Novel Combination Regimens Are Expanding the Prostate Cancer Treatment Paradigm

The FDA approvals of 3 PARP inhibitors, talazoparib (Talzenna), olaparib (Lynparza), and niraparib (Zejula), in combination with hormone therapy have redefined the standard of care (SOC) for patients with metastatic castration-resistant prostate cancer (mCRPC), although the role of single-agent PARP inhibitors in this population remains to be elucidated, according to Marijo Bilusic, MD, PhD.

Olaparib plus abiraterone and prednisone or prednisolone gained FDA approval in May 2023 for the treatment of patients with BRCA-positive mCRPC based on findings from the phase 3 PROpel trial (NCT03732820). In the trial patients with BRCA-mutated disease experienced a median radiographic progression-free survival (rPFS) that was not reached (NR) in the combination arm (n = 47) vs 8 months (95% CI, 6-15) in the placebo plus abiraterone arm (n = 38; HR, 0.24; 95% CI, 0.12-0.45).¹

The PARP inhibitor talazoparib was approved by the FDA in June 2023 in combination with enzalutamide (Xtandi) for patients with homologous recombination repair (HRR) gene–mutated mCRPC based on findings from the phase 3 TALAPRO-2 trial (NCT03395197). Patients with HRR gene–mutated disease experienced a median rPFS of NR in the combination arm (n = 200) vs 13.8 months in the placebo plus enzalutamide arm (n = 199; HR, 0.45; 95% CI, 0.33-0.61; P < .0001).²

Additionally, the combination of niraparib and abiraterone acetate (Akeega) plus prednisone was granted FDA approval in August 2023 for patients with mCRPC with deleterious or suspected deleterious BRCA mutations, based on findings from the phase 3 MAGNITUDE trial (NCT03748641). Patients in the BRCA-positive subgroup who received the combination (n = 113) experienced a median rPFS of 19.5 months vs 10.9 months for those given placebo plus abiraterone and prednisone (n = 112; HR, 0.55; 95% CI, 0.39-0.78).³

“[Those combinations are] nice additions to [our array of] treatment options for patients with CRPC with DNA repair pathway mutations,” Bilusic said in an interview with OncLive^® following a State of the Science Summit on prostate cancer and renal cell carcinoma, which he chaired.

In the interview, Bilusic highlighted key points presented at the meeting, including considerations with PARP inhibitor combinations for patients with mCRPC, how disease characteristics factor into treatment selection for patients with hormone-sensitive prostate cancer (HSPC), and where the prostate cancer treatment field may be headed in the future.

Bilusic is the genitourinary (GU) site disease group lead and the GU SDD medical oncology lead at the University of Miami Miller School of Medicine and the Sylvester Comprehensive Cancer Center in Florida.

OncLive: Based on your presentation, what recent developments have emerged in the management of mCRPC, and how have these advances impacted patient outcomes?

Bilusic: The major highlight of the topic of my talk was that 3 combinations of PARP inhibitors plus anti-androgen therapy were approved in the summer of 2023 for patients with BRCA1- and BRCA2-mutated or HRR-mutated disease, indicating that earlier use of PARP inhibitors in combination with anti-androgen therapy has significantly prolonged PFS. [These regulatory decisions were] based on [findings from the] TALAPRO-2, PROPEL, and MAGNITUDE trials.

The main [point of discussion during my presentation was that] overall survival [OS] data [with these combinations] are not mature yet. The main unanswered question currently is: Do we need to use doublets upfront, or should we do sequential treatment with PARP inhibitors followed by anti-androgen therapy? [The PFS will be improved] with a combined treatment option because we are offering 2 effective treatments to patients. However, the main question is: Is more [treatment] better upfront? Or should we just improve quality of life and [reduce the risk of adverse effects (AEs) by using] 1 treatment after another? Time will tell us [the answer to this question] because all those trials are still ongoing. They’re collecting data, so hopefully in the near future, we’ll have an answer [regarding whether] it makes a difference to use combination regimens. The good news is that we have all these [approved regimens] that we can offer patients. In select patients, after a discussion with them, we may decide to use PARP inhibitor monotherapy or [PAPR inhibitors in] combinations, but it’s good to have that [option].

