Neeraj Agarwal, MD, discusses preclinical data that supported the launch of the TALAPRO-2 trial and key efficacy and safety data on the use of talazoparib plus enzalutamide in patients with metastatic castration-resistant prostate cancer irrespective of homologous recombination repair mutational status.
Efficacy and safety data reported with talazoparib (Talzenna) plus enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) support the regimen’s potential use as a first-line treatment option for this population, regardless of homologous recombination repair (HRR) gene alteration status, according to Neeraj Agarwal, MD.
Previously reported data from the phase 2 TALAPRO-1 trial (NCT03148795) showed that talazoparib monotherapy was well tolerated and had durable antitumor activity in heavily pretreated patients with mCRPC who had HRR-positive disease.1 The phase 3 TALAPRO-2 trial (NCT03395197) was subsequently launched to evaluate enzalutamide plus talazoparib in patients who were unselected for genetic alterations in the HRR pathway.2
Results from the primary analysis were presented at the 2023 Genitourinary Cancers Symposium and showed that talazoparib plus enzalutamide (n = 402) reduced the risk of progression or death by 37% vs enzalutamide plus placebo (n = 403; HR, 0.63; 95% CI, 0.51-0.78; P < .001). The median radiographic progression-free survival (rPFS) was improved with the combination across all subgroups analyzed. The regimen’s toxicity was determined to be consistent with what has been observed with each individual agent, and adverse effects [AEs] were manageable.2
Based on these data, the FDA has granted priority review status to a supplemental new drug application seeking approval of the combination in patients with mCRPC.3
“[If] the combination of talazoparib plus enzalutamide is approved and available [in clinical practice], it will be a standard-of-care [SOC] option for patients in the first-line mCRPC setting, regardless of HRR gene alteration [status],” said Agarwal, who is lead study author and a professor of medicine and the presidential endowed chair of Cancer Research at the Huntsman Cancer Institute at the University of Utah, Salt Lake City, Utah.
In an interview with OncLive®, Agarwal discussed preclinical data that supported the launch of the TALAPRO-2 trial, shared key efficacy and safety data on the use of talazoparib plus enzalutamide in patients with mCRPC irrespective of HRR mutational status, addressed potential study limitations, and emphasized the clinical implications of this research on the treatment paradigm.
Agarwal: [In the] early part of the past decade, emerging preclinical data [indicated] that AR blockade in cancer cells can lead to downregulation of HRR gene expression, and a concurrent increase in PARP activity. This AR blockade creates what we call a BRCAness phenotype inside these cancer cells, thus making them sensitive to PARP inhibition. There was a [also] mouse model xenograft-based study which showed that castration therapy combined with a PARP inhibitor showed much higher activity [in terms of] tumor shrinkage [than] what you would expect from these individual drugs.
Based on these preclinical data, Noel Clarke, MBBS, FRCS, ChM, of Salford Royal Hospital & The Christie, Manchester, UK, published a phase 2 trial [NCT01972217] where patients were randomized to abiraterone acetate [Zytiga] plus olaparib [Lynparza] vs abiraterone only. [The experimental regimen] showed significantly improved rPFS regardless of HRR gene alteration [status]. All these data led to multiple phase 3 trials, including TALAPRO-2.
TALAPRO-2 is a randomized phase 3 trial in which 805 patients with mCRPC were randomized to the combination of talazoparib plus enzalutamide vs enzalutamide plus placebo. All patients had newly diagnosed [disease], and they could not have received any treatment in the castration-resistant setting except continuation of androgen deprivation therapy or older-generation androgen receptor [AR] inhibitors such as bicalutamide [Casodex].
Another important aspect of this trial is that all enrolled patients [in cohort 1] were unselected for HRR gene alterations. Cohort 2 of the trial began to accrue [patients] after cohort 1 finished accrual and is still ongoing.[At the meeting] I [presented data] on patients unselected for HRR gene alterations.
One of the most important [aspects] of the eligibility criteria was the requirement for a prospective assessment of underlying HRR gene alteration status. In fact, [almost all] patients had prospective tumor tissue profiling to [identify] these alterations. That is considered the gold standard in our field.
We also realize that there are going to be patients who [do] not have a clear [HRR status], despite having tissue testing. We call them HRR status-unknown patients. For stratification purposes, they were combined with the HRR-negative patients. Having said that, we also presented an exploratory analysis, which focused only on patients who were HRR negative. These attributes make this trial much more compelling as far as design and results are concerned.
The primary end point of TALAPRO-2 was rPFS as determined by independent radiology review. Other key secondary end points were time to cytotoxic chemotherapy, time to prostate-specific antigen [PSA] progression, time to deterioration in quality of life [QOL], and overall survival [OS].
There was a 37% reduction in risk of disease progression or death with the combination of talazoparib plus enzalutamide compared with enzalutamide plus placebo; it was statistically significant, with a hazard ratio of 0.63 favoring the combination. Interestingly, we saw a very similar hazard ratio of 0.64 in the investigator-assessed review of the scan.
Both independent radiology review and investigator-assessed review strongly showed that the combination of talazoparib plus enzalutamide improved rPFS over a very active control [treatment]. Enzalutamide is very active in the first-line mCRPC setting, and that is evidenced by the rPFS of 21.9 months [reported] in that arm. It is remarkable [for a regimen] to beat that active control arm. The median rPFS in the experimental arm was not reached. If we look at other meaningful secondary end points, such as time to PSA progression, there was a 9-month improvement from about 16 months in the control arm to 26 months in the experimental arm.
