00:22:24: For grade one or two that is mild or moderate adverse events, there is no requirement to interrupt or reduce the dose of TELS operant.

00:22:32: However, grade one or two anemia may warrant dose interruption or reduction if clinically symptomatic.

00:22:39: For example, if the patient has fatigue.

00:22:42: Julia, I think you may have another example from clinical practice.

00:22:46: Yes, I would also suggest a dose introduction or reduction in an older or frail patient if grade one or two anemia was impacting their functional status in a way that puts them at risk for a fall.

00:22:58: Thanks, Julia.

00:23:00: And for grade three or four events, which are those that are severe or life-threatening, it is generally recommended to hold telizoperib and monitor until the event resolves to appropriate levels.

00:23:11: As you mentioned earlier, hematologic toxicity is some of the most common adverse events associated with telizoperib plus enzolutamide in the TELPR-II trial.

00:23:20: If anemia, neutropenia, or thrombocytopenia occur in patients, APPs need to be familiar with the recommended dosing modifications to optimize treatment.

00:23:30: Absolutely, and there are further recommendations for dose modifications after the occurrence of hematologic adverse events.

00:23:38: If they occur, blood count monitoring may be increased from monthly to weekly, as mentioned before.

00:23:44: Then, if blood counts recover, talizaprid can be restarted at a reduced dose.

00:23:50: But if low values persist, more than eight weeks for anemia or more than four weeks for neutropenia or thrombosotopenia, the recommendation is to discontinue talizaprid.

00:24:02: And permanent discontinuation of TAL's operative may also be required to manage non-hematologic adverse events, including laboratory events of grade three lasting for more than fourteen days, or of grade four lasting for more than three days, and non-laboratory grade four events with some exceptions.

00:24:20: Non-laboratory grade four events that do not require discontinuation are vomiting that responds to intervention within three days, Diarrhea managed to grade two or lower within three days, and constipation managed to grade two or lower within seven days.

00:24:37: The full details of Talazoprob dosing modifications in hematologic adverse events and grade three or four non-hematologic adverse events can be found in the U.S.

00:24:47: prescribing information or in our previous publication.

00:24:51: Thanks, Jennifer.

00:24:52: I'd also like to note that with respect to dose modifications, while the recommended guidelines for dose modifications are applicable to most patients, there are some patients who may require dose modification sooner or for a lower grade due to their unique clinical circumstances.

00:25:07: So it's always important to assess the impact of the adverse event on the patient's quality of life and safety when making decisions about dose modifications.

00:25:18: I totally agree.

00:25:20: It's clear that nurses and APPs can play a crucial role in educating patients to understand the dosing regimen of talazoprib and that dose modifications are a standard procedure for managing adverse events.

00:25:32: I also think it's important to reiterate to our listeners that most patients with grade three or four cytopenias are able to tolerate these and continue talazoprib after an initial dose modification.

00:25:45: Thank you, Julia, for joining me today to discuss the role of oncology nurses and APPs in the treatment of patients with HRR-deficient MCRPC receiving telizoperib plus enzolutamide.

00:25:56: We would like to re-emphasize the importance of HRR testing for patients with prostate cancer, as this informs patient eligibility for treatment, such as with telizoperib plus enzolutamide, and helps to identify familial risk of particular cancers.

00:26:11: Nurses and APPs can help to educate patients about genetic and biomarker testing.

00:26:17: Furthermore, nurses and APPs should be familiar with the safety profile of TALAS operab plus enzalutamide.

00:26:24: They can then monitor for and educate patients on the likely adverse events, the need for regular monitoring, and the need to report any event as soon as possible so that appropriate referrals and dust modifications can be implemented.

00:26:38: Thank you to all of our listeners.

00:26:40: We presented a lot of information today.

00:26:43: As a reminder, the key information discussed here can be found in the Teleport II trial publication, the US prescribing information, and the AUA and NCCN guidelines.

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