[In my presentation, I also asked]: Is there a difference between PARP inhibitors now that several of them are approved? There is no comparison [of these agents] in 1 trial, and we cannot compare trials; cross-trial comparisons are not [ideal]. However, some meta-analyses which I presented [at the meeting] show that overall [the PARP inhibitors] all look the same, [but are associated] with slightly different AEs. However, I cannot say that one is better than another or that one is more toxic than another. [Patients in the] talazoparib trial [required] more dose reductions than those in the niraparib trial, but overall, they are similar drugs, so I don’t think one is better [than the others].

The other highlight I discussed was that based on [findings from] the CAPTURE trial, patients with [mCRPC with] BRCA1/2 mutations do poorly [when treated with first-line hormonal therapy or a taxane]. The median OS is much shorter in patients with castration-resistant disease [with BRCA mutations] than in patients without BRCA mutations. Therefore, patients [with BRCA mutations] should have PARP inhibitors earlier, because if we wait for traditional monotherapy with PARP inhibitors to be approved in the second or third line of therapy, many of those patients may not reach that, or may become very sick by the time of their third line of therapy, because they’re symptomatic and have [symptoms such as] bone marrow failure. I offer earlier PARP inhibitors to my patients. The question, which we will hopefully have an answer to shortly, is: Do we have to combine PARP inhibitors with anti-androgen therapy, or is just the PARP inhibitor sufficient?

What emerging prostate cancer therapies or agents hold promise?

A press release [showed] that [the phase 3 CONTACT-02 trial (NCT04446117) investigating] cabozantinib [Cabometyx] plus atezolizumab [(Tecentriq) in patients with mCRPC] was positive. We are anxiously waiting to see those data, which will hopefully be presented at upcoming meetings. That combination could be a novel treatment option.

The phase 3 [COMET-1] trial evaluating cabozantinib monotherapy in patients with CRPC was negative, but it seems that [cabozantinib in] combination with checkpoint inhibitors may be an exciting addition to our toolbox for patients with prostate cancer. [Those data] will probably be discussed soon. Hopefully they are positive and [lead to an FDA] approval so we have another treatment option for our patients. 

Based on the presentation on clinical practices in HSPC, given by Janaki Neela Sharma, MD, of the University of Miami Miller School of Medicine,how do you approach the selection of the most appropriate treatment for individual patients, taking into consideration their disease characteristics?

There is still a substantial fraction of patients with metastatic HSPC who do not receive second-generation anti-androgen therapy or chemotherapy. [This may be because of a] lack of knowledge or [a lack of] referrals [to oncologists by] urologists who see those patients initially. [Regardless], it’s important to emphasize that every patient today should receive at least doublet therapy, so androgen-deprivation therapy [ADT] plus anti-androgen therapy or chemotherapy. Then, [all patients in whom] we’re considering using chemotherapy, usually patients with visceral metastases or high-volume/high-burden disease, should be offered triplet therapy with the [phase 3] PEACE1 trial [NCT01957436] combination of abiraterone [plus prednisone and AD} or with [the phase 3 ARASENS trial (NCT02799602) regimen of] darolutamide [(Nubeqa) plus ADT and docetaxel].

In patients with high-volume disease, chemotherapy should be offered, [as well as] triplet therapy, and then all other patients should be on doublets. No patients should be on single-agent ADT, because that’s a substandard treatment option. We need to change [the SOC to move away from single-agent ADT, and we need to] work hard and educate people [about the] current standard in 2023.

References

1. FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer. FDA. May 31, 2023. Accessed November 30, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-abiraterone-and-prednisone-or-prednisolone-brca-mutated-metastatic-castration
2. FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer. FDA. June 20, 2023. Accessed November 30, 2023. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-talazoparib-enzalutamide-hrr-gene-mutated-metastatic-castration-resistant-prostate
3. U.S. FDA approves AKEEGA (niraparib and abiraterone acetate), the first-and-only dual action tablet for the treatment of patients with BRCA-positive metastatic castration-resistant prostate cancer. News release. Janssen. August 11, 2023. Accessed November 30, 2023. https://www.prnewswire.com/news-releases/us-fda-approves-akeega-niraparib-and-abiraterone-acetate-the-first-and-only-dual-action-tablet-for-the-treatment-of-patients-with-brca-positive-metastatic-castration-resistant-prostate-cancer-301899028.html