Copanlisib Plus Rucaparib Shows Tolerability and Early Activity in mCRPC

Treatment with copanlisib (Aliqopa) plus rucaparib (Rubraca) was well tolerated at the recommended phase 2 dose (RP2D) and produced early signals of antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC), according to findings from the phase 1 portion of a phase 1b/2 study (NCT04253262) published in Cancer Research Communications.¹

Findings showed that the combination posed no new safety concerns and did not exacerbate expected toxicities. Two dose-limiting toxicities (DLTs), grade 3 maculopapular rash and grade 3 increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels, were reported in 5 patients treated at dose level 1 (rucaparib at 400 mg twice per day plus copanlisib at 45 mg on days 1, 8, and 15 of each 28-day cycle), which included grade 3 maculopapular rash and grade 3 AST/ALT elevation attributed to both drugs. These DLTs were attributed to both study drugs. No DLTs were reported in 6 patients treated at dose level –1 (rucaparib at 400 mg twice per day plus copanlisib at 45 mg on days 1 and 15 of each 21-day cycle); this dose level was established as the RP2D. Two additional patients were treated at the RP2D in the phase 2 portion of the trial without significant adverse effects (AEs).

The most common grade 2 or higher treatment-related AEs (TRAEs) reported in the evaluable population across all dose levels (n = 13) included leukopenia (54%), anemia (38%), rash (30%), neutropenia (23%), fatigue (23%), and oral mucositis (15%). The most common grade 2 AEs related to copanlisib included fatigue, anemia, and neutropenia (23% each); the most common grade 3 AEs related to the agent comprised maculopapular rash (15%), increased AST/ALT levels (7.6%), and anemia (7.6%). The most frequently reported grade 2 AEs related to rucaparib included fatigue (23%), anemia (23%), neutropenia (15%), and thrombocytopenia (7.6%); grade 3 rucaparib-related AEs included anemia (15%), maculopapular rash (15%), increased AST levels (7.6%), and leukopenia (7.6%).

“[These] results support further evaluation of dual PARP/PI3K blockade, particularly in the [approximately] 4% of patients with mCRPC with concurrent homologous recombination–deficient [HRD] and PI3K alterations. Future studies could also investigate combinations of novel PARP1-selective agents with PI3K and/or AKT pathway inhibitors,” explained lead study author Andre Luiz De Souza, MD, a hematologist/oncologist at Brown University Health Cancer Institute. “In summary, the results of this study support the safety and efficacy of copanlisib in combination with rucaparib at the RP2D in patients with mCRPC. A randomized clinical trial is required to confirm the clinical benefit and refine biomarkers of response.”

What were the key design features and primary end points of this phase 1b/2 trial of copanlisib plus rucaparib?

The trial evaluated the combination of copanlisib plus rucaparib in patients with histologically confirmed mCRPC who had received at least 1 prior androgen receptor pathway inhibitor and taxane-based chemotherapy; prior chemotherapy was permitted in the castration-sensitive or -resistant settings.^1,2 Prior treatment with a PARP inhibitor, radium Ra 223 dichloride (radium-223; Xofigo), or sipuleucel-T (Provenge) was permitted but not required.¹

In the open-label study, the phase 1 portion used a standard 3+3 dose-escalation design to define the maximum tolerated dose (MTD) and RP2D, assessing rucaparib at 400 to 600 mg orally twice daily with copanlisib at 45 mg on days 1 and 15 of 21-day cycles, or 45 to 60 mg administered on days 1, 8, and 15 of 28-day cycles.

Determining the MTD and RP2D was the primary end point in phase 1b. The primary end point of phase 2 is the proportion of patients with at least a 50% decrease in prostate-specific antigen levels (PSA50 response rate).

What were the baseline characteristics of the study participants?

Among the 13 patients enrolled, the median age was 64 years (range, 55-78), and the median baseline PSA level was 11.7 ng/mL (range, 0.018-2,101.4). Patients had received a median of 2 prior lines of therapy (range, 1-4). Prior cytotoxic chemotherapy had been administered to 53.8% of patients, including docetaxel alone (n = 5), cabazitaxel alone (n = 1), or both docetaxel and cabazitaxel (n = 2). Regarding prior androgen receptor pathway inhibitors, 76.9% of patients had received abiraterone acetate (Zytiga), and 23% had received enzalutamide (Xtandi); 23% had received sipuleucel-T, and 7.6% had received radium-223.

Genomically, 46% of patients harbored PTEN alterations, comprising 3 mutations and 3 copy-number losses, and 61% had HRD mutations, including BRCA2 (n = 4), BRCA1 (n = 1), RAD51C (n = 1), CDK12 (n = 1), and FANCA (n = 1). Notably, HRD mutations were required for inclusion in phase 2 of the study. Among the 6 patients with HRD-mutant tumors enrolled in phase 1, only 1 patient had previously received a PARP inhibitor.

What early efficacy signals were observed in this study?

Ten patients were evaluable for PSA response; some patients were not evaluable due to early progression (n = 2) or treatment discontinuation due to toxicity (n = 1) prior to the 12-week assessment. The confirmed PSA50 response rate was 30%. In the 6 patients with measurable metastatic disease per RECIST 1.1 criteria, 1 patient achieved a confirmed partial response (PR; 16%), and 3 patients achieved stable disease (50%), yielding a clinical benefit rate of 66%.

Among 8 patients with HRD alterations, 3 had confirmed PSA50 responses, 1 achieved a confirmed PR, and 3 achieved stable disease by RECIST 1.1 criteria, including in 1 patient previously treated with the PARP inhibitor olaparib (Lynparza). The patient with the confirmed PR harbored somatic BRCA2 loss and was naive to a PARP inhibitor.

At the May 8, 2024, data cutoff, patients discontinued treatment due to disease progression (69%), withdrawal of consent (15.4%), and toxicity (elevated AST/ALT; n = 1). Notably, the phase 2 portion of the study closed due to restricted support and access to rucaparib. One patient with BRCA2-mutated disease who experienced a prolonged PSA response and improvement of bone metastases over 15 cycles stopped treatment at study closure before transitioning to olaparib with an ongoing PSA response.

Another patient with RAD51C copy-number loss and concurrent alterations, including PIK3R1, PTEN loss, TP53, and SMAD4, achieved marked improvement in bone metastases, a PSA response, and stable disease by RECIST 1.1 criteria, remaining on treatment for 22 prior to progression; investigators suggested that RAD51C loss, together with PI3K pathway alterations and PTEN loss, may have contributed to response. Additionally, 1 patient with a BRCA2 reversion mutation achieved stable disease by RECIST 1.1 criteria and remained on treatment for 5 months.

References

1. De AL, Hadfield MJ, Lu S, et al. BrUOG360: a phase Ib/II study of copanlisib in combination with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC). Cancer Res Comm. 2025;5(12):2142-2148. doi:10.1158/2767-9764.crc-25-0651
2. A study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer. ClinicalTrials.gov. Updated May 4, 2025. Accessed January 5, 2026. https://clinicaltrials.gov/study/NCT04253262