THE "NEW" PROSTATE CANCER INFOLINK

We have noted several times in the past that, at least to date, compared to the results shown by the PD-1 and PD-L1 checkpoint inhibitors in the treatment of cancers like lung cancer, kidney cancer, and melanoma, there has been little evidence of the value of these agents in the treatment of advanced prostate cancer. However, …

It is also clear that this has not stopped the companies that have created these types of drug (Merck, Bristol-Myers Squibb, Roche/Genentech, and others) from trying.

Following is a list of the important Phase II and Phase III clinical trials of the PD-1 and PD-L1 inhibitors that we could identify and that are currently ongoing or planned. We believe that it is reasonably complete, but it is certainly possible that we have missed, overlooked, or ignored a few trials that others might classify as “important”. There are a lot of small trials — and many of those are using two drugs, neither of which have yet been approved in the treatment of any form of prostate cancer.

The trials that are most important  — because they could rapidly lead to the approval of one or more of these drugs are the randomized, multi-center, Phase III clinical trials. We have therefore called out the words “Phase III” here and in bold red type below for ease of identificantion.

• An “unnamed” trial is fully enrolled (n = 58 patients) and still ongoing exclusively in the USA (only at OHSU) started enrolling patients in 2014. It is an open-label, non-randomized trial of pembrolizumab  (Keytruda) in men with metastatic castration-resistant prostate cancer (mCRPC) who had previously progressed on treatment with enzalutamide + standard androgen deprivation therapy — see NCT02312557 for the details. Results of this trial are already due, but we haven’t seen any yet.

• The KEYNOTE-199 trial was initiated in 2016, and is a fully enrolled, 370-patient, multi-cohort, multi-center, open-label, non-randomized, Phase II trial of pembrolizumab (Keytruda) or pembrolizumab + enzalutamide (Xtandi) in men with five slightly different subtypes of metastatic castration-resistant prostate cancer (mCRPC) — see NCT02787005 for the details. Results of this trial are expected in December 2020.

• Another “unnamed” trial is being carried out exclusively in the US (apparently only at UCSF) and has been enrolling patients since 2017. This is an open-label, non-randomized, Phase II trial of pembrolizumab (Keytruda) with or without taxane and platinum chemotherapy in two subsets of men with mCRPC and DNA damage repair defects — see NCT03248570 for the details. Initial results of this trial are expected in 2021.

• A third “unnamed” trial is being carried out at two centers in Boston, MA, and has been enrolling patients since 2017. This is a small, randomized, Phase II study evaluating the addition of pNCT03093428 for the details. Initial results of this trial are expected in 2020.

• The CheckMate 9KD trial is a multi-center, 330-patient trial that has been enrolling patients since 2017. It is an open-label, non-randomized Phase II study of nivolumab (Opdivo) in combination with rucaparib (Rubraca), docetaxel (Taxotere), or enzalutamide (Xtandi) in men with mCRPC — see NCT03338790 for the details. This trial is expected to report data in 2020.

• The IMbassador250 trial also started to enroll 730 patients at nearly 200 centers in 2017. This is a randomized, multi-center, Phase III trial of atezolizumab (Tecentiq [an anti-PD-L1 antibody]) + enzalutamide versus enzalutamide alone in men with mCRPC after progression on an androgen synthesis inhibitor and failure of, ineligibility for, or refusal of a taxane chemotherapy regimen — see NCT03016312 for the details. This trial is fully enrolled and is expected to report initial results in late 2020. It is worth noting that atezolizumab has shown clear therapeutic effect in the treatment of late stage bladder cancer.

• The PERSEUS 1 trial is being carried out only in the UK (at the Royal Marsden Hospital). It has been recruiting patients since 2018, and is a single group, non-randomized, Phase II trial of pembrolizumab (Keytruda) in men who have already had at least one approved treatment for mCRPC, e.g., abiraterone acetate (Zytiga), enzalutamide (Xtandi), docetaxel (Taxotere), cabazitaxel (Jevtana), or radium 223 (Xofigo) — see NCT03506997 for the details. Initial results of this trial are expected in 2023.

• The ImmunoProst trial is a small trial being carried out in Brazil, and has been enrolling patients since 2018. It is a two-stage, multi-center, single-arm, open-label Phase II, trial of nivolumab (Opdivo) in men with mCRPC who have previously progressed on a taxane-based chemotherapy regimen — see NCT03040791 for the details. Initial results of this trial are expected later this year.

• Another small, “unnamed” study was initiated in Boston, MA, in 2018. This is an open-label, single-arm Phase II trial of nivolumab (Opdivo) in treatment of men with high-risk, biochemically recurrent prostate cancer who have progressed after first-line surgery or radiation therapy — see NCT03637543 for the details. Initial results of this trial are not expected until 2022.

• The COMBAT-CRPC trial is another small trial that started to enroll patients in 2018 (exclusively at Johns Hopkins in Baltimore, MD). This is a 44-patient, open-label, non-randomized, single-group, Phase II trial of the combination of bipolar androgen therapy (BAT) with nivolumab (Opdivo) in men with mCRPC — see NCT03554317 for the details. Initial results of this trial are expected some time in 2020.

• An “unnamed” study being conducted by the Spanish Oncology Genitourinary Group started to enroll 135 patients early this year. This study is a three-arm, multi-stage, randomized Phase II/III trial of different combinations of ADT, chemotherapy, and immunotherapy (with nivolumab [Opdivo]) in the treatment of metastatic, hormone-sensitive prostate cancer (mHSPC) — see NCT03879122 for the details. This trial might report initial data some time in 2021.

• The KEYNOTE-921 trial also started to enroll 1,000 patients earlier this year. It is a randomized, double-blind, multi-center, Phase III trial of pembrolizumab (Keytruda) + docetaxel (Taxotere) + prednisone versus a placebo + docetaxel + prednisone in men with chemotherapy-naïve mCRPC who have progressed on a “next-generation” androgen suppressive agent such as abiraterone acetate (Zytiga) or enzalutamide (Xtandi) — see NCT03834506 for the details. The fact that this trial is being done at all suggests that the trial sponsors believe there is a good chance of a positive outcome. Initial results of this trial are projected for 2021.

• The KEYLYNK-010 trial started to enroll 780 patients this month. It is a randomized, open-label, multi-center,  Phase III trial of pembrolizumab< (Keytruda) + olaparib {Lynparza) versus abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in men with mCRPC who are unselected for homologous recombination repair defects and have progressed on prior treatment with one “next-generation” androgen-suppressive agent and chemotherapy — see NCT03834519 for the details. Initial results of this trial are projected for 2021.

• The KEYNOTE-641 trial is expected to start enrolling 1,200 patients later this year. It is a randomized, double-blind, multi-center, Phase III trial of pembrolizumab (Keytruda) + enzalutamide (Xtandi) versus a placebo + enzalutamide in men with mCRPC — see NCT03834493 for the details. Again, the fact that this trial is being done at all suggests that the trial sponsors believe there is a good chance of a positive outcome. Initial results of this trial are projected for 2023.

We should conclude with the fact that a presentation given by Tucker et al. from Duke University at the Genitourinary Cancer Symposium in San Francisco earlier this year reported only very limited activity of pembrolizumab (Keytruda) when used alone in the treatment of 51 heavily pre-treated patients with mCRPC (see here and here). We might be wise to limit our expectations as to the potential of checkpoint inhibition in the treatment of at least very late-stage prostate cancer.

Filed under: Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: atezolizumab. Keytruda, HSPC, mCRPC, nivolumab, Opdivo, PD-1, PD-L1, pembrolizumab, Tecentriq |