Time to cytotoxic chemotherapy and time to progression or death on first subsequent antineoplastic therapy were all significantly improved with talazoparib and enzalutamide vs enzalutamide plus placebo. Time to deterioration in global health status and QOL was [also] significantly delayed in patients on the talazoparib arm vs the control arm.
OS [data] were not mature. The hazard ratio currently stands at 0.89, favoring the enzalutamide plus talazoparib arm. The trial [was] not originally powered for OS. [However,] I hope that we continue to see a strong trend for OS.
Regarding the safety [data] in this trial, the most treated-emergent adverse effects [TRAEs] were anemia, neutropenia, and thrombocytopenia. Anemia, which is a class effect of PARP inhibitors, [was most common]. Importantly, eligibility criteria [for] the trial was quite relaxed. A hemoglobin of [less than] 9 g/dL was the minimal [requirement].
When you look back at the trial population, 49% of patients had grade 1 or 2 anemia at baseline before starting the protocol treatment. During the treatment with talazoparib, 46.5% of patients developed grade 3 or 4 anemia after a median duration of 3 months. Following that, these patients underwent a protocol-mandated dose reduction of talazoparib. Once that happened, talazoparib was well tolerated; [this is] evidenced by only 8.3% patients having to discontinue talazoparib because of anemia.
The [incidence of] grade 3/4 anemia is high because patients are starting with a baseline of grade 1/2 anemia. However, these [effects] were manageable with dose reduction. Also, the median dose intensity in the talazoparib arm was more than 80%. Despite anemia and dose reduction, [treatment] discontinuations were uncommon, and the [dose] intensity of talazoparib was high, at 84%. Those [data] are quite encouraging.
Another aspect of the [safety] profile, which we tend to overlook, are the AEs that impact QOL. [These effects include] grade 3/4 fatigue, anorexia, nausea, and vomiting. Fortunately, [those AEs] were all rare in the talazoparib arm. Overall, the AEs we encountered [occurred] early and were manageable with early dose reduction. We must monitor these patients on a monthly basis or [assess] CVC levels every 2 to 4 weeks [to] know who is going to develop grade 3/4 anemia. Then, once they reduce the dose, most of them tolerate talazoparib.
We have to wait for the approval of this combination by the regulatory bodies across the world. Here, in the United States, we are expecting to get FDA approval in the near future based on the results of the TALAPRO-2 trial. We expect this combination to be a SOC for patients with newly developed or newly diagnosed mCRPC regardless of HRR gene alterations.
Every [study] has inherent limitations. First, this trial was powered for rPFS [rather than] OS after a discussion with regulatory bodies across the world. [Second], the combination of talazoparib plus enzalutamide was compared with an active drug in this setting, which was enzalutamide [alone].
[Third, some would argue] that this population doesn’t exist because most patients would have received novel hormonal therapy before [progressing] to the castrate-resistant setting. Until just 2 years ago, multiple studies [on] the real-world use of novel hormonal therapy in hormone-sensitive metastatic prostate cancer [showed] that most patients are not receiving these drugs. Although the numbers are improving, it remains to be seen whether it will ever reach 100%. Many of these patients who have not received novel hormonal therapy in the hormone-sensitive setting progress to mCRPC. Over the next [few] years, they will remain a candidate for treatment with a novel hormonal therapy in mCRPC.
We also must keep in mind that a substantial number of patients do develop mCRPC after having received radiation therapy for prostate cancer. They receive short-duration ADT, never recover their testosterone, and then develop mCRPC after a long amount of time. Another group of patients [to consider] are those who have biochemical recurrence after surgery or radiation therapy; they receive intermittent ADT.We see a substantial number of [these] patients who have no indication for receiving novel hormonal therapy before they develop mCRPC.
[Overall], there is, and will remain, a substantial number of patients [who would benefit from] treatment with the combination.
At this meeting, we saw exciting, cutting-edge data from multiple clinical trials. The OS results of the [phase 3] PROpel trial [NCT03732820], which showed an absolute OS increase of 7 months in patients who received abiraterone plus olaparib vs abiraterone, are [exciting]. Even though it did not meet statistical significance, 7 months is a clinically meaningful [difference]. If that [regimen] is approved by regulatory bodies, it will be a [great] option for our patients.
We [also] saw the updated results from the [phase 3] MAGNITUDE trial [NCT03748641], in which the combination of abiraterone plus niraparib [Zejula] showed benefit in [patients with] BRCA-positive [disease]. We also [saw] updates [from] the [phase 3] ARASENS trial [NCT02799602,] which compared the triplet therapy of darolutamide [Nubeqa] plus ADT and docetaxel [with] ADT plus docetaxel. This trial showed that OS improved with the triplet [regimen] regardless of [disease] volume and risk status.
Editor’s Note: Dr. Agarwal reports serving as a consultant or in an advisory role for Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Foundation Medicine, Foundation Medicine, Genentech, Gilead Sciences, Janssen Oncology, Lilly, Lilly, Lilly, Medivation/Astellas, MEI Pharma, Merck, Nektar, Novartis, Pfizer, Pfizer, Pharmacyclics, Seagen, he received research funding from Amgen (Inst), Arvinas (Inst), AstraZeneca (Inst), Bayer (Inst), Bristol-Myers Squibb (Inst), Calithera Biosciences (Inst), Celldex (Inst), crispr therapeutics (Inst), Eisai (Inst), Exelixis (Inst), Genentech (Inst), Immunomedics (Inst), Janssen (Inst), Lilly (Inst), Merck (Inst), Nektar (Inst), ORIC Pharmaceuticals (Inst), ORIC Pharmaceuticals (Inst), Pfizer (Inst), Takeda (Inst).